Darunavir; cobicistat is a fixed-dose combination product containing a protease inhibitor (darunavir) and a pharmacokinetic enhancer (cobicistat). The drug is indicated for use in combination with other antiretroviral agents to treat HIV-1 infection in both treatment-naive and treatment-experienced adults and pediatric patients weighing at least 40 kg with no darunavir resistance-associated substitutions. The FDA-approved product labeling recommends genotypic testing prior to initiating treatment in order to identify resistance-associated amino acid substitutions. If testing is not available, the drug can still be used in protease inhibitor-naive patients; however, use is not recommended for those who have previously received a protease inhibitor. Approval in adults was based on efficacy demonstrated in clinical trials of darunavir coadministered with ritonavir. Efficacy in pediatric patients was demonstrated in clinical trials in which stable patients were switched from ritonavir to cobicistat and continued darunavir and 2 NRTIs.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer with food.
Safety of darunavir; cobicistat was evaluated in 1 single-arm clinical trial involving 313 patients with HIV. The adverse reactions observed during this trial were similar to those reported in clinical trials with darunavir and ritonavir coadministration.
Hepatotoxicity has been reported with the use of both cobicistat and darunavir. Patients with preexisting hepatic disease or dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities, including severe hepatic adverse events. Prior to and during treatment, monitor hepatic function with appropriate laboratory testing. Increased AST and ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevated transaminases, especially during the first several months of treatment. Consider interrupting or discontinuing treatment if there is evidence of new or worsening hepatic dysfunction (including clinically significant elevation of hepatic enzymes or symptoms). During cobicistat clinical trials, hyperbilirubinemia (more than 2.5-times upper limit of normal) and elevated hepatic enzymes (AST, ALT, and GGT more than 5-times upper limit of normal) were observed in 65% and 2% to 3% of drug recipients, respectively. In addition, jaundice was observed in 5% to 13%, and ocular icterus was observed in 3% to 15% of patients. Darunavir has been associated with drug-induced hepatitis, including acute hepatitis and cytolytic hepatitis. In darunavir clinical trials, hepatitis was reported in 0.5% of patients receiving darunavir with ritonavir. Cases of hepatitis and elevated transaminases of at least moderate intensity (at least Grade 2) were also reported in Phase 2b and Phase 3 trials. During randomized clinical trials, drug-related grade 2 to 4 laboratory abnormalities reported in the darunavir treatment arm included elevated hepatic enzymes. Increased ALT was reported as Grade 2 in 7% to 9% of adult patients; Grade 3 in 2% to 3% of adult patients and 3% of pediatric patients; and Grade 4 in up to 1% of adult and pediatric patients. Increased AST was reported as Grade 2 in 6% to 7% of adult patients; Grade 3 in 2% to 4% of adult patients and 1% of pediatric patients; and Grade 4 in up to 1% of adult patients. Grade 2 increases in alkaline phosphatase were noted in up to 1% of adult patients; Grade 3 in less than 1% of adult patients. All Grades (2 to 4) of hyperbilirubinemia were reported in less than 1% of adult patients. Postmarketing use of darunavir and ritonavir has been associated with severe hepatotoxicity, with some cases resulting in death. Generally, fatalities occurred in patients with advanced HIV-1 disease, taking multiple concurrent medications, having comorbidities including hepatitis B or C coinfection, or developing immune reconstitution syndrome. A causal relationship with darunavir and ritonavir has not been established.
Skin reactions and hypersensitivity reactions were reported with darunavir in clinical trials. Severe skin reactions, sometimes accompanied by fever or elevated transaminases, have been reported in 0.4% of patients. In clinical trials, Stevens-Johnson Syndrome was reported in less than 0.1% of patients. Rash, all grades, regardless of causality, occurred in 10.3% of all patients, 6% to 7% of adult patients, and 5% to 19% of pediatric patients. If a severe rash develops, discontinue treatment. Rash was mostly mild-to-moderate, often occurring within the first 4 weeks of treatment and resolving with continued dosing. The discontinuation rate due to rash in clinical trials was 0.5%. Pruritus, angioedema, urticaria, and hypersensitivity were noted in less than 2% of adult patients, and pruritus has been reported in up to 8.3% of pediatric patients. Cases of toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) were noted in postmarketing reports. Although not as severe as with darunavir, rash also developed in 5% of cobicistat recipients during clinical trials. According to the manufacturer, the rash events included cases of allergic dermatitis, drug hypersensitivity, pruritus, eosinophilic pustular folliculitis, eczema, generalized rash, rash macular, rash morbilliform, maculopapular rash, papular rash, and urticaria. If signs or symptoms of severe skin reactions occur, discontinue darunavir; cobicistat. These symptoms can include, but are not limited to, severe rash or rash accompanied with fever, general malaise, muscle or joint aches, blisters, oral lesions (oral ulceration), conjunctivitis, hepatitis, or eosinophilia.
Treatment with darunavir-containing regimens has been associated with postmarketing reports of crystal nephropathy and crystalluria. Additionally, renal impairment, renal failure (unspecified), and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) have been associated with the use of cobicistat in combination with antiretroviral regimens that contain tenofovir. During cobicistat clinical trials, 1.5% of drug recipients (n = 6/771) discontinued treatment due to renal adverse events. Of those who discontinued therapy, 5 patients (1.3% overall) developed findings consistent with proximal tubulopathy that improved, but did not completely resolve, following treatment discontinuation. Other events associated with therapy included nephrolithiasis (2%), nephropathy (less than 2%), glycosuria (3%), hematuria (3%) and elevated serum creatinine. The increase in serum creatinine and decrease in estimated creatinine clearance results from inhibition of tubular secretion of creatinine. This occurs early in therapy and without affecting renal glomerular function. During the 48-week clinical trials, the mean change in estimated glomerular filtration rate from baseline was -13.4 mL/minute (+/- 15.2 mL/minute). Monitor estimated creatinine clearance (CrCl) prior to initiating treatment. If used in combination with tenofovir, monitor estimated CrCl, urine glucose, and urine protein before initiation and during treatment. Particularly close monitoring is advised for patients who experience increases in serum creatinine more than 0.4 mg/dL; monitor serum phosphate concentrations in patients at risk for renal impairment. Monitor for bone pain, pain in extremities, fractures, and muscle pain or weakness as these may be manifestations of proximal renal tubulopathy; promptly evaluate renal function in patients experiencing these symptoms. If possible, avoid concurrent use with nephrotoxic drugs.
Gastrointestinal adverse reactions were among the most frequently reported adverse events by recipients of both darunavir and cobicistat during clinical trials. The following were reported in patients during the cobicistat clinical trials: nausea (2% to 16%), elevated lipase concentrations (9%, Grade 3 and 4), hyperamylasemia (4%, more than 2-times upper limit of normal), abdominal pain (less than 2%), diarrhea (less than 2%), and vomiting (less than 2%). Adverse events experienced by recipients of darunavir included diarrhea (9% to 14% of adults; 11% to 24% of pediatrics), abdominal pain (6% of adults; 5% to 10% of pediatrics), nausea (4% to 7% of adults; 4% to 25% of pediatrics), vomiting (2% to 5% of adults; 13% to 33% of pediatrics), dyspepsia (up to 2% of adults), anorexia (2% of adults; 5% of pediatrics), flatulence (less than 2% of adults), abdominal distension (2% of adults), and acute pancreatitis (less than 2% of adults). Cases of adverse events of at least moderate intensity (Grade 2) included diarrhea, nausea, vomiting, acute pancreatitis, elevated pancreatic enzymes, anorexia, and abdominal pain. Elevated pancreatic lipase was reported as Grade 2 in 3% of adults; Grade 3 in up to 2% of adults and 1% of pediatrics; and Grade 4 in less than 1% of adults. Elevated pancreatic amylase (hyperamylasemia) was reported as Grade 2 in 5% to 6% of adults; Grade 3 in 5% to 7% of adults and 4% of pediatrics; and Grade 4 in 1% of pediatrics.
Neurologic events experienced by recipients of cobicistat or darunavir during clinical trials included abnormal dreams or nightmares (less than 2%), depression (less than 2%), headache (3% to 7% of adults; 9% of pediatrics), fatigue (less than 2%), and insomnia (less than 2%).
Elevations in creatine kinase 10-times upper limit of normal or more were observed in 5% of patients receiving treatment with cobicistat during clinical trials. In addition, less than 2% of patients experienced rhabdomyolysis. Rhabdomyolysis (associated with the coadministration of HMG-CoA reductase inhibitors) has also been noted in postmarketing reports for darunavir. Other musculoskeletal adverse events associated with the use of darunavir include asthenia (up to 3%), fatigue (2% of adults; 3% of pediatric patients), and myalgia (less than 2%).
Hyperlipidemia of at least a moderate level of intensity (Grade 2) reported with darunavir treatment includes elevated cholesterol, elevated triglycerides, and elevated low density lipoprotein (LDL). Elevated triglycerides (hypertriglyceridemia) were reported as Grade 2 (500 to 750 mg/dL) in 3% to 10% of adults, Grade 3 (751 to 1,200 mg/dL) in 2% to 7% of adults, and Grade 4 (more than 1,200 mg/dL) in 1% to 3% of adults. Increased total cholesterol (hypercholesterolemia) was reported as Grade 2 (240 to 300 mg/dL) in 23% to 25% of adults and as Grade 3 (more than 300 mg/dL) in 1% to 10% of adults and 1% of pediatrics. Elevated LDL was reported as Grade 2 (160 to 190 mg/dL) in 14% of adults and as Grade 3 (more than 191 mg/dL) in 8% to 9% of adults and 3% of pediatrics. Cobicistat may also be associated with the development of hypercholesterolemia and hypertriglyceridemia. In 307 patients receiving cobicistat-containing regimens for 48 weeks during clinical trials, mean changes in the lipid values from baseline were +4 mg/dL (fasting total cholesterol), +3 mg/dL (fasting HDL-cholesterol), +5 mg/dL (fasting LDL-cholesterol), and +15 mg/dL (fasting triglycerides).
Cases of diabetes mellitus of at least a moderate level of intensity (Grade 2) were noted during clinical trials of darunavir. New onset diabetes mellitus and exacerbation of pre-existing disease were reported in up to 2% of adult patients. Elevated glucose levels (hyperglycemia) were reported as Grade 2 (glucose 126 to 250 mg/dL) in 10% to 11% of adults, Grade 3 (glucose 251 to 500 mg/dL) in 1% of adults, and Grade 4 (more than 500 mg/dL) in less than 1% of adults. Diabetic ketoacidosis has developed in patients receiving treatment with protease inhibitors (PI), such as darunavir. In some cases, initiation or dose adjustments of insulin and oral hypoglycemic agents were required for treatment of these events.
Lipodystrophy has been noted in clinical trials with darunavir. Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement (e.g., gynecomastia), and Cushingoid features have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown and a causal relationship has not been established.
Protease inhibitors have been associated with increased bleeding, including spontaneous hematoma and hemarthrosis, in patients with hemophilia type A and B. Treatment with factor VIII was required to suppress bleeding in some patients. In more than half of the reported cases, protease inhibitor therapy was either continued or re-introduced following treatment discontinuation. A causal relationship with darunavir has not been established.
During baseline evaluation of people with HIV, discuss risk reduction measures and the need for status disclosure to sexual or needle-sharing partners, especially with untreated patients who are still at high risk of HIV transmission. Include the importance of adherence to therapy to achieve and maintain a plasma HIV RNA less than 200 copies/mL. Maintaining a plasma HIV RNA less than 200 copies/mL, including any measurable value below this threshold, with antiretroviral therapy prevents sexual transmission of HIV to their partners. Patients may recognize this concept as Undetectable = Untransmittable or U=U. Instruct patients to achieve sustained viral suppression (i.e., 2 recorded measurements of plasma viral loads that are below the limits of detection and taken at least 3 months apart) before attempting to conceive a child in order to maximize their health, prevent HIV sexual transmission, and minimize the risk of HIV transmission to the infant once conception occurs. For partners with different HIV status when the person with HIV is on antiretroviral therapy and has achieved sustained viral suppression, sexual intercourse without a condom allows conception without sexual HIV transmission to the person without HIV. Expert consultation is recommended.
Unplanned antiretroviral therapy interruption may be necessary for specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), severe hyperemesis gravidarum unresponsive to antiemetics, or drug non-availability. If short-term treatment interruption (i.e., less than 1 to 2 days) is necessary, in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption occurs in a pregnant patient or is because of a serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered as stopping all simultaneously in a regimen containing drugs with differing half-lives may result in functional monotherapy of the drug with the longest half-life and may increase the risk for resistant mutations. Healthcare providers are advised to reinitiate a complete and effective antiretroviral regimen as soon as possible after an interruption of therapy. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.
Darunavir contains a sulfonamide moiety; therefore, darunavir; cobicistat should be used with caution and appropriate monitoring in patients with a known sulfonamide hypersensitivity.
Drug-induced hepatitis (including acute hepatitis and cytolytic hepatitis) has been reported with use of darunavir; in clinical trials, hepatitis was reported in 0.5% of patients receiving darunavir with ritonavir. Patients with preexisting hepatic disease or dysfunction, including chronic active hepatitis, have an increased risk for liver function abnormalities (e.g., jaundice), including severe hepatic adverse events. Postmarketing cases of hepatic injury (unspecified), including fatalities, have been reported. The cases have generally occurred in patients with advanced HIV disease receiving multiple concomitant medications, having co-morbidities including hepatitis and HIV coinfection, and developing immune reconstitution syndrome. A causal relationship with darunavir has not been established. Prior to and during treatment with darunavir; cobicistat, monitor hepatic function with appropriate laboratory testing. Increased monitoring of AST/ALT concentrations should be considered in patients with underlying chronic hepatitis, cirrhosis, or patients with pre-treatment elevations of transaminases, especially during the first several months of darunavir; cobicistat treatment. Consider interrupting or discontinuing treatment if there is evidence of new or worsening hepatic dysfunction (including clinically significant elevation of hepatic enzymes and symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly). Patients that present with HIV infection should be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. All patients with hepatitis B and HIV coinfection should be started on a fully suppressive antiretroviral (ARV) regimen with activity against both viruses (regardless of CD4 counts and HBV DNA concentrations). HIV treatment guidelines recommend these patients receive an ARV regimen that contains a dual NRTI backbone of tenofovir alafenamide or tenofovir disoproxil fumarate with either emtricitabine or lamivudine. If tenofovir cannot be used, entecavir should be used in combination with a fully suppressive ARV regimen (note: entecavir should not be considered part of the ARV regimen). Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, tenofovir, or entecavir as the only active agent) as this may result in HIV resistant strains. Further, HBV treatment regimens that include adefovir or telbivudine should also be avoided, as these regimens are associated with a higher incidence of toxicities and increased rates of HBV treatment failure. Most patients with coinfection should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. If treatment must be discontinued, monitor transaminase concentrations every 6 weeks for the first 3 months, and every 3 to 6 months thereafter. For patients who refuse a fully suppressive ARV regimen, but still require treatment for HBV, consider 48 weeks of peginterferon alfa; do not administer HIV-active medications in the absence of a fully suppressive ARV regimen. Instruct patients with coinfection to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as progressive multifocal leukoencephalopathy (PML), mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, autoimmune hepatitis, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.
HIV treatment guidelines recommend all patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experience with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid consuming alcohol, limit ingestion of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
Patients with diabetes mellitus or hyperglycemia may experience an exacerbation of their condition during treatment with protease inhibitors, including darunavir; cobicistat. Some patients may require either initiation or dose adjustments of insulin or oral hyperglycemic agents. Patients should be monitored closely for new onset diabetes mellitus, diabetic ketoacidosis, or hyperglycemia.
Protease inhibitors, such as darunavir; cobicistat, should be used cautiously in patients with hemophilia A or B due to reports of spontaneous bleeding episodes requiring treatment with additional factor VIII. In many cases, treatment with protease inhibitors was continued or restarted. A causal relationship has not been established.
Darunavir; cobicistat should not be used in children younger than 3 years of age due to toxicity and mortality observed in juvenile rats dosed with darunavir (from 20 mg/kg to 1,000 mg/kg).
Consider patient specific factors, such as preexisting hyperlipidemia, when selecting an antiretroviral treatment regimen. Hyperlipidemia is a recognized side effect of protease inhibitor-based regimens. Obtain a random or fasting lipid profile at entry of care, initiation or modification of antiretroviral therapy, every 12 months, and as clinically indicated. Possible interventions for patients who develop hyperlipidemia during treatment with darunavir, cobicistat include dietary modification, use of lipid lowering agents, or switching to a regimen with a more favorable lipid profile. Clinicians should be aware of the potential for drug interactions with certain cholesterol-lowering drugs.
Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. The prevalence of transmitted drug resistance (TDR) in high-income countries ranges from 9% to 14% and varies by country. In most TDR surveys, non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance and nucleoside reverse transcriptase inhibitor (NRTI) resistance are the most common mutation class types detected, followed by protease inhibitor (PI) and integrase strand transfer inhibitor (INSTI) resistance mutations, respectively. Resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test result kept in the patient's medical record until it becomes clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. It should also be noted that varying degrees of cross-resistance among protease inhibitors have been observed. Continued administration of darunavir; cobicistat therapy following loss of viral suppression may increase the likelihood of antimicrobial resistance to other protease inhibitors. Darunavir displays a less than 10-fold decreased susceptibility against 90% (n = 3,309) of HIV-1 isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir. Darunavir-resistant viruses were not susceptible to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir in cell culture. However, 6 of 9 darunavir-resistant viruses selected in cell culture from protease inhibitor-resistant viruses showed a fold change in EC50 values less than 3 for tipranavir, indicating limited cross-resistance between darunavir and tipranavir. Of viruses isolated from subjects experiencing virologic failure on darunavir/ritonavir 600/100 mg twice daily, 41% were still susceptible to tipranavir, 10% were susceptible to saquinavir, and less than 2% were susceptible to other protease inhibitors.
Patients receiving darunavir; cobicistat may be at increased risk of developing serious rash. Most occurred within the first 4 weeks of treatment, were mild/moderate in severity, and resolved with continued treatment. However, darunavir therapy has also been associated with more severe rashes. During the clinical development program (n = 3,063), 0.4% of patients receiving darunavir plus ritonavir reported a severe skin reaction. Further, cases of Stevens-Johnson Syndrome (< 0.1%), toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have also been rarely reported. Discontinue treatment immediately in any patient who develops signs of severe skin reactions, such as severe rash or rash accompanied with fever, fatigue, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, hepatitis, or eosinophilia.
Cobicistat decreases estimated creatinine clearance by inhibiting tubular section without affecting glomerular function; therefore, an estimated creatinine clearance (CrCl) should be assessed in all patients prior to initiating treatment with darunavir; cobicistat. The use of darunavir; cobicistat in combination with tenofovir should be avoided in patients with a CrCl < 70 mL/minute (including dialysis patients) because tenofovir is eliminated by a combination of glomerular filtration and active renal tubular secretion. When considering treatment with a regimen that includes both darunavir; cobicistat and tenofovir, obtain a baseline estimated CrCl, urine glucose, and urine protein prior to initiating therapy. An estimated CrCl, urine glucose, and urine protein should also be performed during therapy as clinically appropriate. Patients who experience a serum creatinine increase of > 0.4 mg/dL from baseline should be more closely monitored. Further, monitoring of serum phosphate concentrations is advised for patients at risk for developing renal dysfunction. During clinical trials, the combination of cobicistat and tenofovir was associated with renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia). During the 48-week study period, 6 patients (1.5%) discontinued treatment due to renal adverse effects, with 5 of the 6 patients (1.3%) having laboratory finding suggestive of proximal renal tubulopathy. None of the five had renal impairment (CrCl < 70 mL/minute) at baseline. Manifestations of proximal renal tubulopathy may include persistent or worsening bone pain, pain in extremities, bone fractures, and/or muscle pain/weakness; closely evaluate the renal function of patients who experience these symptoms while receiving darunavir; cobicistat with tenofovir. Avoid administering concurrently with or recently after a nephrotoxic agent, including high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDS), as this may increase the risk for renal adverse effects.
Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. Darunavir; cobicistat is not recommended for use as an initial therapy in pregnant patients and those who are trying to conceive, as substantially lower exposures to darunavir and cobicistat during the second and third trimesters may result in viral breakthroughs. Consider the use of more effective antiretroviral regimens, such as replacing cobicistat with low-dose ritonavir as a darunavir pharmacokinetic enhancer during pregnancy. For people who conceive while suppressed on darunavir; cobicistat, guidelines recommend the provider and patient engage in shared decision-making regarding continued use. If the decision is made with the patient to continue use during pregnancy, viral loads should be monitored more frequently (i.e., every 1 to 2 months). Available data from the Antiretroviral Pregnancy Registry (APR), which includes 737 first trimester exposures to darunavir and 560 first trimester exposures to cobicistat, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When exposure occurred in the first trimester, the prevalence of defects was 3.7% (95% CI: 2.4 to 5.3) for darunavir and 3.6% (95% CI: 2.2 to 5.5) for cobicistat. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than or equal to 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years and have CD4 counts less than 300 cells/mm3, patients with inconsistent adherence, or patients with detectable viral loads. For patients on HAART less than 2 years but have CD4 counts greater than or equal to 300 cells/mm3, monitor CD4 counts every 6 months. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of planned delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at deliver. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks' gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for development of resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to darunavir; cobicistat; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.
HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission. Advise patients who receive a diagnosis of HIV infection while breast-feeding (acute HIV) to immediately discontinue breast-feeding and switch to replacement feeding in order to reduce the risk of postnatal HIV transmission to the infant. Replacement feeding is also recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). There are limited data regarding the use of cobicistat during breast-feeding, and its excretion into human breast milk is unknown. Data from 2 mother-infant pairs (where the mothers received ritonavir boosted darunavir) suggest breast milk transfer of darunavir is low, with a median darunavir breast milk-to-maternal plasma concentration ratio of 0.12, median estimated infant darunavir dose of 0.05 mg/kg, and no detectable darunavir in infant plasma. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.
Initiation of therapy for HIV treatment:
-For adults, initiation of treatment immediately (or as soon as possible) after HIV diagnosis is recommended in all patients to reduce the risk of disease progression and to prevent the transmission of HIV, including perinatal transmission and transmission to sexual partners. Starting antiretroviral therapy early is particularly important for patients with AIDS-defining conditions, those with acute or recent HIV infection, and individuals who are pregnant; delaying therapy in these subpopulations has been associated with high risks of morbidity, mortality, and HIV transmission.
-Prior to initiating treatment, obtain baseline plasma HIV RNA (viral load) and CD4 count; results do not need to be available before starting therapy.
-Antiretroviral drug-resistance testing:-Genotypic drug-resistance testing is recommended prior to initiation of therapy in all antiretroviral treatment-naive patients and prior to changing therapy for treatment failure.
--Standard genotypic drug-resistance testing in treatment-naive people should focus on testing for mutations in reverse transcriptase (RT) and protease (PR) genes.
-Testing for mutations in the integrase gene should also be performed if integrase strand transfer inhibitor (INSTI) resistance is a concern (e.g., people who acquire HIV after pre-exposure prophylaxis with long-acting cabotegravir).
-Phenotypic resistance testing may be used in conjunction with the genotypic test for patients with known or suspected complex drug-resistance mutation patterns.
-HIV-1 proviral DNA resistance testing is available for use in patients with HIV RNA concentrations below the limits of detection or with low-level viremia (i.e., less than 1,000 copies/mL), where genotypic testing is unlikely to be successful; however, the clinical utility of this assay has not been fully determined.
-It is not necessary to delay treatment until resistance test results are available; however, subsequent modifications to the treatment regimen should be made, if needed, once the test results are available.
-Pediatric guidelines are also available.
Place in therapy for HIV treatment:
-Darunavir; cobicistat given with tenofovir alafenamide or tenofovir disoproxil fumarate and either emtricitabine or lamivudine is a recommended treatment option for non-pregnant patients with acute HIV.
-In certain clinical situations, darunavir; cobicistat given in combination with 2 NRTIs is a preferred initial treatment regimen for some non-pregnant adults and adolescents (Sexual Maturity Rating of 4 or 5) with HIV-1, HIV-2, or HIV-1/HIV-2 coinfection, including people who have a history of using long-acting cabotegravir as pre-exposure prophylaxis and need to start treatment before results of INSTI genotypic resistance testing are available. It is recommended as part of an alternative initial regimen for adolescents who are not sexually mature.
-Darunavir; cobicistat is not recommended for use in pregnant women as an initial treatment, as inadequate darunavir and cobicistat concentrations during the second and third trimesters may result in viral breakthroughs.
-Pediatric guidelines are also available.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretrovirals in patients with no darunavir resistance-associated substitutions:
Oral dosage:
Adults: 800 mg/150 mg PO once daily in treatment-naive and treatment-experienced patients with no darunavir-resistance-associated substitutions (V11I, V32I, L33F, I47V, 150V, 154L, 154M, T74P, L76V, I84V, L89V).
Children and Adolescents weighing 40 kg or more: 800 mg/150 mg PO once daily in treatment-naive and treatment-experienced patients with no darunavir-resistance-associated substitutions (V11I, V32I, L33F, I47V, 150V, 154L, 154M, T74P, L76V, I84V, L89V).
Maximum Dosage Limits:
-Adults
1 tablet/day PO (800 mg darunavir; 150 mg cobicistat).
-Geriatric
1 tablet/day PO (800 mg darunavir; 150 mg cobicistat).
-Adolescents
weighing 40 kg or more: 1 tablet/day PO (800 mg darunavir; 150 mg cobicistat).
weighing less than 40 kg: Safety and efficacy have not been established.
-Children
weighing 40 kg or more: 1 tablet/day PO (800 mg darunavir; 150 mg cobicistat).
weighing less than 40 kg: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Darunavir; cobicistat is not recommended for use in patients with severe hepatic impairment.
Patients with Renal Impairment Dosing
Darunavir; cobicistat is not recommended in patients with a CrCl less than 70 mL/minute who are also receiving concomitant tenofovir disoproxil fumarate, nor in patients with CrCl less than 30 mL/minute who are receiving concomitant tenofovir alafenamide. No specific dosage recommendations are available in patients not receiving tenofovir with renal insufficiency; however, as singular agents, darunavir and cobicistat are not adjusted in patients with mild to moderate renal impairment.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Abemaciclib: (Major) If coadministration with cobicistat is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If cobicistat is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of cobicistat. Abemaciclib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients. (Major) If coadministration with darunavir is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If darunavir is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of darunavir. Abemaciclib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and cobicistat; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Major) Avoid the concomitant use of acalabrutinib and darunavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
Acarbose: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with cobicistat may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Concomitant use of dihydrocodeine with darunavir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of darunavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Darunavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Chlorpheniramine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
Acetaminophen; Dextromethorphan: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Diphenhydramine: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like cobicistat can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If cobicistat is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like darunavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If darunavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and cobicistat. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and cobicistat are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state. (Moderate) Monitor for an increase in adverse effects from both drugs during concomitant use of adagrasib and darunavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib and darunavir are both CYP3A substrates and strong CYP3A inhibitors. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state.
Adefovir: (Major) Patients who are concurrently taking adefovir with antiretrovirals like the protease inhibitors, are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Ado-Trastuzumab emtansine: (Major) Avoid coadministration of cobicistat with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until cobicistat has cleared from the circulation (approximately 3 half-lives of cobicistat) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; cobicistat is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted. (Major) Avoid coadministration of darunavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until darunavir has cleared from the circulation (approximately 3 half-lives of darunavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; darunavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Afatinib: (Moderate) If the concomitant use of cobicistat and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of cobicistat. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Albuterol; Budesonide: (Moderate) Avoid coadministration of oral budesonide and cobistat due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Elevated budesonide serum concentrations may result in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and P-gp. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of budesonide with darunavir may cause elevated budesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of protease inhibitors is necessary. If the protease inhibitor is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like protease inhibitors can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If the protease inhibitor is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil. (Moderate) The plasma concentrations of alfentanil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as hypotension, nausea, itching, and respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor and alfentanil is a CYP3A4 substrate.
Alfuzosin: (Contraindicated) Alfuzosin is contraindicated for use with cobicistat due to the potential for serious/life-threatening reactions, including hypotension. Coadministration is expected to reduce the metabolism and increase systemic exposure to alfuzosin. Alfuzosin is primarily metabolized by CYP3A4; cobicistat is a strong inhibitor of this enzyme. Coadministration of another strong CYP3A4 inhibitor increased the alfuzosin AUC by 2.5-fold to 3.2-fold. (Contraindicated) Concurrent use of alfuzosin and protease inhibitors is contraindicated due to increased alfuzosin exposure. Alfuzosin is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. When coadministered with another strong CYP3A inhibitor, the AUC of alfuzosin was increased by 2.5-fold to 3.2-fold.
Aliskiren: (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate. (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate. (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4.
Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with cobicistat is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and cobicistat should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%. (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with darunavir is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and darunavir should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
Alogliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Alogliptin; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Alogliptin; Pioglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
Alosetron: (Major) Caution is warranted when darunavir is administered with alosetron as there is a potential for elevated alosetron concentrations. Alosetron is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. (Moderate) Concomitant use of alosetron with cobicistat may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A4; cobicistat is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
Alpelisib: (Major) Avoid coadministration of alpelisib with cobicistat due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and cobicistat is a BCRP inhibitor.
Alpha-glucosidase Inhibitors: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Alprazolam: (Contraindicated) Coadministration of cobicistat and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with cobicistat, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold. (Contraindicated) Coadministration of darunavir and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with darunavir, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
Amiodarone: (Major) Avoid concomitant use of amiodarone and cobicistat due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Major) Avoid concomitant use of amiodarone and darunavir due to the risk for increased amiodarone exposure which may increase the risk for adverse effects. Amiodarone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Amitriptyline: (Major) Coadministration of darunavir and amitriptyline may result in increased amitriptyline plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope, and consider a lower dose of amitriptyline with concurrent use. Amitriptyline is metabolized by CYP2D6 and also partially metabolized by CYP3A4. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Atorvastatin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with darunavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP.
Amobarbital: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%. (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Apalutamide: (Major) Coadministration of cobicistat with apalutamide is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. In addition, there is a potential for increased apalutamide exposure. If these drugs are used together, monitor for an increase in apalutamide-related adverse reactions. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Apalutamide is a substrate and strong inducer of CYP3A4. Cobicistat is a substrate and strong inhibitor of CYP3A4. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively. The steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%. (Major) Coadministration of darunavir with apalutamide is not recommended as there is a potential for decreased darunavir concentrations; exposure to apalutamide may also increase. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
Apixaban: (Major) Reduce the apixaban dose by 50% when administered with darunavir. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid coadministration. Concomitant administration of apixaban and darunavir may result in increased exposure to apixaban and an increase in the risk of bleeding. Apixaban is a P-gp and CYP3A substrate; darunavir is a P-gp and strong CYP3A inhibitor. In a drug interaction study, administration of another combined P-gp/strong CYP3A inhibitor increased the apixaban AUC by 2-fold. (Major) Reduce the apixaban dose by 50% when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as cobicistat containing medications. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration. Concomitant administration results in increased exposure to apixaban and an increase in the risk of bleeding.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use due to substantially increased exposure of aprepitant; increased cobicistat exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in cobicistat- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Cobicistat is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased the AUC of aprepitant by approximately 5-fold, and the mean terminal half-life by approximately 3-fold. Cobicistat is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and did not result in a clinically significant increase in the AUC of a sensitive substrate. (Major) Avoid the concomitant use of darunavir with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased darunavir exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in darunavir- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Darunavir is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Darunavir is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may additionally increase plasma concentrations of darunavir. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) Recommendations for managing aripiprazole and cobicistat vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer a quarter of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 200 mg/month or from 300 mg to 160 mg/month. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg; avoid use in patients known to be poor metabolizers of CYP2D6. Further dosage reductions may be required in patients who are also receiving a strong CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; cobicistat is a weak CYP2D6 and strong CYP3A inhibitor. (Major) Recommendations for managing aripiprazole and cobicistat vary by aripiprazole dosage form. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg. For extended-release aripiprazole lauroxil injections (Aristada) in patients who are known to be poor metabolizers of CYP2D6, reduce the dose to 441 mg; no dosage adjustment is necessary for patients already tolerating 441 mg. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a strong CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; cobicistat is a weak CYP2D6 and strong CYP3A inhibitor. (Major) Recommendations for managing aripiprazole and darunavir vary by aripiprazole dosage form and CYP2D6 metabolizer status. For aripiprazole oral dosage forms, administer half of the usual dose; administer a quarter of the usual dose to patients known to be poor metabolizers of CYP2D6. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 300 mg/month or from 300 mg to 200 mg/month; administer 200 mg/month to patients known to be poor metabolizers of CYP2D6. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg; avoid use in patients known to be poor metabolizers of CYP2D6. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP3A and CYP2D6 substrate; darunavir is a strong CYP3A inhibitor. (Major) Recommendations for managing aripiprazole and darunavir vary by aripiprazole dosage form and CYP2D6 metabolizer status. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg. For extended-release aripiprazole lauroxil injections (Aristada) in patients who are known to be poor metabolizers of CYP2D6, reduce the dose to 441 mg; no dosage adjustment is necessary for patients already tolerating 441 mg. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP3A and CYP2D6 substrate; darunavir is a strong CYP3A inhibitor.
Armodafinil: (Major) Coadministration of cobicistat with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor of CYP3A4 and P-gp, and a substrate of CYP3A4. (Major) Coadministration of darunavir with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer. Darunavir is an inhibitor/substrate of CYP3A4.
Artemether; Lumefantrine: (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrate and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold. (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrates and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. In a drug interaction study, administration of a strong CYP3A4 inhibitor, resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of lumefantrine are elevated when artemether; lumefantrine, a CYP3A4 substrate, is administered concurrently with darunavir, a CYP3A4 substrate/inhibitor. Although dose adjustments are not required, concomitant use warrants caution due to the potential for increased side effects, including an increased potential for QT prolongation.
Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with cobicistat is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with darunavir is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Asenapine: (Moderate) Caution is warranted when cobicistat is administered with asenapine as there is a potential for increased aspenapine concentrations. Asenapine is a substrate of CYP3A4 and CYP2D6. Cobicistat is an inhibitor of CYP3A4 and CYP2D6. (Moderate) Caution is warranted when darunavir is administered with asenapine as there is a potential for increased aspenapine concentrations. Asenapine is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6.
Aspirin, ASA; Butalbital; Caffeine: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
Aspirin, ASA; Omeprazole: (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like cobicistat can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If cobicistat is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like darunavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If darunavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Contraindicated) Coadministration of atazanavir with darunavir; cobicistat is not recommended, as more than one antiretroviral would require pharmacokinetic enhancement (boosting). Pharmacokinetic data are not available to provide appropriate dosage recommendations, and use of these drugs together may lead to loss of antiretroviral efficacy and development of resistance.
Atazanavir; Cobicistat: (Contraindicated) Coadministration of atazanavir with darunavir; cobicistat is not recommended, as more than one antiretroviral would require pharmacokinetic enhancement (boosting). Pharmacokinetic data are not available to provide appropriate dosage recommendations, and use of these drugs together may lead to loss of antiretroviral efficacy and development of resistance.
Atogepant: (Major) Avoid use of atogepant and cobicistat when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with cobicistat. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and OATP1B1/3; cobicistat is a strong CYP3A inhibitor and an OATP1B1/3 inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration. (Major) Avoid use of atogepant and darunavir when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with darunavir. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and darunavir is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration.
Atomoxetine: (Moderate) The plasma concentrations of atomoxetine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as dizziness, drowsiness, hypertension, and other cardiac adverse events, is recommended during coadministration and dosage adjustments for atomoxetine may be warranted. Cobicistat is a CYP2D6 inhibitor and atomoxetine is a CYP2D6 substrate. (Moderate) The plasma concentrations of atomoxetine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as dizziness, drowsiness, hypertension, and other cardiac adverse events, is recommended during coadministration and dosage adjustments for atomoxetine may be warranted. Darunavir is a CYP2D6 inhibitor, and atomoxetine is a CYP2D6 substrate.
Atorvastatin: (Major) Do not exceed 20 mg/day of atorvastatin if coadministration with darunavir plus ritonavir is necessary due to an increased risk of myopathy and rhabdomyolysis. Carefully weigh the potential benefits and risk of combined therapy. Use the lowest possible atorvastatin dose. Closely monitor patients for signs and symptoms of muscle pain, tenderness, or weakness especially during the initial months of therapy and during upward titration of either drug. There is no assurance that periodic monitoring of creatinine phosphokinase (CPK) will prevent the occurrence of myopathy. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of cobicistat is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold. (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of darunavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Avanafil: (Major) Coadministration of avanifil with darunavir is not recommended. Concurrent use may increase avanafil concentrations. Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking moderate CYP3A4 inhibitors, including darunavir, should take avanafil with caution and adhere to a maximum recommended adult avanafil dose of 50 mg/day. (Major) Do not use avanafil in patients receiving cobicistat due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Avapritinib: (Major) Avoid coadministration of avapritinib with cobicistat due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state. (Major) Avoid coadministration of avapritinib with darunavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Axitinib: (Major) Avoid coadministration of axitinib with cobicistat due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers. (Major) Avoid coadministration of axitinib with darunavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after darunavir is discontinued. Axitinib is a CYP3A4/5 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and cobicistat is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Major) Coadministration of inhaled fluticasone propionate and darunavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Barbiturates: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as darunavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, darunavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity. (Major) Concurrent use of bedaquiline and cobicistat should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with cobicistat may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of cobicistat in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Cobicistat is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. (Moderate) Concurrent use of benzhydrocodone with darunavir may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of darunavir in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4. Darunavir is a strong inhibitor of CYP3A4.
Berotralstat: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with berotralstat as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor. (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with berotralstat. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor.
Betamethasone: (Moderate) Consider an alternative corticosteroid that is less affected by CYP3A4 (i.e., beclomethasone or prednisolone), particularly for long-term use, in patients receiving darunavir. Coadministration may significantly increase betamethasone exposure increasing the risk for Cushing's syndrome and adrenal suppression. Darunavir is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%. (Moderate) Monitor for corticosteroid-related adverse effects if coadministration is necessary. Consider using an alternative treatment to betametasone, such as a corticosteroid less affected by CYP3A4 (i.e., beclomethasone or prednisolone), particularly if long term use is indicated. Cobicistat is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving cobicistat. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving cobicistat. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; cobicistat inhibits P-gp.
Bexarotene: (Major) Coadministration of cobicistat with bexarotene is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Bexarotene is a CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
Bortezomib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of cobicistat is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%. (Moderate) The plasma concentrations of bortezomib may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as gastrointestinal side effects, hypotension, or peripheral neuropathy, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while bortezomib is a CYP3A4 substrate.
Bosentan: (Major) Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at the recommended initial dose once daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at the recommended initial dose once daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied. (Major) The plasma concentrations of bosentan may increase when administered with regimens containing cobicistat and atazanavir or darunavir. In addition, coadministration may result in decreased concentrations of cobicistat, atazanavir, and darunavir. In patients receiving the antiretrovirals for at least 10 days, start bosentan at 62.5 mg daily or every other day (depending on tolerability). When the antiretrovirals are initiated in a patients currently receiving bosentan, discontinue bosentan at least 36 hours prior to starting the antiretroviral regimen. After at least 10 days, restart bosentan at 62.5 mg daily or every other day based on tolerability. If switching from a ritonavir boosted antiretroviral regimen to a cobicistat boosted regimen, maintain current bosentan dose.
Bosutinib: (Major) Avoid concomitant use of bosutinib and cobicistat; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor. (Major) Avoid concomitant use of bosutinib and darunavir; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and darunavir is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor.
Brentuximab vedotin: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with cobicistat is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%. (Minor) Concomitant administration of brentuximab vedotin and darunavir may increase exposure of monomethyl auristatin E (MMAE); if concurrent administration is necessary, monitor patients for adverse reactions. MMAE is one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate; darunavir is a CYP3A4 inhibitor.
Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as darunavir. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. Because brexpiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a moderate to strong CYP3A4 inhibitor and moderate to strong CYP2D6 inhibitor should have their brexpiprazole dose reduced to one-quarter (25%) of the usual dose. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level. (Major) Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 in combination with a moderate to strong inhibitor of CYP2D6. Cobicistat is a moderate to strong inhibitor of both CYP3A4 and CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. If cobicistat is discontinued, adjust the brexpiprazole dosage to its original level.
Brigatinib: (Major) Avoid coadministration of brigatinib with cobicistat if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of cobicistat, resume the brigatinib dose that was tolerated prior to initiation of cobicistat. Brigatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. (Major) Avoid coadministration of brigatinib with darunavir if possible due to increased plasma exposure of brigatinib and altered exposure to darunavir. If concomitant use is unavoidable, closely monitor for changes in the clinical efficacy or side effect profile of the antiretroviral regimen and reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); if darunavir is discontinued, resume the brigatinib dose that was tolerated prior to initiation of darunavir. Brigatinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. Darunavir is also a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. At clinically relevant concentrations, brigatinib induced CYP3A via activation of the pregnane X receptor (PXR); this may decrease concentrations of sensitive CYP3A substrates. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Brigatinib is also a P-gp inhibitor in vitro and may have the potential to increase exposure to P-gp substrates.
Brimonidine; Timolol: (Moderate) A dose decrease may be needed for timolol when administered with darunavir/ritonavir as serum concentrations for timolol may be increased. Caution is warranted and clinical monitoring is recommended. (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as timolol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advised.
Brincidofovir: (Moderate) Postpone the administration of cobicistat for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and cobicistat is necessary. Brincidofovir is an OATP1B1/3 substrate and cobicistat is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with cobicistat ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; cobicistat is a strong inhibitor of CYP3A4. (Major) When bromocriptine is used for diabetes, avoid coadministration with darunavir ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; boosted darunavir is a strong inhibitor of CYP3A4.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Budesonide: (Moderate) Avoid coadministration of oral budesonide and cobistat due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Elevated budesonide serum concentrations may result in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and P-gp. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of budesonide with darunavir may cause elevated budesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and cobistat due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Elevated budesonide serum concentrations may result in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and P-gp. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of budesonide with darunavir may cause elevated budesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide and cobistat due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Elevated budesonide serum concentrations may result in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and P-gp. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of budesonide with darunavir may cause elevated budesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Bupivacaine Liposomal: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
Bupivacaine: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
Bupivacaine; Epinephrine: (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
Bupivacaine; Lidocaine: (Major) Darunavir can inhibit CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and darunavir should be carefully monitored due to the potential for serious toxicity. (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
Bupivacaine; Meloxicam: (Moderate) The plasma concentrations of meloxicam may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while meloxicam is a CYP3A4 substrate. (Minor) Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
Buprenorphine: (Moderate) Concomitant administration of darunavir with buprenorphine increases the concentrations of norbuprenorphine, a metabolite of buprenorphine. Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated by the cytochrome CYP3A4 isozyme, which in inhibited by darunavir. Clinical monitoring is recommended if these drugs are used together. (Moderate) Concomitant use of buprenorphine and cobicistat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when cobicistat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping cobicistat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If cobicistat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and cobicistat is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant administration of darunavir with buprenorphine increases the concentrations of norbuprenorphine, a metabolite of buprenorphine. Buprenorphine undergoes both N-dealkylation to norbuprenorphine and glucuronidation. The N-dealkylation pathway is mediated by the cytochrome CYP3A4 isozyme, which in inhibited by darunavir. Clinical monitoring is recommended if these drugs are used together. (Moderate) Concomitant use of buprenorphine and cobicistat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when cobicistat is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping cobicistat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If cobicistat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and cobicistat is a CYP3A inhibitor. (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
Bupropion: (Moderate) Caution is warranted when cobicistat is administered with bupropion as there is a potential for elevated cobicistat concentrations. Bupropion is a CYP2D6 inhibitor in vitro, while cobicistat is a substrate of CYP2D6.
Bupropion; Naltrexone: (Moderate) Caution is warranted when cobicistat is administered with bupropion as there is a potential for elevated cobicistat concentrations. Bupropion is a CYP2D6 inhibitor in vitro, while cobicistat is a substrate of CYP2D6.
Buspirone: (Moderate) A low dose of buspirone used cautiously is recommended when coadministered with cobicistat. If a patient has been titrated to a stable dosage of buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone. Administering cobicistat with buspirone may increase buspirone concentration and risk for adverse events. Buspirone is a sensitive substrate of CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the buspirone AUC by 19-fold with an increased incidence of buspirone-related adverse effects. (Moderate) The plasma concentrations of buspirone may be elevated when administered concurrently with darunavir. Close clinical monitoring is recommended during coadministration; buspirone dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Darunavir is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of buspirone. These drugs used in combination may result in elevated buspirone plasma concentrations, causing an increased risk for buspirone-related adverse events.
Butalbital; Acetaminophen: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with cobicistat if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%. (Major) Avoid coadministration of cabazitaxel with darunavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering the combination of darunavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Darunavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and cobicistat due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with cobicistat 2 to 3 days after discontinuation of cobicistat. Cabozantinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%. (Major) Avoid concomitant use of cabozantinib and darunavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with darunavir 2 to 3 days after discontinuation of darunavir. Cabozantinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
Canagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Canagliflozin; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Capivasertib: (Major) Avoid coadministration of capivasertib with cobicistat due to increased capivasertib exposure which may increase the risk for capivasertib-related adverse effects. If coadministration is necessary, reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off; monitor for adverse reactions. Capivasertib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.7-fold. (Major) Avoid coadministration of capivasertib with darunavir due to increased capivasertib exposure which may increase the risk for capivasertib-related adverse effects. If coadministration is necessary, reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off; monitor for adverse reactions. Capivasertib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.7-fold.
Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with cobicistat is necessary. Capmatinib is a CYP3A substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with darunavir is necessary. Capmatinib is a CYP3A substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
Carbamazepine: (Contraindicated) Coadministration of carbamazepine with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. In addition, inhibition of CYP3A4 by cobicistat may result in elevated carbamazepine concentrations. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Closely monitor for carbamazepine toxicity during coadministration; clinical monitoring of carbamazepine concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and carbamazepine may result in increased carbamazepine concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with carbamazepine.
Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as darunavir, is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For adult patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. (Major) The dose of cariprazine should be reduced in patients also receiving cobicistat. When cobicistat is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When initiating cariprazine in a patient who is stable on cobicistat, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, and then increased to a maximum dose of 3 mg daily. If cobicistat is withdrawn, the cariprazine dosage may need to be increased. Cariprazine is metabolized by CYP3A4 to its major active metabolite. Cobicistat is a strong CYP3A4 inhibitor. Concurrent use with another strong CYP3A4 inhibitor increased the exposure of cariprazine by about 4-fold; increased the AUC of DDCAR metabolite by about 1.5-fold; and decreased DCAR metabolite AUC by about one-third.
Carvedilol: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as carvedilol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advise.
Celecoxib; Tramadol: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. (Major) Concurrent use of tramadol with darunavir may decrease the CYP3A4 and CYP2D6 metabolism of tramadol; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Cenobamate: (Moderate) Coadministration of cobicistat with cenobamate may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. (Moderate) Coadministration of darunavir with cenobamate may result in significant decreases in the plasma concentrations of darunavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Ceritinib: (Major) Avoid concomitant use of ceritinib with cobicistat due to increased ceritinib exposure which may increase the incidence and severity of adverse reactions; cobicistat exposure may also increase. If concomitant use is necessary, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg and monitor for ceritinib-related adverse reactions. After cobicistat is discontinued, resume the dose of ceritinib taken prior to initiating cobicistat. Both drugs are CYP3A substrates and strong CYP3A4 inhibitors. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold. (Major) Avoid concomitant use of ceritinib with darunavir due to increased ceritinib exposure which may increase the incidence and severity of adverse reactions; darunavir exposure may also increase. If concomitant use is necessary, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg and monitor for ceritinib-related adverse reactions. After darunavir is discontinued, resume the dose of ceritinib taken prior to initiating darunavir. Both drugs are CYP3A substrates and a strong CYP3A4 inhibitosr. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold.
Chloramphenicol: (Moderate) Caution is warranted when cobicistat is administered with chloramphenicol as there is a potential for elevated cobicistat concentrations. Chloramphenicol is a CYP3A4 inhibitor and cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with chloramphenicol as there is a potential for elevated concentrations of darunavir. Chloramphenicol is a CYP3A4 inhibitor; darunavir is a substrate of CYP3A4.
Chlordiazepoxide: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed. (Moderate) The plasma concentrations of chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
Chlordiazepoxide; Amitriptyline: (Major) Coadministration of darunavir and amitriptyline may result in increased amitriptyline plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope, and consider a lower dose of amitriptyline with concurrent use. Amitriptyline is metabolized by CYP2D6 and also partially metabolized by CYP3A4. (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations. (Moderate) The plasma concentrations of chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
Chlordiazepoxide; Clidinium: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed. (Moderate) The plasma concentrations of chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
Chlorpheniramine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Chlorpheniramine; Codeine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
Chlorpheniramine; Dextromethorphan: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Chlorpheniramine; Hydrocodone: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Chlorpheniramine; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Chlorpheniramine; Pseudoephedrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Chlorpromazine: (Major) Caution is warranted when cobicistat is administered with chlorpromazine as there is a potential for elevated chlorpromazine and cobicistat concentrations. Chlorpromazine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Ciclesonide: (Moderate) Coadministration of ciclesonide with cobicistat may cause elevated ciclesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Ciclesonide is a CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of ciclesonide with darunavir may cause elevated ciclesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Ciclesonide is a CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Cidofovir: (Moderate) Additive adverse effects may be seen when cidofovir is given with other agents that cause neutropenia. Patients receiving anti-retroviral protease inhibitors in combination with cidofovir may have an increased risk of iritis or uveitis.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with cobicistat. Monitor for an increase in cilostazol-related adverse reactions. Cobicistat is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%. (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with protease inhibitors and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A substrate; protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a strong CYP3A inhibitor increased the cilostazol AUC by 117%. Coadministration with a moderate CYP3A inhibitor increased the AUC of cilostazol (single dose) by 73%; the AUC of 4-trans-hydroxycilostazol increased by 141%.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of cobicistat and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%. (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of darunavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Ciprofloxacin: (Moderate) Caution is warranted when darunavir is administered with ciprofloxacin as there is a potential for elevated concentrations of darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Ciprofloxacin is a CYP3A4 inhibitor, while darunavir is a CYP3A4 substrate.
Cisapride: (Contraindicated) Coadministration of cisapride with cobicistat is contraindicated. Cobicistat is a strong inhibitor of CYP3A4, and plasma concentrations of drugs extensively metabolized by this enzyme, such as cisapride, are expected to increase with concurrent use. Elevated plasma concentrations of cisapride have been associated with QT prolongation and serious cardiovascular adverse events including death due to torsade de pointes. (Contraindicated) Concomitant use of protease inhibitors and cisapride is contraindicated; use increases cisapride exposure and the risk for cisapride-related adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Concomitant use of cisapride with CYP3A inhibitors also is disallowed under the Propulsid Limited Access Program.
Citalopram: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Clarithromycin: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%.
Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of cobicistat as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of darunavir as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4.
Clobazam: (Major) Coadministration of cobicistat with clobazam is not recommended. There is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Cobicistat is a substrate of CYP3A4. (Major) Coadministration of darunavir with clobazam is not recommended. There is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Darunavir is a substrate of CYP3A4.
Clomipramine: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with cobicistat; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in increase in treatment-related adverse reactions. Cobicistat is a strong CYP3A4 inhibitor and clonazepam is a CYP3A4 substrate. (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with protease inhibitors; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors.
Clopidogrel: (Major) Avoid coadministration of clopidogrel with cobicistat due to the potential for decreased clopidogrel efficacy. Prasugrel may be preferred to clopidogrel if coadministration with cobicistat is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Cobicistat is a strong CYP3A4 inhibitor. (Major) Avoid coadministration of clopidogrel with darunavir. Concomitant use may reduce concentrations of the active metabolite of clopidogrel, therefore decreasing the antiplatelet activity of clopidogrel.
Clorazepate: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of N-desmethyldiazepam, the active metabolite of clorazepate, and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy. (Moderate) Use caution if coadministration of cobicistat with clorazepate is necessary, as the systemic exposure of the active metabolite of clorazepate may be increased resulting in an increase in treatment-related adverse reactions; adjust the dose of clorazepate if necessary. Cobicistat is a strong CYP3A4 inhibitor. Clorazepate is a pro-drug converted to N-desmethyldiazepam in the GI tract; N-desmethyldiazepam is metabolized by 2C19 and 3A4.
Clozapine: (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Caution is advisable during concurrent use of darunavir and clozapine. Darunavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through inhibition of CYP1A2, CYP2D6, or CYP3A4 may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Cobimetinib: (Major) Avoid coadministration of darunavir with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold. (Major) Avoid the concurrent use of cobimetinib with chronic cobicistat due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of cobicistat is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of cobicistat, resume cobimetinib at the previous dose. Use an alternative to cobicistat in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; cobicistat is a moderate inhibitor of both P-gp and CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Cocaine: (Moderate) Caution is warranted when cobicistat is administered with cocaine as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Both drugs are substrates and inhibitors of CYP3A4. Cocaine is also an inhibitor of CYP2D6; cobicistat is a CYP2D6 substrates/inhibitors. (Moderate) Caution is warranted when darunavir is administered with cocaine as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Both drugs are substrates and inhibitors of CYP3A4.
Codeine: (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
Codeine; Promethazine: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with darunavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of darunavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If darunavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Darunavir is a strong inhibitor of CYP3A4.
Colchicine: (Major) Avoid concomitant use of colchicine and cobicistat due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and cobicistat is a dual strong CYP3A and P-gp inhibitor. Concomitant use with other dual strong CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 3- to 4-fold. (Major) Avoid concomitant use of colchicine and darunavir due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg followed by 0.3 mg. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Conivaptan: (Contraindicated) Coadministration of conivaptan and cobicistat is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase cobicistat exposure and risk for cobicistat-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold. (Contraindicated) Coadministration of conivaptan and darunavir is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase darunavir exposure and risk for darunavir-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
Conjugated Estrogens: (Moderate) Darunavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
Conjugated Estrogens; Bazedoxifene: (Moderate) Darunavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
Conjugated Estrogens; Medroxyprogesterone: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with medroxyprogesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Moderate) Darunavir increases the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and cobicistat if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. The AUC of copanlisib increased by 53% when a single IV dose of copanlisib 60 mg was administered following 10 days of another strong CYP3A4 inhibitor in a drug interaction study in patients with cancer. (Major) Avoid the concomitant use of copanlisib and darunavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; darunavir is a strong CYP3A inhibitor.
Crizotinib: (Major) Avoid concomitant use of crizotinib and cobicistat due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to cobicistat may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%. (Major) Avoid concomitant use of crizotinib and darunavir due to the risk for increased crizotinib exposure which may increase the risk for crizotinib-related adverse effects; exposure to darunavir may also increase. If concomitant use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Crizotinib is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Cyclophosphamide: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. Use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
Cyclosporine: (Moderate) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with cobicistat is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-gp substrate and cobicistat is a P-gp inhibitor.
Dabrafenib: (Major) Avoid coadministration of dabrafenib and cobicistat due to the potential for decreased cobicistat concentrations and increased dabrafenib exposure. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for reduced antiretroviral efficacy and dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity. Both drugs are CYP3A4 substrates. Darafenib is a moderate CYP3A4 inducer, while cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%. (Major) The concomitant use of dabrafenib and darunavir may lead to altered concentrations of either drug. Use of an alternative agent is recommended. If concomitant use of these agents together is unavoidable, monitor patients for loss of darunavir efficacy. Dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer; darunavir is a sensitive CYP3A4 substrate and a moderate CYP3A4 inhibitor.
Daclatasvir: (Major) The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as cobicistat. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. (Moderate) Concurrent administration of daclatasvir, a CYP3A4 substrate, with darunavir, a moderate CYP3A4 inhibitor, may increase daclatasvir serum concentrations. If these drugs are administered together, monitor patients for daclatasvir-related adverse effects, such as headache, fatigue, nausea, and diarrhea. The manufacturer does not recommend daclatasvir dose reduction for adverse reactions. When darunavir is boosted with cobicistat, the dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily.
Dalfopristin; Quinupristin: (Moderate) Caution is warranted when cobicistat is administered with dalfopristin; quinupristin as there is a potential for elevated cobicistat concentrations. Quinupristin is a CYP3A4 inhibitor and cobicistat is substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with dalfopristin; quinupristin as there is a potential for elevated concentrations of darunavir. Quinupristin is a CYP3A4 inhibitor; darunavir is a substrate of CYP3A4.
Danazol: (Moderate) Caution is warranted when cobicistat is administered with danazol as there is a potential for elevated cobicistat concentrations. Danazol is a CYP3A4 inhibitor and cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with danazol as there is a potential for elevated concentrations of darunavir. Danazol is a CYP3A4 inhibitor; darunavir is a substrate of CYP3A4.
Dapagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Dapagliflozin; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Dapagliflozin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with cobicistat due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively. (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with darunavir due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A substrate; darunavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the saxagliptin AUC up to 3.7-fold. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Dapsone: (Minor) Plasma concentrations of dapsone may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as hemolytic anemia, methemoglobinemia, or peripheral neuropathy, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while dapsone is a CYP3A4 substrate. (Minor) The plasma concentrations of dapsone may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as hemolytic anemia, methemoglobinemia, or peripheral neuropathy, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while dapsone is a CYP3A4 substrate.
Daridorexant: (Major) Avoid concomitant use of daridorexant and cobicistat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%. (Major) Avoid concomitant use of daridorexant and darunavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darifenacin: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with cobicistat due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with darunavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor.
Darolutamide: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with cobicistat is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Cobicistat is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
Dasatinib: (Major) Avoid coadministration of dasatinib and cobicistat due to the potential for increased dasatinib exposure and subsequent toxicity. An alternative to cobicistat with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Concomitant use of cobicistat is not recommended in patients receiving dasatinib 60 mg or 40 mg daily. If dasatinib is not tolerated after dose reduction, consider alternative therapies. If cobicistat is stopped, allow a washout of approximately 1 week before increasing the dasatinib dose. Dasatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively. (Major) Avoid coadministration of dasatinib and darunavir due to the potential for increased dasatinib exposure and subsequent toxicity. An alternative to darunavir with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Concomitant use of darunavir is not recommended in patients receiving dasatinib 60 mg or 40 mg daily. If dasatinib is not tolerated after dose reduction, consider alternative therapies. If darunavir is stopped, allow a washout of approximately 1 week before increasing the dasatinib dose. Dasatinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with cobicistat. Concurrent use may significantly increase concentrations of 21-desDFZ , the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Administration of deflazacort with another strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold. (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with darunavir. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; boosted darunavir is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Delavirdine: (Moderate) Delavirdine and darunavir are both substrates and inhibitors of CYP3A4. In addition, darunavir may inhibit the CYP2D6 metabolism of delavirdine. Coadministration may result in increased plasma concentrations of either drug. It is not clear if any dosage adjustments are needed. (Moderate) The plasma concentrations of delavirdine and cobicistat may be elevated when administered concurrently. Clinical monitoring for adverse effects is recommended during coadministration. Delavirdine is a CYP2D6 and CYP3A4 substrate/inhibitor. Cobicistat is a substrate/inhibitor of both CYP2D6 and CYP3A4.
Desipramine: (Major) Coadministration of darunavir and desipramine may result in increased desipramine plasma concentrations. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of desipramine and ritonavir. If desipramine is used with a CYP3A inhibitor such as darunavir, the combination should be used with caution and a lower dose of desipramine should be considered. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Desogestrel; Ethinyl Estradiol: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with desogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with desogestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of desogestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Desvenlafaxine: (Moderate) Caution is warranted when cobicistat is administered with desvenlafaxine as there is a potential for elevated cobicistat concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Desvenlafaxine is an inhibitor of CYP2D6; cobicistat is partially metabolized by CYP2D6.
Dexamethasone: (Major) Avoid concurrent use of dexamethasone with cobicistat-containing regimens due to the risk of decreased antiretroviral efficacy and the potential development of viral resistance. In addition, serum concentrations of dexamethasone may be increased, potentially resulting in Cushing's syndrome and adrenal suppression. Consider an alternative corticosteroid (i.e., beclomethasone, prednisone, prednisolone) for long-term use. If concomitant use is necessary, monitor virologic response and for corticosteroid-related adverse effects. Dexamethasone is a CYP3A4 substrate and weak CYP3A inducer; cobicistat is a CYP3A4 substrate and strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. (Moderate) Monitor for steroid-related adverse reactions and a decrease in darunavir efficacy if concomitant use of dexamethasone and darunavir is necessary. If long term coadministration is required, consider using an alternative corticosteroid, such as prednisone or prednisolone. Concomitant use may increase dexamethasone concentrations and decrease darunavir exposure. Dexamethasone is a CYP3A substrate and CYP3A inducer; darunavir is a CYP3A substrate and strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dexlansoprazole: (Minor) The plasma concentrations of dexlansoprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while dexlansoprazole is a CYP3A4 substrate.
Dextromethorphan: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Bupropion: (Moderate) Caution is warranted when cobicistat is administered with bupropion as there is a potential for elevated cobicistat concentrations. Bupropion is a CYP2D6 inhibitor in vitro, while cobicistat is a substrate of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Quinidine: (Major) Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use. Coadministration of darunavir with quinidine should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of quinidine with cobicistat. Quinidine is a substrate for CYP3A4 and P-glycoprotein (P-gp) and an inhibitor of CYP2D6 and P-gp; cobicistat is a substrate and inhibitor of both these enzymes and an inhibitor of P-gp. Concurrent use may result in elevated plasma concentration of both drugs. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors. (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
Diclofenac: (Moderate) Caution is warranted when cobicistat is administered with diclofenac as there is a potential for increased diclofenac concentrations. Diclofenac is a substrate of CYP3A4 and CYP2C9. Cobicistat is an inhibitor of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with diclofenac as there is a potential for elevated diclofenac concentrations. Diclofenac is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
Diclofenac; Misoprostol: (Moderate) Caution is warranted when cobicistat is administered with diclofenac as there is a potential for increased diclofenac concentrations. Diclofenac is a substrate of CYP3A4 and CYP2C9. Cobicistat is an inhibitor of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with diclofenac as there is a potential for elevated diclofenac concentrations. Diclofenac is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
Didanosine, ddI: (Moderate) While a drug interaction between darunavir and didanosine, ddi is not known, because of the specific administration guidelines didanosine (administered on an empty stomach) should be administered 1 hour before or 2 hours after darunavir (administered with food).
Dienogest; Estradiol valerate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with dienogest. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with dienogest have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of dienogest. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Digoxin: (Major) The lowest dose of digoxin should initially be prescribed when given with darunavir/ritonavir, as increased serum concentrations of digoxin may occur. Monitor serum digoxin concentrations for dosage titration. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of digoxin with cobicistat. Digoxin is a substrate for P-gp; cobicistat is an inhibitor of this drug transporter. Concurrent use may result in elevated digoxin plasma concentration.
Dihydroergotamine: (Contraindicated) Concomitant use of ergotamine with cobicistat is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Contraindicated) Concomitant use of ergotamine with darunavir is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Diltiazem: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Complex interactions can be expected with coadministered with diltiazem or verapamil, as both are substrates and inhibitors of CYP3A4. (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with cobicistat is necessary. Diltiazem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Diphenhydramine: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6.
Diphenhydramine; Ibuprofen: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6.
Diphenhydramine; Naproxen: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6.
Diphenhydramine; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6.
Disopyramide: (Major) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of disopyramide with cobicistat. Disopyramide is a substrate for CYP3A4; cobicistat is a strong inhibitor of this enzyme. Concurrent use may result in elevated disopyramide plasma concentration. Cases of life-threatening interactions have been reported for disopyramide when given with another strong CYP3A4 inhibitor. (Major) Darunavir can inhibit CYP3A4, an isoenzyme that is partially responsible for the metabolism of disopyramide. Although no definitive clinical data have yet confirmed this interaction, the concurrent use of disopyramide with darunavir should be approached with caution due to the potential for serious disopyramide toxicity.
Disulfiram: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate. (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
Docetaxel: (Major) Avoid coadministration of docetaxel with cobicistat if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold. (Major) Avoid coadministration of docetaxel with darunavir if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Major) Coadministration of CYP3A4 inhibitors, such as darunavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
Dolasetron: (Major) The plasma concentrations of hydrodolasetron (primary dolasetron metabolite) may be elevated when dolasetron is administered concurrently with darunavir. Clinical monitoring for adverse effects, such as headache or cardiovascular effects, is recommended during coadministration. Darunavir is a CYP3A4 and CYP2D6 inhibitor, while hydrodolasetron is a CYP3A4 and CYP2D6 substrate. (Moderate) The plasma concentrations of hydrodolasetron (primary dolasetron metabolite) may be elevated when dolasetron is administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as headache or cardiovascular effects, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while hydrodolasetron is a CYP3A4 and CYP2D6 substrate.
Dolutegravir: (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Dolutegravir; Lamivudine: (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Dolutegravir; Rilpivirine: (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp. (Moderate) Close clinical monitoring is advised when administering the combination of darunavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Darunavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Donepezil: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
Donepezil; Memantine: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
Doravirine: (Minor) Coadministration of doravirine and cobicistat may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; cobicistat is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant. (Minor) Coadministration of doravirine and darunavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; darunavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events. (Minor) Coadministration of doravirine and cobicistat may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; cobicistat is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant. (Minor) Coadministration of doravirine and darunavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; darunavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Dorzolamide; Timolol: (Moderate) A dose decrease may be needed for timolol when administered with darunavir/ritonavir as serum concentrations for timolol may be increased. Caution is warranted and clinical monitoring is recommended. (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as timolol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advised.
Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution. (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with darunavir. Darunavir is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
Doxepin: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Doxercalciferol: (Moderate) Protease inhibitors may decrease efficacy of doxercalciferol. Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including protease inhibitors, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if these drugs are administered together.
Doxorubicin Liposomal: (Major) Avoid coadministration of cobicistat and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp); doxorubicin is a major CYP2D6, CYP3A4, and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. (Major) Avoid coadministration of darunavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Darunavir is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of cobicistat and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp); doxorubicin is a major CYP2D6, CYP3A4, and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. (Major) Avoid coadministration of darunavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Darunavir is a strong CYP3A4 inhibitor and doxorubicin is a major substrate of CYP3A4. Concurrent use of CYP3A4 inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Major) Use caution if coadministration of dronabinol with darunavir is necessary, and closely monitor for an increase in dronabinol-related adverse reactions (e.g., cognitive impairment, psychosis, seizures, and hemodynamic instability, as well as feeling high, dizziness, confusion, somnolence). Darunavir is a strong inhibitor of CYP3A4, and is contraindicated with sensitive drugs that are highly dependent on CYP3A4/5 for clearance. Dronabinol is a CYP2C9 and 3A4 substrate; concomitant use may result in elevated plasma concentrations of dronabinol. (Moderate) Use caution if coadministration of dronabinol with cobicistat is necessary, and closely monitor for an increase in dronabinol-related adverse reactions (e.g., cognitive impairment, psychosis, seizures, and hemodynamic instability, as well as feeling high, dizziness, confusion, somnolence). Concomitant use may result in elevated plasma concentrations of dronabinol. Cobicistat is a strong inhibitor of CYP3A4; dronabinol is a CYP2C9 and 3A4 substrate.
Dronedarone: (Contraindicated) Coadministration of cobicistat with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations. Dronedarone is a CYP3A4 inhibitor/substrate and a CYP2D6 inhibitor. Cobicistat is an inhibitor/substrate of both CYP3A4 and CYP2D6. (Contraindicated) Coadministration of darunavir with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations and the potential for serious and/or life threatening reactions, such as cardiac arrhythmias. Dronedarone is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4.
Drospirenone: (Major) Drospirenone may be administered concurrently with cobicistat; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with cobicistat may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Major) Drospirenone may be administered concurrently with darunavir; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with darunavir may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms.
Drospirenone; Estetrol: (Major) Drospirenone may be administered concurrently with cobicistat; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with cobicistat may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Major) Drospirenone may be administered concurrently with darunavir; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with darunavir may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms.
Drospirenone; Estradiol: (Major) Drospirenone may be administered concurrently with cobicistat; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with cobicistat may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Major) Drospirenone may be administered concurrently with darunavir; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with darunavir may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Drospirenone; Ethinyl Estradiol: (Major) Drospirenone may be administered concurrently with cobicistat; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with cobicistat may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Major) Drospirenone may be administered concurrently with darunavir; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with darunavir may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Drospirenone may be administered concurrently with cobicistat; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with cobicistat may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Major) Drospirenone may be administered concurrently with darunavir; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with darunavir may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Dulaglutide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Duloxetine: (Moderate) Caution is warranted when cobicistat is administered with duloxetine as there is a potential for elevated duloxetine and cobicistat concentrations. Duloxetine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Dutasteride: (Moderate) Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) The plasma concentrations of dutasteride may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as impotence or libido decrease, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while dutasteride is a CYP3A4 substrate.
Dutasteride; Tamsulosin: (Major) Concurrent use of tamsulosin and cobicistat is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is metabolized by CYP3A4 and CYP2D6 hepatic enzymes. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided. (Moderate) Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) The plasma concentrations of dutasteride may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as impotence or libido decrease, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while dutasteride is a CYP3A4 substrate.
Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity of both drugs when coadministered with darunavir. Coadministration may increase the exposure of both drugs. Duvelisib is a substrate and moderate inhibitor of CYP3A; darunavir is a sensitive substrate and strong inhibitor of CYP3A. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as darunavir. (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with cobicistat. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as cobicistat.
Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Edoxaban: (Moderate) Coadministration of edoxaban and cobicistat may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cobicistat; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
Efavirenz: (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates. (Moderate) Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates. (Moderate) Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates. (Moderate) Concurrent administration of darunavir with efavirenz results in decreased darunavir concentrations (13% reduction in AUC and 31% reduction in Cmin) and increased efavirenz concentration (21% increase in AUC and 17% increase in Cmin). No dosage adjustment recommendations are required for either medication. Use this combination with caution. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
Elacestrant: (Major) Avoid concomitant use of elacestrant and cobicistat due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold. (Major) Avoid concomitant use of elacestrant and darunavir due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as cobicistat is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Cobicistat is a combined inhibitor; it is a potent inhibitor of CYP3A and inhibits OATP1B1 and P-gp. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. (Major) Concomitant use of elagolix 200 mg twice daily and darunavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and darunavir to 6 months. Monitor for elagolix-related side effects and reduced response to darunavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; darunavir is a strong inhibitor of CYP3A and a sensitive CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease darunavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as cobicistat is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Cobicistat is a combined inhibitor; it is a potent inhibitor of CYP3A and inhibits OATP1B1 and P-gp. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. (Major) Concomitant use of elagolix 200 mg twice daily and darunavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and darunavir to 6 months. Monitor for elagolix-related side effects and reduced response to darunavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; darunavir is a strong inhibitor of CYP3A and a sensitive CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease darunavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with darunavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Darunavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3. (Major) Concurrent administration of elbasvir with cobicistat is not recommended. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with cobicistat should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir and may result in adverse effects (i.e., elevated ALT concentrations). Cobicistat is an inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
Eletriptan: (Contraindicated) Eletriptan is contraindicated for use within 72 hours of using any drug that is a potent CYP3A4 inhibitor as described in the prescribing information of the interacting drug including protease inhibitors. Eletriptan is metabolized via CYP3A4, and coadministration with protease inhibitors may cause increased eletriptan concentrations and thus toxicity. (Contraindicated) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of cobicistat due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively.
Elexacaftor; tezacaftor; ivacaftor: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with cobicistat; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; cobicistat is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with darunavir; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; darunavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with cobicistat; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor/ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); cobicistat is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with darunavir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); darunavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Eliglustat: (Major) Coadministration of darunavir and eliglustat is contraindicated in intermediate or poor CYP2D6 metabolizers (IMs or PMs). Use of these agents together is also contraindicated in any patient also receiving a moderate or strong CYP2D6 inhibitor, such as ritonavir. In extensive CYP2D6 metabolizers (EMs), coadministration of eliglustat and darunavir requires dosage adjustment of eliglustat to 84 mg PO once daily. Darunavir is a strong CYP3A inhibitor. Eliglustat is a CYP3A and CYP2D6 substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Use of these drugs together may result in increased plasma concentrations of eliglustat, increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is greatest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A. (Major) Coadministration of eliglustat and cobicistat is contraindicated in intermediate or poor CYP2D6 metabolizers (IMs or PMs). In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with cobicistat and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors, such as cobicistat, increases eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A. The product labeling for cobicistat states that coadministration of other drugs for which altered plasma concentrations are associated with serious and/or life-threatening effects is contraindicated; however, the interaction between ketoconazole (another potent CYP3A inhibitor) and eliglustat was studied during clinical trials. The resultant data supports eliglustat dosage reduction in EMs instead of contraindication.
Eluxadoline: (Major) When administered concurrently with cobicistat, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); cobicistat is an OATP1B1/1B3 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of darunavir boosted with cobicistat and elvitegravir is not recommended. Dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretrovirals, resulting in reduction of antiretroviral efficacy and development of viral resistance. However, elvitegravir may be administered with darunavir if boosted with ritonavir. When elvitegravir is administered in combination with darunavir and ritonavir, the recommended dosing is: elvitegravir 150 mg PO once daily with darunavir/ritonavir 600/100 mg PO twice daily. No data are available for use of other dosage for this combination. (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of darunavir boosted with cobicistat and elvitegravir is not recommended. Dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretrovirals, resulting in reduction of antiretroviral efficacy and development of viral resistance. However, elvitegravir may be administered with darunavir if boosted with ritonavir. When elvitegravir is administered in combination with darunavir and ritonavir, the recommended dosing is: elvitegravir 150 mg PO once daily with darunavir/ritonavir 600/100 mg PO twice daily. No data are available for use of other dosage for this combination. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
Empagliflozin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Linagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Linagliptin; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Close clinical monitoring is advised when administering the combination of darunavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Darunavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4. (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering the combination of darunavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Darunavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Emtricitabine; Tenofovir alafenamide: (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
Encorafenib: (Major) Avoid coadministration of cobicistat and encorafenib due to the risk of decreased cobicistat exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Cobicistat is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold. (Major) Avoid coadministration of darunavir and encorafenib due to the risk of decreased darunavir exposure which may increase the risk for virologic failure and drug resistance and increased encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Darunavir is a CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Enfortumab vedotin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with cobicistat is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; cobicistat is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Entrectinib: (Major) Avoid coadministration of entrectinib with cobicistat due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold. (Major) Avoid coadministration of entrectinib with darunavir due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Enzalutamide: (Major) Coadministration of cobicistat with enzalutamide is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer. (Major) Coadministration of darunavir with enzalutamide is not recommended as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
Eplerenone: (Contraindicated) Coadministration of darunavir and eplerenone is contraindicated. Darunavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension. (Contraindicated) Eplerenone is contraindicated for use with cobicistat due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Cobicitat is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and cobicistat due to the risk for increased plasma concentrations of erdafitinib. If concomitant use is necessary, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. Erdafitinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased erdafitinib overall exposure by 134%. (Major) Avoid coadministration of erdafitinib and darunavir due to the risk for increased plasma concentrations of erdafitinib. If concomitant use is necessary, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. Erdafitinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased erdafitinib overall exposure by 134%.
Ergotamine: (Contraindicated) Concomitant use of ergotamine with cobicistat is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Contraindicated) Concomitant use of ergotamine with darunavir is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Ergotamine; Caffeine: (Contraindicated) Concomitant use of ergotamine with cobicistat is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Contraindicated) Concomitant use of ergotamine with darunavir is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Erlotinib: (Major) Avoid coadministration of erlotinib with cobicistat if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%. (Major) Avoid coadministration of erlotinib with darunavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
Ertugliflozin; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Ertugliflozin; Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Erythromycin: (Major) Avoid concurrent use of erythromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of erythromycin, cobicistat, atazanavir and darunavir. Erythromycin is a CYP3A4 inhibitor and a P-glycoprotein (P-gp) substrate. Cobicistat is a substrate of CYP3A4 and a P-gp inhibitor, while both atazanavir and darunavir are CYP3A4 substrates. (Moderate) Concentrations of darunavir may be increased with coadministration, as erythromycin is a CYP3A4 inhibitor and darunavir is a CYP3A4 substrate. Patients should be monitored for increased side effects.
Escitalopram: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Eslicarbazepine: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration may result in significant decreases in the plasma concentrations of the CYP3A4 substrates, cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant. (Major) Plasma concentrations of darunavir may be reduced if administered concurrently with eslicarbazepine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant. In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Darunavir is a substrate of CYP3A4.
Esomeprazole: (Minor) Use caution when administering cobicistat and esomeprazole concurrently. Cobicistat is an inhibitor of CYP3A, and esomeprazole is partially metabolized by CYP3A. Coadministration of cobicistat with CYP3A substrates, such as esomeprazole, can theoretically increase esomeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Estazolam: (Moderate) In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by CYP3A. In theory, CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity (i.e., prolonged sedation and respiratory depression). (Moderate) The plasma concentrations of estazolam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; estazolam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of estazolam. These drugs used in combination may result in elevated estazolam plasma concentrations, causing an increased risk for estazolam-related adverse events.
Esterified Estrogens: (Moderate) Darunavir is expected to increase the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
Esterified Estrogens; Methyltestosterone: (Moderate) Darunavir is expected to increase the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. Patients should be instructed to report any breakthrough bleeding or adverse events to their prescribers.
Estradiol: (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Estradiol; Levonorgestrel: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with levonorgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with levonorgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Estradiol; Norethindrone: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Estradiol; Norgestimate: (Major) Concurrent administration of cobicistat and norgestimate results in increased norgestimate serum concentrations. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is also the potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norgestimate have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norgestimate. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Estradiol; Progesterone: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. The metabolism of progesterone may also be inhibited by cobicistat, a strong inhibitor of the CYP3A4 hepatic enzyme. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency. (Moderate) Use caution if coadministration of darunavir with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Darunavir is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estropipate: (Moderate) Darunavir is expected to increase the metabolism of estrogens. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Eszopiclone: (Major) The adult dose of eszopiclone should not exceed 2 mg/day during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving. (Major) The total dose of eszopiclone should not exceed 2 mg when administered with cobicistat. Coadministration may increase eszopiclone exposure resulting in increased risk of next-day psychomotor or memory impairment and decreased ability to perform tasks requiring full mental alertness such as driving. CYP3A4 is a primary metabolic pathway for eszopiclone; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased eszopiclone exposure by 2.2-fold.
Ethinyl Estradiol; Norelgestromin: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norelgestromin. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Ethinyl Estradiol; Norgestrel: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Ethosuximide: (Moderate) Close clinical monitoring is advised when administering ethosuximide with cobicistat. Coadministration may result in elevated ethosuximide plasma concentrations. Predictions regarding this interaction may be made based on the metabolic pathway of both drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ethosuximide. (Moderate) Darunavir may inhibit the CYP3A4 metabolism of ethosuximide, and may necessitate up to a 50% dose reduction of ethosuximide. Closely monitor patients during concurrent therapy.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with ethynodiol diacetate. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethynodiol diacetate have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethynodiol diacetate. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Etonogestrel: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with etonogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as darunavir may increase the serum concentration of etonogestrel.
Etonogestrel; Ethinyl Estradiol: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with etonogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns. (Minor) Coadministration of etonogestrel and strong CYP3A4 inhibitors such as darunavir may increase the serum concentration of etonogestrel.
Etrasimod: (Major) Avoid concomitant use of etrasimod and cobicistat in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Etrasimod is a CYP2C9 and CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Major) Avoid concomitant use of etrasimod and darunavir in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Etrasimod is a CYP2C9 and CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Etravirine: (Major) Due to the potential for decreased antiretroviral efficacy and potential for adverse events, use of etravirine with cobicistat is not recommended. When these drugs are given together, the concentrations of cobicistat and etravirine may be decreased and increased, respectively. Both drugs are substrates for CYP3A4. Etravirine is also a CYP3A4 inducer, while cobicistat is a strong CYP3A4 inhibitor. Coadministration of etravirine with another strong CYP3A4 inhibitor increased etravirine exposure by 1.42-fold. (Minor) In Phase 3 clinical trials of etravirine, darunavir (boosted with ritonavir) was used as part of the background treatment regimen. Coadministration of etravirine and darunavir is considered safe and effective, and although coadministration does result in a decreased mean systemic exposure (AUC) of etravirine, by about 37%, no dosage adjustments are required.
Everolimus: (Major) Avoid coadministration of everolimus with cobicistat due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold. (Major) Avoid coadministration of everolimus with darunavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and P-glycoprotein (P-gp) substrate. Darunavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
Exenatide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Ezetimibe; Simvastatin: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Fedratinib: (Major) Avoid coadministration of fedratinib with cobicistat as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If cobicistat is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold. (Major) Avoid coadministration of fedratinib with darunavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If darunavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Felodipine: (Moderate) Concurrent use of felodipine and cobicistat should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively. (Moderate) Concurrent use of felodipine and protease inhibitors should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Concurrent use of a strong CYP3A inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively. Concurrent use of a moderate CYP3A inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like cobicistat can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If cobicistat is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If darunavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with anti-retroviral protease inhibitors. Avoid use of fesoterodine and protease inhibitors in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine. (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with cobicistat. Avoid use of fesoterodine and cobicistat in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
Fexinidazole: (Major) Avoid concomitant use of fexinidazole and cobicistat and monitor for decreased fexinidazole efficacy if coadministration is necessary. Concomitant use may limit conversion of fexinidazole to its active metabolites. Fexinidazole is converted to its active metabolites via CYP3A and cobicistat is a strong CYP3A inhibitor. (Major) Avoid concomitant use of fexinidazole and darunavir and monitor for decreased fexinidazole efficacy if coadministration is necessary. Concomitant use may limit conversion of fexinidazole to its active metabolites. Fexinidazole is converted to its active metabolites via CYP3A and darunavir is a strong CYP3A inhibitor.
Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil and cobicistat for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of cobicistat for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A. Potent inhibitors of CYP3A, such as cobicistat, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Finerenone: (Contraindicated) Concomitant use of finerenone and cobicistat is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%. (Contraindicated) Concomitant use of finerenone and darunavir is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
Flecainide: (Major) Coadministration of darunavir with flecainide should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of flecainide with cobicistat. Flecainide is a substrate for CYP2D6; cobicistat is an inhibitor of this enzyme. Concurrent use may result in elevated flecainde plasma concentration.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors such as cobicistat is contraindicated due to increased flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following the use of cobicistat, start flibanserin at least 2 weeks after the last dose of cobicistat. If initiating cobicistat following flibanserin use, begin therapy at least 2 days after the last dose of flibanserin. In cases where the benefit of initiating cobicistat therapy within 2 days of stopping flibanserin clearly outweighs the risk of flibanserin-related hypotension and syncope, monitor the patient for signs of hypotension and syncope. (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as darunavir, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin. A similar contraindication applies to combination products containing darunavir such as darunavir; cobicistat.
Fluconazole: (Moderate) Caution is warranted when cobicistat is administered with fluconazole as there is a potential for elevated cobicistat concentrations. Fluconazole is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with fluconazole as there is a potential for elevated concentrations of darunavir. Fluconazole is a CYP3A4 inhibitor, while darunavir is a CYP3A4 substrate.
Fluoxetine: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Fluphenazine: (Moderate) Caution is warranted when cobicistat is administered with fluphenazine as there is a potential for elevated concentrations of fluphenazine and cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Fluphenazine and cobicistat are substrates and inhibitors of CYP2D6.
Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. (Moderate) The plasma concentrations of flurazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; flurazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4; inhibitors of this isoenzyme may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity.
Flutamide: (Major) Caution is warranted when cobicistat is administered with flutamide as there is a potential for elevated flutamide concentrations and decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Flutamide is a substrate and inducer of CYP3A4. Cobicistat is a CYP3A4 substrate and inhibitor. (Major) Caution is warranted when darunavir; cobicistat is administered with flutamide as there is a potential for elevated flutamide concentrations and decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Flutamide is a substrate and inducer of CYP3A4. Darunavir is a CYP3A4 substrate and inhibitor.
Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and cobicistat is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Major) Coadministration of inhaled fluticasone propionate and darunavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with cobicistat. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Avoid concomitant use of salmeterol with darunavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Coadministration of inhaled fluticasone propionate and cobicistat is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Major) Coadministration of inhaled fluticasone propionate and darunavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and cobicistat is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Major) Coadministration of inhaled fluticasone propionate and darunavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Caution is warranted when cobicistat is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Cobicistat is an inhibitor of CYP3A4, CYP2D6, and P-gp inhibitor. (Moderate) Caution is warranted when darunavir is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6.
Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and cobicistat is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Major) Coadministration of inhaled fluticasone propionate and darunavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Caution is warranted when cobicistat is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Cobicistat is an inhibitor of CYP3A4, CYP2D6, and P-gp inhibitor. (Moderate) Caution is warranted when darunavir is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6.
Fluvastatin: (Major) The plasma concentrations of fluvastatin may increase when administered with cobicistat. Use the lowest starting dose of fluvastatin and carefully titrate while monitoring for adverse events. (Moderate) Concurrent use of darunavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Darunavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, darunavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
Fluvoxamine: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Food: (Major) Advise patients to avoid cannabis use during cobicistat treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and cobicistat is a strong CYP3A inhibitor. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively. (Major) Advise patients to avoid cannabis use during protease inhibitor treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and protease inhibitors are strong CYP3A inhibitors. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively.
Formoterol; Mometasone: (Moderate) Coadministration of mometasone with cobicistat may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of mometasone with darunavir may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Fosamprenavir: (Major) Coadministration of cobicistat with fosamprenavir is not recommended because pharmacokinetic data are not available to provide appropriate dosing recommendations. Cobicistat is not interchangeable with ritonavir as a boosting agent to fosamprenavir. (Moderate) Monitor for an increase in adverse reactions from both drugs if concomitant use of darunavir and fosamprenavir is necessary. Concomitant use may increase the exposure of both drugs and the risk for adverse effects. Darunavir boosted with ritonavir or cobicistat is a CYP3A substrate and strong CYP3A inhibitor; fosamprenavir is a CYP3A substrate and moderate CYP3A inhibitor.
Fosphenytoin: (Contraindicated) Coadministration of fosphenytoin with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Closely monitor for decreased fosphenytoin efficacy during coadministration; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and fosphenytoin may result in decreased phenytoin concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenytoin.
Fostamatinib: (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%. (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%.
Futibatinib: (Major) Avoid concurrent use of futibatinib and cobicistat. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; cobicistat is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with darunavir is necessary. Gefitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Gilteritinib: (Major) Consider an alternative to cobicistat during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Major) Consider an alternative to darunavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
Glasdegib: (Major) Consider an alternative to cobicistat during treatment with glasdegib. Concurrent use may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. If coadministration cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended. Glasdegib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study. (Major) Consider an alternative to darunavir during treatment with glasdegib. Concurrent use may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. If coadministration cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended. Glasdegib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with darunavir is not recommended as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4. Additionally, darunavir is a P-gp substrate and glecaprevir is a P-gp inhibitor; concentrations of darunavir may also be increased. In drug interaction studies, coadministration of darunavir boosted with ritonavir with glecaprevir; pibrentasvir resulted in an approximately 5-fold increase in the AUC of glecaprevir and a 29% increase in the AUC of darunavir. (Major) Coadministration of pibrentasvir with darunavir is not recommended as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of the drug transporter P-glycoprotein (P-gp); darunavir is an inhibitor of P-gp. Additionally, darunavir is a P-gp substrate and pibrentasvir is a P-gp inhibitor; concentrations of darunavir may also be increased. In drug interaction studies, coadministration of darunavir boosted with ritonavir with glecaprevir; pibrentasvir resulted in a 29% increase in the AUC of darunavir. (Moderate) Caution is advised with the coadministration of glecaprevir and cobicistat as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP) 1B1/3, and breast cancer resistance protein (BCRP); cobicistat is an inhibitor of all these transporters. (Moderate) Caution is advised with the coadministration of pibrentasvir and cobicistat as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); cobicistat is an inhibitor of P-gp and BCRP.
Glimepiride: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Glipizide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Glipizide; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Glyburide: (Moderate) Caution is warranted when cobicistat is administered with glyburide as there is a potential for elevated glyburide concentrations. Glyburide is a substrate of P-glycoprotein (P-gp) and cobicistat is an inhibitor of P-gp. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Glyburide; Metformin: (Moderate) Caution is warranted when cobicistat is administered with glyburide as there is a potential for elevated glyburide concentrations. Glyburide is a substrate of P-glycoprotein (P-gp) and cobicistat is an inhibitor of P-gp. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Granisetron: (Minor) Plasma concentrations of granisetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while granisetron is a CYP3A4 substrate. (Minor) The plasma concentrations of granisetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while granisetron is a CYP3A4 substrate.
Grapefruit juice: (Moderate) Caution is warranted when cobicistat is administered with grapefruit juice as there is a potential for elevated cobicistat concentrations. Grapefruit juice is a CYP3A4 and CYP2D6 inhibitor, while cobicistat is a substrate of CYP3A4 and CYP2D6.
Guanfacine: (Major) Darunavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If darunavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4. Darunavir is a strong CYP3A4 inhibitor, and when administered with ritonavir, potent inhibition is expected. (Major) If coadministration of cobicistat with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If cobicistat is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Cobicistat may significantly increase guanfacine plasma concentrations.
Haloperidol: (Moderate) Caution is warranted when cobicistat is administered with haloperidol as there is a potential for elevated haloperidol concentrations. Haloperidol is a CYP3A4 substrate and CYP2D6 substrate. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6. (Moderate) Darunavir is a substrate and inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and substrates or inhibitors of CYP3A4. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like darunavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If darunavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydroxyprogesterone: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with hydroxyprogesterone caproate. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with cobicistat. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively. (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with darunavir. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively.
Ibrutinib: (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold. (Major) Avoid concomitant use of ibrutinib and darunavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like cobicistat can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If cobicistat is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like darunavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If darunavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Major) Coadministration of idelalisib with cobicistat may increase the exposure of both drugs; avoid use and use alternative agents if possible. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. If use of both drugs is required, monitor for idelalisib- and cobicistat-related adverse reactions. Coadministration with a strong CYP3A inhibitor increased idelalisib expoure by 1.8-fold. (Major) Coadministration of idelalisib with darunavir may increase the exposure of both drugs; avoid use and use alternative agents if possible. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. The exposure of another sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Additionally, coadministration with a strong CYP3A inhibitor increased idelalisib expoure by 1.8-fold.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with cobicistat is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Cobicistat is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment. (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with darunavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Darunavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Reduce the iloperidone dose by one-half if coadministered with cobicistat If chloramphenicol is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP3A4 substrate. Chloramphenicol is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively. (Major) Reduce the iloperidone dose by one-half if coadministered with darunavir. If darunavir is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP3A4 substrate. Darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively.
Imatinib: (Major) Protease Inhibitors inhibit cytochrome P450 CYP3A4 and may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse reactions. In addition, because imatinib inhibits CYP2C9, CYP2D6, and CYP3A4/5, the metabolism of protease inhibitors may be decreased by imatinib. Close monitoring of the antiviral and antineoplastic responses is recommended. (Moderate) Caution is warranted when cobicistat is administered with imatinib, STI-571 as there is a potential for elevated imatinib and/or cobicistat concentrations. Imatinib is a CYP3A4 substrate and moderate iinhibitor, a weak inhibitor of CYP2D6, and a breast cancer resistance protein (BCRP) substrate. Cobicistat is a strong inhibitor of CYP3A4, a BCRP inhibitor, and a substrate of CYP2D6 and CYP3A4. Coadministration of imatinib with another strong CYP3A4 inhibitor increased imatinib exposure by 40%.
Imipramine: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations. (Moderate) Coadministration of darunavir and imipramine may result in increased imipramine plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope. Consider a lower dose of imipramine with concurrent use. Imipramine is metabolized by CYP2D6 and also partially metabolized by CYP3A4.
Incretin Mimetics: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Indacaterol; Glycopyrrolate: (Moderate) Clinical monitoring for adverse effects, such as headache, nervousness, tremor, or cardiovascular effects, is recommended during coadministration. Plasma concentrations of indacaterol may be elevated when administered concurrently with cobicistat. Cobicistat is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) inhibitor, while indacaterol is a CYP3A4, CYP2D6, and P-gp substrate. Coadministration with other dual inhibitors of CYP3A4 and P-gp has increased exposure of indacaterol from 1.4- to 1.9- fold.
Indinavir: (Contraindicated) Concomitant use of indinavir with regimens containing cobicistat and atazanavir is contraindicated. Cobicistat is an inhibitor of CYP3A4, while both atazanavir and indinavir are CYP3A4 substates. In addition, both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. Taking these drugs together may increase the risk for hepatic adverse events, such as hyperbilirubinemia. (Moderate) Concurrent administration of darunavir and indinavir results in increased darunavir and indinavir concentrations. The clinical significance of this interaction has not been established, and dosage adjustment recommendations have not been established. Use this combination with caution.
Infigratinib: (Major) Avoid concomitant use of infigratinib and cobicistat. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%. (Major) Avoid concomitant use of infigratinib and darunavir. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
Insulin Aspart: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Insulin Aspart; Insulin Aspart Protamine: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Insulin Degludec: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Insulin Degludec; Liraglutide: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Insulin Detemir: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Insulin Glargine: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Insulin Glargine; Lixisenatide: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Insulin Glulisine: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Insulin Lispro: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Insulin Lispro; Insulin Lispro Protamine: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Insulin, Inhaled: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Insulins: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Interferon Alfa-2b: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Interferon Alfa-n3: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Interferon Beta-1a: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Interferon Beta-1b: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Interferon Gamma-1b: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Interferons: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Irinotecan Liposomal: (Major) Avoid administration of cobicistat during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if cobicistat is boosted with atazanavir. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Cobicistat is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38. (Major) Avoid administration of darunavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Irinotecan: (Major) Avoid administration of cobicistat during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if cobicistat is boosted with atazanavir. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Cobicistat is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38. (Major) Avoid administration of darunavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; darunavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure of irinotecan and SN-38.
Isavuconazonium: (Contraindicated) Coadministration of isavuconazonium with cobicistat is contraindicated due to the risk of increased isavuconazole exposure. Isavuconazole is a sensitive substrate of CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased isavuconazole exposure by 422%. (Contraindicated) Concomitant use of isavuconazonium with darunavir is contraindicated due to the risk for increased isavuconazole serum concentrations and serious adverse reactions, such as hepatic toxicity. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; darunavir is a strong inhibitor of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inhibitors is contraindicated. Isavuconazole serum concentrations were increased 5-fold when coadministered with ketoconazole, another strong CYP3A4 inhibitor. Elevated darunavir concentrations would also be expected with coadministration, as darunavir is a CYP3A4 substrate and isavuconazole is a moderate CYP3A4 inhibitor.
Isoniazid, INH: (Moderate) Caution is warranted when cobicistat is administered with isoniazid, INH as there is a potential for elevated cobicistat concentrations. Isoniazid is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4. (Moderate) Isoniazid, INH is a CYP3A4 inhibitor, and serum concentrations of darunavir, a CYP3A4 substrate, may increase with coadministration. Coadminister these drugs with caution due to the potential for darunavir toxicity.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Coadministration of rifampin with cobicistat is contraindicated. Rifampin induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Contraindicated) Darunavir is contraindicated for use with rifampin. Rifampin induces CYP3A4, thereby decreasing the plasma concentrations and AUC of most protease inhibitors by roughly 90% and leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Moderate) Caution is warranted when cobicistat is administered with isoniazid, INH as there is a potential for elevated cobicistat concentrations. Isoniazid is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4. (Moderate) Isoniazid, INH is a CYP3A4 inhibitor, and serum concentrations of darunavir, a CYP3A4 substrate, may increase with coadministration. Coadminister these drugs with caution due to the potential for darunavir toxicity.
Isoniazid, INH; Rifampin: (Contraindicated) Coadministration of rifampin with cobicistat is contraindicated. Rifampin induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Contraindicated) Darunavir is contraindicated for use with rifampin. Rifampin induces CYP3A4, thereby decreasing the plasma concentrations and AUC of most protease inhibitors by roughly 90% and leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Moderate) Caution is warranted when cobicistat is administered with isoniazid, INH as there is a potential for elevated cobicistat concentrations. Isoniazid is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4. (Moderate) Isoniazid, INH is a CYP3A4 inhibitor, and serum concentrations of darunavir, a CYP3A4 substrate, may increase with coadministration. Coadminister these drugs with caution due to the potential for darunavir toxicity.
Isophane Insulin (NPH): (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Isradipine: (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as isradipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate reductions are advised. (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with protease inhibitors is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors.
Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with cobicistat as istradefylline exposure and adverse effects may increase. Cobicistat is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study. (Major) Do not exceed 20 mg once daily of istradefylline if administered with darunavir as istradefylline exposure and adverse effects may increase. Darunavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Itraconazole: (Major) Avoid concurrent use of itraconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increased plasma concentrations of itraconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined. (Major) If darunavir monotherapy is coadministered with itraconazole, high doses (i.e., more than 200 mg) of itraconazole should be avoided. When cobicistat is added to darunavir as in the darunavir; cobicistat combination product, avoid coadministration with itraconazole. Additionally, plasma concentrations of itraconazole may be increased when coadministered with darunavir (in the FDA approved dosage regimen). Both darunavir and itraconazole are strong inhibitors and substrates of CYP3A.
Ivabradine: (Contraindicated) Coadministration of cobicistat with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4; cobicistat is a strong inhibitor of CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold. (Contraindicated) Coadministration of ivabradine and darunavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ivacaftor: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with cobicistat due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If cobicistat is discontinued, wait at least 5 half-lives of cobicistat before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax. (Major) Avoid coadministration of ivosidenib with darunavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation; darunavir exposure may also decrease. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. Monitor for loss of efficacy of darunavir. If darunavir is discontinued, wait at least 5 half-lives of darunavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and inducer. Darunavir is a strong CYP3A4 inhibitor and sensitive substrate. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and cobicistat due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%. (Major) Avoid concurrent use of ixabepilone and darunavir due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%.
Ketoconazole: (Major) Avoid cobicistat for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and cobicistat are CYP3A substrates and strong CYP3A inhibitors. (Major) Avoid darunavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and darunavir are CYP3A substrates and strong CYP3A inhibitors.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
Lansoprazole: (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%. (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Lapatinib: (Major) Avoid coadministration of lapatinib with cobicistat due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If cobicistat is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold. (Major) Avoid coadministration of lapatinib with darunavir due to increased plasma concentrations of lapatinib; darunavir exposure may also increase. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily and monitor for an increase in treatment-related adverse reactions. If darunavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and a P-glycoprotein (P-gp) inhibitor. Darunavir is a strong CYP3A4 inhibitor and a P-gp substrate. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study. (Major) Avoid coadministration of larotrectinib with darunavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If darunavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of darunavir. Larotrectinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Ledipasvir; Sofosbuvir: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect. (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
Lefamulin: (Major) Avoid coadministration of cobicistat with oral lefamulin due to increased lefamulin exposure; cobicistat may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively. (Major) Avoid coadministration of darunavir with oral lefamulin due to increased lefamulin exposure; darunavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Lemborexant: (Major) Avoid coadministration of lemborexant and cobicistat as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold. (Major) Avoid coadministration of lemborexant and darunavir as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenacapavir: (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with lenacapavir. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor.
Leniolisib: (Major) Avoid concomitant use of leniolisib and cobicistat due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold. (Major) Avoid concomitant use of leniolisib and darunavir due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold.
Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of darunavir may occur if given with letermovir; monitor for darunavir-related adverse events. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Darunavir is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) Administering cobicistat concurrently with letermovir may result in increased concentrations of both drugs. The impact on the concentration of cobicistat may be increased in patients who are receiving letermovir with cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, and gastrointestinal events. Cobicistat is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide; Norethindrone: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Levoketoconazole: (Major) Avoid cobicistat for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and cobicistat are CYP3A substrates and strong CYP3A inhibitors. (Major) Avoid darunavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and darunavir are CYP3A substrates and strong CYP3A inhibitors.
Levomilnacipran: (Major) Do not exceed a levomilnacipran dose of 80 mg once daily if coadministration with cobicistat is necessary. Levomilnacipran is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased levomilnacipran exposure by about 50%.
Levonorgestrel: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with levonorgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with levonorgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
Levonorgestrel; Ethinyl Estradiol: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with levonorgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with levonorgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with levonorgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with levonorgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with levonorgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with levonorgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Lidocaine: (Major) Darunavir can inhibit CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and darunavir should be carefully monitored due to the potential for serious toxicity. (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Lidocaine; Epinephrine: (Major) Darunavir can inhibit CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and darunavir should be carefully monitored due to the potential for serious toxicity. (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Lidocaine; Prilocaine: (Major) Darunavir can inhibit CYP3A4, an isoenzyme partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and darunavir should be carefully monitored due to the potential for serious toxicity. (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Linagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Linagliptin; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Liraglutide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Lixisenatide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Lomitapide: (Contraindicated) Concomitant use of cobicistat and lomitapide is contraindicated due to the potential of markedly increased lomitapide concentrations and the associated elevation of serum transaminases. Cobicistat is a strong CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence another strong CYP3A4 inhibitor. (Contraindicated) Concomitant use of darunavir and lomitapide is contraindicated due to the potential for markedly increased lomitapide concentrations and the associated elevation of serum transaminases. Darunavir is a strong CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence another strong CYP3A4 inhibitor.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and cobicistat is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; cobicistat is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Contraindicated) Coadministration of lonafarnib and darunavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Both drugs are sensitive CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with cobicistat. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold. (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with darunavir. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with cobicistat. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold. (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with darunavir. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Lopinavir; Ritonavir: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. (Major) Coadministration of darunavir with lopinavir is not recommended. Coadministration of darunavir with lopinavir; ritonavir resulted in decreased darunavir exposure by approximately 38% to 41% depending on lopinavir; ritonavir dose. Appropriate dose adjustments for this combination have not been established.
Lorcaserin: (Moderate) Caution is warranted when cobicistat is administered with lorcaserin as there is a potential for elevated cobicistat concentrations. Lorcaserin is a CYP2D6 inhibitor. Cobicistat is a substrate of CYP2D6.
Lorlatinib: (Major) Avoid coadministration of lorlatinib with cobicistat due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of cobicistat may also decrease. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If cobicistat is discontinued, resume the original dose of lorlatinib after 3 half-lives of cobicistat. Lorlatinib is a CYP3A4 substrate and a moderate CYP3A4 inducer. Cobicistat is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Coadministration of cobicistat with moderate CYP3A4 inducers may reduce antiretroviral efficacy and increase the potential development of viral resistance. (Major) Avoid coadministration of lorlatinib with darunavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Plasma concentrations of darunavir may also occur, leading to a reduction of antiviral efficacy and the potential development of viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If darunavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of darunavir. Lorlatinib is a CYP3A substrate and moderate inducer. Darunavir is a strong CYP3A inhibitor as well as a sensitive CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
Losartan: (Minor) Caution is warranted when cobicistat is administered with losartan as there is a potential for increased losartan concentrations. Losartan is a substrate of CYP3A4; cobicistat is an inhibitor of CYP3A4. (Minor) Caution is warranted when darunavir is administered with losartan as there is a potential for elevated losartan concentrations. Losartan is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
Losartan; Hydrochlorothiazide, HCTZ: (Minor) Caution is warranted when cobicistat is administered with losartan as there is a potential for increased losartan concentrations. Losartan is a substrate of CYP3A4; cobicistat is an inhibitor of CYP3A4. (Minor) Caution is warranted when darunavir is administered with losartan as there is a potential for elevated losartan concentrations. Losartan is a substrate of CYP3A4; darunavir is an inhibitor of CYP3A4.
Lovastatin: (Contraindicated) Concomitant use of lovastatin with cobicistat is contraindicated due to the potential for myopathy, including rhabdomyolysis. Coadministration is expected to significantly increase lovastatin plasma concentrations. Lovastatin is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A. Coadministration with another strong CYP3A4 inhibitor increased lovastatin exposure by 11 to 36-fold. (Contraindicated) Concurrent use of lovastatin and anti-retroviral protease inhibitors is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with anti-retroviral protease inhibitors. Lovastatin is a substrate of CYP3A4 and anti-retroviral protease inhibitors are strong inhibitors of CYP3A4; therefore, coadministration may result in substantial increases in plasma concentrations of lovastatin.
Lumacaftor; Ivacaftor: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of cobicistat; avoid concurrent use if possible. If concomitant use of cobicistat is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when cobicistat is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking cobicistat, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking cobicistat. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Cobicistat is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of cobicistat and decrease its therapeutic efficacy. Although cobicistat is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of darunavir; avoid concurrent use if possible. If concomitant use of darunavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when darunavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking darunavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking darunavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Darunavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of darunavir and decrease its therapeutic efficacy. Although darunavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of cobicistat; avoid concurrent use if possible. If concomitant use of cobicistat is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when cobicistat is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking cobicistat, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking cobicistat. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Cobicistat is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of cobicistat and decrease its therapeutic efficacy. Although cobicistat is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of darunavir; avoid concurrent use if possible. If concomitant use of darunavir is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when darunavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking darunavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking darunavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Darunavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of darunavir and decrease its therapeutic efficacy. Although darunavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of cobicistat is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold. (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of darunavir is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Contraindicated) Coadministration of cobicistat (or cobicistat containing medications) with lurasidone is contraindicated due to the potential for serious or life-threatening reactions, such as CNS effects and extrapyramidal symptoms. The plasma concentrations of lurasidone may be elevated when administered concurrently with cobicistat. Cobicistat is a strong CYP3A4 inhibitor, while lurasidone is a sensitive CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lurasidone exposure by 9-fold. (Contraindicated) Concurrent use of lurasidone with darunavir is contraindicated. Lurasidone is primarily metabolized by CYP3A4; darunavir is a CYP3A4 inhibitor. Increased lurasidone plasma concentrations are expected when the drug is co-administered with inhibitors of CYP3A4.
Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and cobicistat due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold. (Major) Avoid concomitant use of lurbinectedin and darunavir due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold.
Macitentan: (Major) Avoid coadministration of macitentan with cobicistat due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
Macitentan; Tadalafil: (Major) Avoid coadministration of macitentan with cobicistat due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold. (Major) Avoid coadministration of tadalafil and cobicistat for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of cobicistat for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A. Potent inhibitors of CYP3A, such as cobicistat, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Maprotiline: (Major) The plasma concentrations of maprotiline may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Maprotiline serum concentration monitoring may be useful to guide dosage adjustments and prevent toxicity. Cobicistat is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate. (Major) The plasma concentrations of maprotiline may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Maprotiline serum concentration monitoring may be useful to guide dosage adjustments and prevent toxicity. Darunavir is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate.
Maraviroc: (Major) Coadministration of maraviroc (a substrate of CYP3A, P-gp, and OATP1B1) with cobicistat (a CYP3A4, P-gp, OATP1B1 inhibitor) may result in increased maraviroc concentrations. Reduce the dose of maraviroc when coadministered with cobicistat; coadministration is contraindicated in patients with CrCl less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with cobicistat (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily; children weighing 2 to 9 kg: use not recommended. (Major) Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors such as darunavir; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCL less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with darunavir (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily; children weighing 2 to 9 kg: use not recommended.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with cobicistat due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure and may decrease the plasma concentrations of cobicistat leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mavacamten is a substrate and moderate inducer of CYP3A and cobicistat is a substrate and strong inhibitor of CYP3A. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%. (Contraindicated) Mavacamten is contraindicated for use with darunavir due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure and may decrease plasma concentrations of darunavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mavacamten is a substrate and moderate inducer of CYP3A and darunavir is a substrate and strong inhibitor of CYP3A. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%.
Meclizine: (Moderate) The plasma concentrations of meclizine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP2D6 inhibitor, while meclizine is a CYP2D6 substrate.
Medroxyprogesterone: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with medroxyprogesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Darunavir is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure. (Moderate) The plasma concentrations of mefloquine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or neurophsychiatric effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and P-glycoprotein (P-gp) inhibitor, while mefloquine is a CYP3A4 and P-gp substrate.
Meloxicam: (Moderate) The plasma concentrations of meloxicam may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while meloxicam is a CYP3A4 substrate.
Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Repaglinide: (Moderate) Coadministration of repaglinide and cobicistat may increase plasma concentrations of repaglinide; if coadministration is necessary, repaglinide dosage adjustment may be required and an increased frequency of glucose monitoring is recommended. Cobicistat is a strong CYP3A4 inhibitor and an inhibitor of organic anion transporting polypeptide (OATP). Repaglinide is a CYP3A4 and OATP1B1 substrate. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold. (Moderate) Coadministration of repaglinide and protease inhibitors may increase or decrease glucose concentrations and increase repaglinide AUC; if coadministration is necessary, repaglinide dosage adjustment may be necessary and increased frequency of glucose monitoring is recommended. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are potent CYP3A4 inhibitors and inhibitors of OATP. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with cobicistat due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively. (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with darunavir due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A substrate; darunavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the saxagliptin AUC up to 3.7-fold. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Sitagliptin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Methadone: (Moderate) Coadministration of darunavir with methadone is expected to result in decreased methadone concentrations. Patients should be monitored for opiate abstinence syndrome; an increase in methadone dosage may be considered based on clinical response. (Moderate) The plasma concentrations of methadone may be elevated when administered concurrently with cobicistat. When initiating methadone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest methadone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on methadone, an adjustment of methadone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Methadone is metabolized primarily by the cytochrome P450 isoenzymes CYP2C19, CYP3A4, and CYP2B6, and to a lesser extent, by CYP2C9 and CYP2D6. Methadone also is a substrate of P-glycoprotein (P-gp). Cobicistat is an inhibitor of CYP3A4, CYP2D6, and P-gp.
Methamphetamine: (Moderate) The plasma concentrations of methamphetamine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP2D6 inhibitor, while methamphetamine is a CYP2D6 substrate. (Moderate) The plasma concentrations of methamphetamine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a CYP2D6 inhibitor, while methamphetamine is a CYP2D6 substrate.
Methohexital: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Methylergonovine: (Major) Avoid concomitant use of methylergonovine with cobicistat. Concomitant use may increase methylergonovine exposure and the risk for vasospasm which may lead to cerebral or peripheral ischemia. Methylergonovine is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Major) Avoid concomitant use of methylergonovine with darunavir. Concomitant use may increase methylergonovine exposure and the risk for vasospasm which may lead to cerebral or peripheral ischemia. Methylergonovine is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Methylprednisolone: (Moderate) Coadministration of methylprednisolone with cobicistat may cause elevated methylprednisolone serum concentrations, potentially resulting in Cushing's syndrome or adrenal suppression. Cobicistat is a CYP3A4 inhibitor, while methylprednisolone is a CYP3A4 substrate. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Monitor for corticosteroid-related adverse events if methylprednisolone is used with darunavir. Concurrent use may increase the exposure of methylprednisolone. Methylprednisolone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Other strong CYP3A inhibitors have been reported to decrease the metabolism of certain corticosteroids by up to 60%.
Metoclopramide: (Moderate) Caution is warranted when cobicistat is administered with metoclopramide as there is a potential for elevated metoclopramide and cobicistat concentrations. Metoclopramide is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
Metoprolol: (Moderate) A dose decrease may be needed for metroprolol when administered with darunavir/ritonavir as serum concentrations for metoprolol may be increased. Caution is warranted and clinical monitoring is recommended. (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; cobicistat is a weak CYP2D6 inhibitor.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) A dose decrease may be needed for metroprolol when administered with darunavir/ritonavir as serum concentrations for metoprolol may be increased. Caution is warranted and clinical monitoring is recommended. (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; cobicistat is a weak CYP2D6 inhibitor.
Mexiletine: (Major) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with darunavir. Concurrent use may result in elevated mexiletine plasma concentration. Mexiletine is a substrate for CYP2D6; darunavir is an inhibitor of this enzyme. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with cobicistat. Mexiletine is a substrate for CYP2D6; cobicistat is an inhibitor of this enzyme. Concurrent use may result in elevated mexiletine plasma concentration.
Midazolam: (Major) Protease inhibitors may increase midazolam concentrations; the risk for midazolam-related adverse effects varies by midazolam dosage form and route of administration. Oral midazolam use is contraindicated. Intranasal midazolam should be avoided when possible. Additional monitoring and a dosage reduction may be necessary with parenteral midazolam. Midazolam is a CYP3A substrate and protease inhibitors are CYP3A inhibitors. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation. (Major) Use of orally administered midazolam with cobicistat is contraindicated due to the risk for prolonged/increased sedation and respiratory depression. Midazolam is extensively metabolized by CYP3A4; cobicistat is a strong inhibitor of this enzyme. Concurrent use is expected to produce large increases in the plasma concentrations of midazolam. Elevations in midazolam concentrations may also be observed with the parenteral formulation of midazolam; however, this formulation may be administered with cobicistat if given in as setting with close clinical monitoring and appropriate medical management. Consider reducing the dose of parenteral midazolam.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and cobicistat due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone. (Major) Avoid the concomitant use of midostaurin and darunavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Mifepristone: (Major) Caution is advised when administering cobicistat with mifepristone because increased serum concentrations of either drug may occur. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with cobicistat should be done only when necessary, and in such cases the dose of mifepristone should be limited to a maximum dose of 900 mg per day. In a patient already receiving cobicistat, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with cobicistat is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with cobicistat is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with cobicistat is initiated in a patient already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with cobicistat is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and cobicistat are substrates and strong inhibitors of CYP3A4. (Major) Caution is advised when administering darunavir with mifepristone because increased serum concentrations of either drug may occur. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with darunavir should be done only when necessary, and in such cases the dose of mifepristone should be limited to a maximum dose of 900 mg per day. In a patient already receiving darunavir, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with darunavir is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with darunavir is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with darunavir is initiated in a patient already receiving 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with darunavir is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and darunavir are substrates and strong inhibitors of CYP3A4.
Miglitol: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Mirabegron: (Moderate) Caution is warranted when cobicistat is administered with mirabegron as there is a potential for elevated cobicistat concentrations. Mirabegron is a moderate CYP2D6 inhibitor. Cobicistat is a substrate of CYP2D6 and CYP3A4.
Mirtazapine: (Moderate) Concurrent administration of mirtazapine and darunavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4. (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with cobicistat is necessary. Mirtazapine is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of cobicistat is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure. (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of darunavir is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with cobicistat due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold. (Major) Avoid coadministration of mitapivat with darunavir due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
Mitotane: (Contraindicated) Coadministration of mitotane with cobicistat is contraindicated. Mitotane is a strong inducer of CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Contraindicated) Darunavir is contraindicated for use with mitotane due to potential decreased darunavir concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitotane is a strong CYP3A4 inducer and darunavir is a CYP3A4 substrate. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 16), the ratio of darunavir pharmacokinetic parameters was significantly affected as follows (where 1 = no change): Cmax, 0.44 (90% CI, 0.4 to 0.48) and AUC, 0.21 (90% CI, 0.19 to 0.23).
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and cobicistat. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions such as QT prolongation. Mobocertinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%. (Major) Avoid concomitant use of mobocertinib and darunavir. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions such as QT prolongation. Mobocertinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
Modafinil: (Major) Coadministration of cobicistat with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4. (Major) Coadministration of darunavir with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Darunavir is an inhibitor/substrate of CYP3A4.
Momelotinib: (Moderate) Monitor for an increase in momelotinib-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase momelotinib exposure. Momelotinib is an OATP1B1/3 substrate; cobicistat is an OATP1B1/3 inhibitor. Coadministration with another OATP1B1/1B3 inhibitor increased momelotinib exposure by 57%; exposure of its active M21 metabolite increased by 12%.
Mometasone: (Moderate) Coadministration of mometasone with cobicistat may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of mometasone with darunavir may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Morphine: (Moderate) The plasma concentrations of morphine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a P-glycoprotein (P-gp) inhibitor, while morphine is a P-gp substrate.
Morphine; Naltrexone: (Moderate) The plasma concentrations of morphine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a P-glycoprotein (P-gp) inhibitor, while morphine is a P-gp substrate.
Nafcillin: (Major) Caution is warranted when cobicistat is administered with nafcillin as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Cobicistat is a CYP3A4 substrate. (Major) Caution is warranted when darunavir is administered with nafcillin as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Darunavir is a CYP3A4 substrate.
Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with cobicistat. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a moderate P-gp inhibitor and strong CYP3A4 inhibitor. (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with darunavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4; darunavir is a strong CYP3A4 inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with cobicistat is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as cobicistat, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. (Contraindicated) Concomitant use of naloxegol with darunavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as darunavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Naloxone: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with cobicistat is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors. (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with darunavir is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and cobicistat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Naproxen; Esomeprazole: (Minor) Use caution when administering cobicistat and esomeprazole concurrently. Cobicistat is an inhibitor of CYP3A, and esomeprazole is partially metabolized by CYP3A. Coadministration of cobicistat with CYP3A substrates, such as esomeprazole, can theoretically increase esomeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Nateglinide: (Moderate) Concurrent administration of nateglinide with some protease inhibitors may result in elevated nateglinide plasma concentrations via inhibition of CYP2C9. Ritonavir may induce CYP2C9 leading to a reduction of nateglinide concentrations. Monitor blood glucose concentrations during coadministration as hypoglycemia or hyperglycemia could occur. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Monitor blood glucose concentrations during coadministration. Caution and close monitoring are advised if these drugs are administered together.
Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cobicistat. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cobicistat, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cobicistat. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cobicistat, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP.
Nefazodone: (Major) Nefazodone inhibits the metabolism of anti-retroviral protease inhibitors. Nefazodone has been used to treat depression in patients on these medications concurrently. However, the potential drug interactions with anti-retroviral agents indicate that it is essential to evaluate for appropriate dosing of both agents to avoid adverse effects of either the anti-retroviral or nefazodone treatment. (Moderate) Caution is warranted when cobicistat is administered with nefazodone as there is a potential for elevated nefazodone and cobicistat concentrations. Both nefazodone and cobicistat are substrates and strong inhibitors of CYP3A4.
Neratinib: (Major) Avoid concomitant use of cobicistat with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Major) Avoid concomitant use of darunavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Darunavir is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Darunavir is a strong CYP3A4 inhibitor. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as cobicistat. The plasma concentrations of cobicistat can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Cobicistat has been shown to be a strong CYP3A4 inhibitor, and may increase netupitant exposure. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
Nevirapine: (Contraindicated) Coadministration of nevirapine with regimens containing cobicistat and atazanavir are contraindicated; use of nevirapine with regimens containing cobicistat and darunavir are also not recommended. Nevirapine is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, while atazanavir are darunavir are CYP3A4 substrates. If these drugs are used together, the concentrations of nevirapine may increase and the concentrations of atazanavir, darunavir, and cobicistat may decrease; thereby, increasing the risk for nevirapine-associated adverse reactions and potentally decreasing the antiretroviral efficacy of atazanavir and darunavir. (Moderate) Monitor for an increase in nevirapine-related adverse reactions if coadministration with darunavir is necessary. Nevirapine is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A4 inhibitor may also increase nevirapine exposure.
Nicardipine: (Moderate) Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. (Moderate) Coadministration of cobicistat with nicardipine may result in elevated cobicistat serum concentrations. Cobicistat is a substrate of CYP3A4 and CYP2D6. Nicardipine is an inhibitor of CYP2D6 and CYP3A4.
Nicotine: (Minor) Caution is warranted when cobicistat is administered with nicotine as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nicotine is an inducer of CYP2D6; cobicistat is a CYP2D6 substrate.
NIFEdipine: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Nifedipine undergoes significant metabolism via CYP3A4 and increased plasma concentrations would be expected with coadministration. Cautious dose titration of calcium-channel blockers should be considered; the patient should be monitored for the proper clinical responses to calcium-channel blocker therapy. (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as nifedipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate reductions are advised.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and cobicistat. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If cobicistat is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and cobicistat is a substrate and a strong inhibitor of CYP3A4. (Major) Avoid the concomitant use of nilotinib and darunavir; increased plasma concentrations of either drug may occur. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If darunavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and darunavir is a sensitive substrate and strong inhibitor of CYP3A4.
Nimodipine: (Major) Avoid coadministration of nimodipine with cobicistat due to the risk of significant hypotension. If concomitant use is unavoidable, monitor blood pressure and reduce the dose of nimodipine as clinically appropriate. Nimodipine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Moderate) Anti-retroviral protease inhibitors are CYP3A4 inhibitors and may decrease the hepatic metabolism of nimodipine, leading to increased plasma concentrations of nimodipine. In addition, ritonavir and calcium channel blockers both prolong the PR interval and the manufacturer for ritonavir recommends caution during coadministration. Monitor therapeutic response and for adverse effects, such as hypotension. Decreased calcium-channel blocker doses may be warranted.
Nintedanib: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as cobicistat, may increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Cobicistat is a mild inhibitor of both P-gp and CYP3A4; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
Nirmatrelvir; Ritonavir: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and cobicistat due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase cobicistat exposure and the risk for cobicistat-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold. (Major) Avoid concomitant use of nirogacestat and darunavir due to the risk for increased nirogacestat exposure which may increase the risk for nirogacestat-related adverse effects. Concomitant use may also increase darunavir exposure and the risk for darunavir-related adverse effects. Nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor; darunavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with cobicistat due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Major) Avoid coadministration of nisoldipine with protease inhibitors due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Norethindrone: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
Norethindrone; Ethinyl Estradiol: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Norgestimate; Ethinyl Estradiol: (Major) Concurrent administration of cobicistat and norgestimate results in increased norgestimate serum concentrations. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is also the potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norgestimate have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norgestimate. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Norgestrel: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norgestrel have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
Nortriptyline: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations. (Moderate) Coadministration of darunavir and nortriptyline may result in increased nortriptyline plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope. Consider a lower dose of nortriptyline with concurrent use. Nortriptyline is metabolized by CYP2D6 and also partially metabolized by CYP3A4.
Olanzapine: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
Olanzapine; Fluoxetine: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Olanzapine; Samidorphan: (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
Olaparib: (Major) Avoid coadministration of olaparib with cobicistat due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after cobicistat is discontinued. Olaparib is a CYP3A substrate and cobicistat is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%. (Major) Avoid coadministration of olaparib with darunavir due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after darunavir is discontinued. Olaparib is a CYP3A substrate and darunavir is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and cobicistat is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and cobicistat may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If cobicistat is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and darunavir is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and darunavir may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If darunavir is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Olopatadine; Mometasone: (Moderate) Coadministration of mometasone with cobicistat may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of mometasone with darunavir may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and cobicistat. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold. (Major) Avoid concomitant use of omaveloxolone and darunavir. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole: (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concurrent use of rifabutin and cobicistat-containing antiretroviral regimens. Concomitant use may decrease cobicistat exposure which may reduce its efficacy and increase rifabutin exposure and risk of adverse effects. Rifabutin is a CYP3A substrate and moderate CYP3A inducer; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with darunavir is necessary. Avoid concurrent use of rifabutin and darunavir boosted with cobicistat. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with darunavir boosted with ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with darunavir increased the AUC of the active metabolite of rifabutin by 881%. (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Omeprazole; Sodium Bicarbonate: (Moderate) Coadministration of omeprazole and darunavir boosted with ritonavir may result in decreased omeprazole concentrations. Monitor patients receiving these drugs concurrently for reduced omeprazole efficacy and, if needed, consider increasing the dose of omeprazole up to a maximum of 40 mg per day. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Ondansetron: (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp) inhibitor. Ondansetron is a CYP3A4, CYP2D6, and P-gp substrate. (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6. Ondansetron is a CYP3A4 and CYP2D6, and substrate.
Oritavancin: (Major) Darunavir is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of darunavir may be reduced if these drugs are administered concurrently. (Major) Plasma concentrations and efficacy of cobicistat and/or the drugs that are boosted by cobicistat may be reduced if these drugs are administered concurrently with oritavancin. Cobicistat is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Cobicistat is a CYP3A4 inhibitor indicated to increase systemic exposure of other antiretrovirals.
Orlistat: (Major) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral protease inhibitors. Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Osilodrostat: (Major) Reduce the dose of osilodrostat by one-half during coadministration of cobicistat; concurrent use may increase osilodrostat exposure and the risk of osilodrostat-related adverse reactions. Osilodrostat is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Major) Reduce the dose of osilodrostat by one-half during coadministration of darunavir; concurrent use may increase osilodrostat exposure and the risk of osilodrostat-related adverse reactions. Osilodrostat is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor.
Osimertinib: (Moderate) Monitor for an increase in darunavir-related adverse reactions if coadministration with osimertinib is necessary. Darunavir may be a P-glycoprotein (P-gp) substrate; osimertinib is a P-gp inhibitor. Coadministration with drugs that inhibit P-gp may decrease the clearance of darunavir, resulting in increased plasma concentrations.
Ospemifene: (Moderate) Caution is warranted when darunavir is administered with ospemifene as there is a potential for elevated concentrations of ospemifene. Clinical monitoring for ospemifene adverse effects is recommended. Darunavir is an inhibitor of CYP3A4. (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with cobicistat is necessary. Ospemifene is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Oxcarbazepine: (Major) Coadministration of oxcarbazepine with regimens containing cobicistat and atazanavir or darunavir should be avoided. If these drugs are used together, significant decreases in the plasma concentrations of cobicistat, atazanavir and potentally darunavir may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Oxcarbazepine may increase the metabolism of darunavir and lead to decreased antiretroviral efficacy. Treatment failures have been reported with other protease inhibitors when carbamazepine was used concomitantly. If darunavir is added to anticonvulsant therapy, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or seizure control. Monitor serum concentrations.
Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with protease inhibitors is necessary. Oxybutynin is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with another strong CYP3A inhibitor increased mean oxybutynin plasma concentrations by approximately 2-fold. Concomitant use with moderate CYP3A inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown. (Moderate) The plasma concentrations of oxybutynin may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as increased anticholinergic activity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while oxybutynin is a CYP3A4 substrate.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like cobicistat can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If cobicistat is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of darunavir is necessary. If darunavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like darunavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If darunavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Paclitaxel: (Moderate) Plasma concentrations of paclitaxel may be elevated when administered concurrently with cobicistat. Cobicistat is a strong inhibitor of CYP3A4 and P-glycoprotein (P-gp) inhibitor, while paclitaxel is a CYP3A4 and P-gp substrate. Some experts state that pharmacokinetic interactions between paclitaxel and some CYP3A4 inhibitors do not appear to be clinically significant. However, combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with cobicistat is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. (Contraindicated) Concurrent use of pacritinib with darunavir is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Palbociclib: (Major) Avoid coadministration of cobicistat with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If cobicistat is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of cobicistat) to the dose used before initiation of cobicistat. Palbociclib is primarily metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. (Major) Avoid coadministration of darunavir with palbociclib; significantly increased palbociclib exposure may occur. Concentrations of darunavir may also increase. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If darunavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of darunavir) to the dose used before initiation of darunavir. Palbociclib is primarily metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively. Palbociclib is also a weak time-dependent inhibitor of CYP3A while darunavir is a sensitive CYP3A4 substrate.
Palonosetron: (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Darunavir is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
Palovarotene: (Major) Avoid concomitant use of palovarotene and cobicistat due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold. (Major) Avoid concomitant use of palovarotene and darunavir due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Panobinostat: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with cobicistat. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Paricalcitol: (Moderate) Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with both paricalcitol and cobicistat, or during periods of dose titration. If hypercalcemia occurs, the dose of paricalcitol should be reduced or withheld until these parameters are normalized. Paricalcitol is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor approximately doubled the exposure of paricalcitol. (Moderate) Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as protease inhibitors. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
Paroxetine: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4. (Moderate) Use caution when coadministering darunavir with paroxetine, as decreased SSRI concentrations may be seen. If paroxetine is coadministered with darunavir, carefully titrate the dose of paroxetine based on a clinical assessment of antidepressant response.
Pazopanib: (Major) Avoid coadministration of pazopanib and cobicistat due to the potential for increased exposure of both pazopanib and cobicistat. If concurrent use is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. Pazopanib is an inhibitor and substrate of CYP3A4; cobicistat is a strong CYP3A4 inhibitor and a CYP3A4 substrate. Concurrent use of pazopanib another strong CYP3A4 inhibitor increased the Cmax and AUC of pazopanib by 1.5-fold and 1.7-fold, respectively. In addition, pazopanib is a substrate/inhibitor of P-glycoprotein (P-gp), an inhibitor of CYP2D6, and a substrate of breast cancer resistance protein (BCRP). Cobicistat is an inhibitor of P-gp, BCRP, and a substrate/inhibitor of CYP2D6. (Major) Avoid coadministration of pazopanib and darunavir due to the potential for increased pazopanib exposure. If concurrent use is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. Pazopanib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased the Cmax and AUC of pazopanib by 1.5-fold and 1.7-fold, respectively.
Peginterferon Alfa-2a: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Peginterferon Alfa-2b: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Peginterferon beta-1a: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and cobicistat due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If cobicistat is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of cobicistat. Pemigatinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%. (Major) Avoid coadministration of pemigatinib and darunavir due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If darunavir is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of darunavir. Pemigatinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
Pentamidine: (Moderate) The plasma concentrations of pentamidine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as nephrotoxicity or electrolyte disorders, is recommended during coadministration. Cobicistat is a CYP2D6 inhibitor, while pentamidine is a CYP2D6 substrate. (Moderate) The plasma concentrations of pentamidine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as nephrotoxicity or electrolyte disorders, is recommended during coadministration. Darunavir is a CYP2D6 inhibitor, while pentamidine is a CYP2D6 substrate.
Pentazocine; Naloxone: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
Pentobarbital: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Perampanel: (Major) Caution is warranted when cobicistat is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Cobicistat is a CYP3A4 substrate and inhibitor. (Major) Caution is warranted when darunavir is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Darunavir is a CYP3A4 substrate and inhibitor.
Perindopril; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Perphenazine: (Moderate) The plasma concentrations of perphenazine may be elevated when administered concurrently with cobicistat. During coadministration, a reduction in the perphenazine dose may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP2D6, an isoenzyme responsible for the metabolism of perphenazine. These drugs used in combination may result in elevated perphenazine plasma concentrations, causing an increased risk for perphenazine-related adverse events. (Moderate) The plasma concentrations of perphenazine may be elevated when administered concurrently with darunavir. During coadministration, a reduction in the perphenazine dose may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Darunavir is an inhibitor of CYP2D6, an isoenzyme responsible for the metabolism of perphenazine. These drugs used in combination may result in elevated perphenazine plasma concentrations, causing an increased risk for perphenazine-related adverse events.
Perphenazine; Amitriptyline: (Major) Coadministration of darunavir and amitriptyline may result in increased amitriptyline plasma concentrations. Darunavir inhibits CYP3A. When administered as approved by the FDA (i.e., 'boosted' with ritonavir), further inhibition of CYP3A is seen and clinically significant drug interactions are expected with CYP3A substrates. Darunavir plus ritonavir is also an inhibitor of CYP2D6. Monitor for increased tricyclic antidepressant (TCA) adverse effects, such as nausea, dizziness, hypotension, and syncope, and consider a lower dose of amitriptyline with concurrent use. Amitriptyline is metabolized by CYP2D6 and also partially metabolized by CYP3A4. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations. (Moderate) The plasma concentrations of perphenazine may be elevated when administered concurrently with cobicistat. During coadministration, a reduction in the perphenazine dose may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is an inhibitor of CYP2D6, an isoenzyme responsible for the metabolism of perphenazine. These drugs used in combination may result in elevated perphenazine plasma concentrations, causing an increased risk for perphenazine-related adverse events. (Moderate) The plasma concentrations of perphenazine may be elevated when administered concurrently with darunavir. During coadministration, a reduction in the perphenazine dose may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Darunavir is an inhibitor of CYP2D6, an isoenzyme responsible for the metabolism of perphenazine. These drugs used in combination may result in elevated perphenazine plasma concentrations, causing an increased risk for perphenazine-related adverse events.
Pexidartinib: (Major) Avoid concomitant use of pexidartinib and cobicistat due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects; concomitant use may also decrease cobicistat plasma concentrations and reduce its efficacy. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If cobicistat is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of cobicistat. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%. (Major) Avoid concomitant use of pexidartinib and darunavir due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects; concomitant use may also decrease darunavir plasma concentrations and reduce its efficacy. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If darunavir is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of darunavir. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer; darunavir is a CYP3A substrate and strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%.
Phenobarbital: (Contraindicated) Coadministration of phenobarbital with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Contraindicated) Coadministration of phenobarbital with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Phentermine; Topiramate: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with topiramate as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Darunavir is a substrate of CYP3A4.
Phenytoin: (Contraindicated) Coadministration of phenytoin with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Closely monitor for decreased phenytoin efficacy during coadministration; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted. Coadministration of darunavir and phenytoin may result in decreased phenytoin concentrations. In drug interaction studies, the concentration of darunavir was unaffected during coadministration with phenytoin.
Pimavanserin: (Major) Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends that the pimavanserin dose be reduced to 10 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as darunavir. If these agents are used in combination, the patient should be carefully monitored for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation. (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with cobcistat is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
Pimozide: (Contraindicated) Coadministration of pimozide with cobicistat is contraindicated. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor; plasma concentrations of drugs extensively metabolized by these enzymes, such as pimozide, are expected to increase with concurrent use. Elevated plasma concentrations of pimozide have been associated with QT prolongation and serious cardiovascular adverse events including death due to torsade de pointes. (Contraindicated) Coadministration of pimozide with protease inhibitors is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Pimozide is thought to be metabolized through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Elevated pimozide plasma levels are probable when coadministered with CYP450 inhibitors, such as the protease inhibitors. Increased plasma concentrations of pimozide have been associated with QT prolongation and serious cardiovascular adverse events including death due to TdP.
Pioglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
Pioglitazone; Glimepiride: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
Pioglitazone; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
Pirfenidone: (Moderate) Caution is warranted when cobicistat is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a substrate/inhibitor of CYP3A4 and CYP2D6. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor. (Moderate) Caution is warranted when darunavir is administered with pirfenidone as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Darunavir is a substrate/inhibitor of CYP3A4 and a CYP2D6 inhibitor. Pirfenidone is a substrate/inhibitor of CYP2D6 and a CYP3A4 inhibitor.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and cobicistat due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of cobicistat use. Resume the previous dose of pirtobrutinib after cobicistat is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%. (Major) Avoid concomitant use of pirtobrutinib and darunavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of darunavir use. Resume the previous dose of pirtobrutinib after darunavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Pitavastatin: (Major) The plasma concentrations of pitavastatin may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as rhabdomyolysis or GI effects, is recommended during coadministration. Cobicistat is a organic anion transporting polypeptide (OATP) inhibitor, while pitavastatin is a OATP1B1 substrate.
Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of cobicistat due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%. (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of darunavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; darunavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Ponatinib: (Major) Avoid coadministration of ponatinib and cobicistat due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of cobicistat and consider alternative therapy. After cobicistat has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting cobicistat. Ponatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%. (Major) Avoid coadministration of ponatinib and darunavir due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of darunavir and consider alternative therapy. After darunavir has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting darunavir. Ponatinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Posaconazole: (Major) Caution is warranted when cobicistat is administered with posaconazole as there is a potential for elevated posaconazole and cobicistat concentrations. Posaconazole is a CYP3A4 inhibitor and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor of P-gp and a substrate of CYP3A4. (Moderate) Posaconazole and darunavir should be coadministered with caution due to an increased potential for adverse events. Both posaconazole and darunavir are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of darunavir. This complex interaction may cause alterations in the plasma concentrations of both posaconazole and darunavir, ultimately resulting in an increased risk of adverse events.
Pralsetinib: (Major) Avoid concomitant use of cobicistat and pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of pralsetinib to 200 mg once daily for patients taking a daily dose of 400 mg or 300 mg, and to 100 mg once daily for patients taking a daily dose of 200 mg. Pralsetinib is a CYP3A and P-gp substrate and cobicistat is a combined strong CYP3A and P-gp inhibitor. Coadministration with a combined strong CYP3A and P-gp inhibitor is predicted to increase the overall exposure of pralsetinib by 251%. (Major) Avoid concomitant use of darunavir with pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the daily dose of pralsetinib by 100 mg. Pralsetinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor is predicted to increase the overall exposure of pralsetinib by 122%.
Pramlintide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Pravastatin: (Major) The plasma concentrations of pravastatin may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as rhabdomyolysis or GI effects, is recommended during coadministration. Cobicistat is a organic anion transporting polypeptide (OATP) inhibitor, while pravastatin is a OATP1B1 substrate. (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with pravastatin. If treatment with darunavir is required, consider using an alternate HMG-CoA reductase inhibitor (such as pitavastatin or fluvastatin). When concurrent administration is unavoidable, initiate pravastatin at the lowest possible dose with gradual dose increases based on clinical response. Carefully monitor for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. When pravastatin is coadministered with darunavir (in the FDA approved dosage regimen), its AUC is increased by 81% and its Cmax is increased by 63%.
Prednisone: (Moderate) Coadministration of prednisone with cobicistat may cause elevated prednisone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, while prednisone is a CYP3A4 and P-gp substrate. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of prednisone with darunavir may cause elevated prednisone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Prednisone is a CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Primidone: (Contraindicated) Coadministration of primidone with cobicistat-containing regimens is contraindicated. Primidone is converted to phenobarbital, a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and cobicistat due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and cobicistat is a dual strong CYP3A and P-gp inhibitor. Concomitant use with other dual strong CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 3- to 4-fold. (Major) Avoid concomitant use of colchicine and darunavir due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg followed by 0.3 mg. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A substrate and darunavir is a strong CYP3A inhibitor.
Progesterone: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. The metabolism of progesterone may also be inhibited by cobicistat, a strong inhibitor of the CYP3A4 hepatic enzyme. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Moderate) Use caution if coadministration of darunavir with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Darunavir is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Promethazine: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
Promethazine; Dextromethorphan: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Promethazine; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
Propafenone: (Major) Coadministration of darunavir with propafenone should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of propafenone with cobicistat. Propafenone is a substrate for CYP3A4 and a substrate and inhibitor of CYP2D6; cobicistat is a substrate and inhibitor of both these enzymes. Concurrent use may result in elevated propafenone plasma concentration.
Propranolol: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as propranolol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advised.
Protriptyline: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Quazepam: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity. A decrease in the quazepam dose may be needed. (Moderate) The plasma concentrations of quazepam may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS depression, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while quazepam is a CYP3A4 substrate.
Quetiapine: (Major) Avoid concurrent use of quetiapine and darunavir. Darunavir may inhibit the CYP3A4 metabolism of quetiapine, resulting in elevated quetiapine plasma concentrations. If coadministration is required, reduce the quetiapine dose to one-sixth of the current dose and monitor for quetiapine-related adverse events. If darunavir is discontinued, increase the quetiapine dose by 6-fold. (Major) The plasma concentrations of quetiapine may be elevated when administered concurrently with cobicistat. The manufacturer of quetiapine recommends a quetiapine dose reduction to one-sixth the original dose during concurrent administration of CYP3A4 inhibitors, such as cobicistat. When cobicistat is discontinued, the dose should be increased by 6-fold.
Quinidine: (Major) Darunavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use. Coadministration of darunavir with quinidine should be done with extreme caution. Therapeutic monitoring of antiarrhythmic concentrations is recommended. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of quinidine with cobicistat. Quinidine is a substrate for CYP3A4 and P-glycoprotein (P-gp) and an inhibitor of CYP2D6 and P-gp; cobicistat is a substrate and inhibitor of both these enzymes and an inhibitor of P-gp. Concurrent use may result in elevated plasma concentration of both drugs.
Quinine: (Major) Anti-retroviral protease inhibitors can inhibit the metabolism of CYP3A4 substrates such as quinine. In theory, this interaction could potentially result in drug accumulation and quinine toxicity. Monitor for potential quinine toxicity and decrease quinine dosage if needed. (Moderate) Concurrent administration of cobicistat with quinine may elevate the concentrations of both drugs; thereby increasing the potential for adverse events. CYP3A4 is the major enzyme responsible for quinine metabolism. Other isoenzymes, including CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1, have some role in the metabolism of quinine; however, the extent of involvement of each of these differs depending on methodology used in the studies. Quinine is also a substrate of P-glycoprotein (P-gp) drug transporter. Cobicistat is a strong inhibitor of CYP3A4, and an inhibitor of CYP2D6 and P-gp. Quinine may inhibit CYP3A4, while cobicistat is metabolized by CYP3A4.
Quizartinib: (Major) Avoid concomitant use of cobicistat with quizartinib due to the risk of increased quizartinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of quizartinib to 26.5 mg for patients taking a daily dose of 53 mg, and to 17.7 mg for patients taking a daily dose of 35.4 mg or 26.5 mg; interrupt quizartinib therapy for the duration of the strong CYP3A inhibitor use for patients already taking a daily dose of 17.7 mg. Quizartinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%. (Major) Avoid concomitant use of darunavir with quizartinib due to the risk of increased quizartinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of quizartinib to 26.5 mg for patients taking a daily dose of 53 mg, and to 17.7 mg for patients taking a daily dose of 35.4 mg or 26.5 mg; interrupt quizartinib therapy for the duration of the strong CYP3A inhibitor use for patients already taking a daily dose of 17.7 mg. Quizartinib is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%.
Rabeprazole: (Minor) Use caution when administering cobicistat and rabeprazole concurrently. Cobicistat is an inhibitor of CYP3A and rabeprazole is partially metabolized by CYP3A. Co-administration can theoretically increase rabeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Ramelteon: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with cobicistat is necessary. Ramelteon is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%. (Moderate) The serum concentrations of ramelteon may increase when ramelteon is administered with strong CYP3A4 inhibitors like the anti-retroviral protease inhibitors. Because there is the potential for multiple CYPP450 enzyme inhibition interactions between protease inhibitors and ramelteon, caution should be used if these 2 drugs are coadministered. The patient should be monitored closely for toxicity even though ramelteon has a wide therapeutic index.
Ranitidine: (Minor) No change in darunavir concentrations was observed when coadministered with ranitidine. Darunavir can be coadministered with H2-blockers without any dosage adjustments.
Ranolazine: (Contraindicated) Coadministration of darunavir with ranolazine is contraindicated due to the potential for elevated ranolazine concentrations and the potential for serious and life threatening reactions, such as cardiac arrhythmias. Ranolazine is a CYP3A4 substrate; darunavir is an inhibitor of CYP3A4. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Coadministration of a strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. (Contraindicated) Concomitant use of ranolazine with cobicistat is contraindicated due to the potential for increased ranolazine plasma concentrations and therefore increased risk of QTc prolongation and possibly torsade de pointes. Ranolazine is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-gp. Coadministration of another strong CYP3A4 inhibitor increased plasma concentrations of ranolazine by 220%. Serum concentrations of cobicistat could also be increased as ranolazine is a CYP3A4 and CYP2D6 inhibitor, and cobicistat is a CYP3A4 and CYP2D6 substrate.
Red Yeast Rice: (Contraindicated) The risk of myopathy, including rhabdomyolysis, may be increased when anti-retroviral protease inhibitors are given in combination with most HMG-CoA reductase inhibitors. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, coadministration of red yeast rice with anti-retroviral protease inhibitors is not recommended.
Regorafenib: (Major) Avoid coadministration of regorafenib with cobicistat due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each. (Major) Avoid coadministration of regorafenib with darunavir due to increased plasma concentrations of regorafenib and decreased plasma concentrations of the active metabolites M-2 and M-5, which may lead to increased toxicity. Regorafenib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of M-2 and M-5 by 93% each.
Regular Insulin: (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Regular Insulin; Isophane Insulin (NPH): (Moderate) Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Relugolix: (Major) Avoid concomitant use of relugolix and oral cobicistat. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer cobicistat at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral cobicistat. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer cobicistat at least 6 hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with norethindrone have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norethindrone. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Darunavir is expected to increase the metabolism of estradiol. Women using estrogens for hormone replacement therapy should be monitored for signs of estrogen deficiency.
Repaglinide: (Moderate) Coadministration of repaglinide and cobicistat may increase plasma concentrations of repaglinide; if coadministration is necessary, repaglinide dosage adjustment may be required and an increased frequency of glucose monitoring is recommended. Cobicistat is a strong CYP3A4 inhibitor and an inhibitor of organic anion transporting polypeptide (OATP). Repaglinide is a CYP3A4 and OATP1B1 substrate. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold. (Moderate) Coadministration of repaglinide and protease inhibitors may increase or decrease glucose concentrations and increase repaglinide AUC; if coadministration is necessary, repaglinide dosage adjustment may be necessary and increased frequency of glucose monitoring is recommended. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are potent CYP3A4 inhibitors and inhibitors of OATP.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with cobicistat due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Concomitant use may also decrease cobicistat exposure and efficacy and may lead to the development of viral resistance. Repotrectinib is a CYP3A and P-gp substrate and moderate CYP3A inducer; cobicistat is a CYP3A substrate and strong CYP3A and P-gp inhibitor. Coadministration with another strong CYP3A and P-gp inhibitor increased repotrectinib exposure by 5.9-fold. (Major) Avoid coadministration of repotrectinib with darunavir due to increased repotrectinib exposure which may increase the risk for repotrectinib-related adverse effects. Concomitant use may also decrease darunavir exposure and efficacy which may increase the risk for viral resistance. Repotrectinib is a CYP3A substrate and moderate CYP3A inducer; darunavir is a CYP3A substrate and strong CYP3A inhibitor.
Resmetirom: (Major) Avoid concomitant use of resmetirom and cobicistat due to the risk for increased resmetirom exposure which may increase the risk for resmetirom-related adverse effects. Resmetirom is an OATP1B1/3 substrate and cobicistat is an OATP1B1/3 inhibitor.
Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as cobicistat, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate. (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as darunavir boosted with ritonavir, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
Revefenacin: (Major) Coadministration of revefenacin is not recommended with cobicistat because it could lead to an increase in systemic exposure of the active metabolite of revefenacin and an increased potential for anticholinergic adverse effects. The active metabolite of revefenacin is a substrate of OATP1B1 and OATP1B3; cobicistat is an inhibitor of OATP1B1 and OATP1B3.
Ribavirin: (Major) The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Ribociclib: (Contraindicated) Coadministration of ribociclib with cobicistat is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to cobicistat may also increase. Ribociclib is extensively metabolized by CYP3A4 and is a strong CYP3A4 inhibitor; cobicistat is a strong CYP3A4 inhibitor and CYP3A4 substrate. Coadministration of ribociclib with another strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. (Contraindicated) Coadministration of ribociclib with darunavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to darunavir may also increase. Ribociclib is extensively metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Additionally, ribociclib is a strong CYP3A4 inhibitor and darunavir is a CYP3A4 substrate.
Ribociclib; Letrozole: (Contraindicated) Coadministration of ribociclib with cobicistat is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to cobicistat may also increase. Ribociclib is extensively metabolized by CYP3A4 and is a strong CYP3A4 inhibitor; cobicistat is a strong CYP3A4 inhibitor and CYP3A4 substrate. Coadministration of ribociclib with another strong inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. (Contraindicated) Coadministration of ribociclib with darunavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to darunavir may also increase. Ribociclib is extensively metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Additionally, ribociclib is a strong CYP3A4 inhibitor and darunavir is a CYP3A4 substrate.
Rifabutin: (Major) Avoid concurrent use of rifabutin and cobicistat-containing antiretroviral regimens. Concomitant use may decrease cobicistat exposure which may reduce its efficacy and increase rifabutin exposure and risk of adverse effects. Rifabutin is a CYP3A substrate and moderate CYP3A inducer; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with darunavir is necessary. Avoid concurrent use of rifabutin and darunavir boosted with cobicistat. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with darunavir boosted with ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with darunavir increased the AUC of the active metabolite of rifabutin by 881%.
Rifampin: (Contraindicated) Coadministration of rifampin with cobicistat is contraindicated. Rifampin induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Contraindicated) Darunavir is contraindicated for use with rifampin. Rifampin induces CYP3A4, thereby decreasing the plasma concentrations and AUC of most protease inhibitors by roughly 90% and leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
Rifapentine: (Major) Avoid coadministration of protease inhibitors and rifapentine as concurrent use may result in significant decreases in the plasma concentrations of the antiretroviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and rifapentine is a strong CYP3A4 inducer. Additionally, HIV patients treated with rifapentine have a higher rate of TB relapse than those treated with other rifamycin-based regimens; an alternative agent is recommended. (Major) Coadministration of cobicistat and rifapentine is not recommended as concurrent use may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with cobicistat is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and cobicistat is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Moderate) Close clinical monitoring is advised when administering the combination of darunavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Darunavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Rimegepant: (Major) Avoid coadministration of rimegepant with cobicistat; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 and P-gp substrate and cobicistat is a strong CYP3A4 inhibitor and a P-gp inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold. (Major) Avoid coadministration of rimegepant with darunavir; concurrent use may significantly increase rimegepant exposure. Rimegepant is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold.
Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with cobicistat. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%. (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with darunavir. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Risperidone: (Major) Coadministration of risperidone, a CYP2D6 substrate, and cobicistat, a potent CYP2D6 inhibitor, may increase plasma concentrations of risperidone. When oral risperidone is given with a potent CYP2D6 inhibitor, the dose of risperidone should not exceed 8 mg/day PO in adults. When initiating therapy, titrate risperidone slowly. Upon discontinuation of the CYP2D6 inhibitor, the risperidone dose should be re-evaluated and increased if necessary. For the long-acting risperidone injection, the current adult dosage should be closely monitored when a potent CYP2D6 inhibitor is initiated or discontinued. An adjustment of the dose may be required. (Major) Decreased risperidone doses may be required when coadministered with darunavir/ritonavir. Darunavir/ritonavir is expected to decrease the hepatic metabolism of the risperidone, resulting in increased risperidone concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring.
Ritlecitinib: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with ritlecitinib as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with ritlecitinib. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4.
Rivaroxaban: (Major) Avoid concomitant administration of rivaroxaban and cobicistat; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Cobicistat is a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and another combined P-gp and strong CYP3A4 inhibitor increased the steady-state rivaroxaban AUC and Cmax by 150% and 60%, respectively. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with cobicistat is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of roflumilast by 99%.
Rolapitant: (Major) Use caution if cobicistat and rolapitant are used concurrently, and monitor for cobicistat-related adverse effects. Cobicistat is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
Romidepsin: (Moderate) Concurrent administration of romidepsin and darunavir may cause an increase in systemic romidepsin concentrations. Use caution when concomitant administration of these agents is necessary. Romidepsin is a substrate for CYP3A4. Darunavir is an inhibitor of CYP3A4. (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with cobicistat. Romidepsin is a CYP3A4 and P-gp substrate; cobicistat is a P-gp inhibitor and strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
Ropeginterferon alfa-2b: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Ropivacaine: (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate. (Moderate) The plasma concentrations of ropivacaine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as hypotension, bradycardia or GI effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while ropivacaine is a CYP3A4 substrate.
Rosiglitazone: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
Rosuvastatin: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with most HMG-CoA reductase inhibitors. When coadministered with darunavir (in the FDA approved dosage regimen), increased rosuvastatin concentrations are seen, although the drugs can be coadministered with careful monitoring when rosuvastatin is started at the lowest possible dose; gradual dose increases may be considered based on clinical response. The dose of rosuvastatin should not exceed 20 mg/day when given with darunavir boosted with cobicistat.
Rosuvastatin; Ezetimibe: (Major) Avoid concurrent administration of cobicistat and rosuvastatin. Taking these drugs together results in elevated rosuvastatin concentrations. If these drugs must be used together, use the lowest starting dose of rosuvastatin and carefully titrate while monitoring for adverse events (myopathy). Rosuvastatin is taken up into human hepatocytes mainly by organic anion transporting polypeptide (OATP)1B1 and OATP1B3. Cobicistat is an inhibitor of OATP. (Major) The risk of myopathy, including rhabdomyolysis, may be increased when darunavir is given in combination with most HMG-CoA reductase inhibitors. When coadministered with darunavir (in the FDA approved dosage regimen), increased rosuvastatin concentrations are seen, although the drugs can be coadministered with careful monitoring when rosuvastatin is started at the lowest possible dose; gradual dose increases may be considered based on clinical response. The dose of rosuvastatin should not exceed 20 mg/day when given with darunavir boosted with cobicistat.
Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with cobicistat in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of cobicistat in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. Ruxolitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Major) Reduce the ruxolitinib dosage when coadministered with darunavir in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of darunavir in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. Ruxolitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor.
Sacubitril; Valsartan: (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP.
Salmeterol: (Major) Avoid concomitant use of salmeterol with cobicistat. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Avoid concomitant use of salmeterol with darunavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
Saquinavir: (Contraindicated) Use of saquinavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Saquinavir is a substrate/inhibitor of CYP3A4 and P-glycoprotein (P-gp) substrate, cobicistat is a substrate/inhibitor of CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates. (Major) Coadministration of darunavir and saquinavir results in decreased exposure to darunavir (26% decrease in AUC). Appropriate dosage adjustments for this combination have not been established. Coadministration, with or without additional low-dose ritonavir, is not recommended.
Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with cobicistat due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively. (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with darunavir due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A substrate; darunavir is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the saxagliptin AUC up to 3.7-fold.
Secobarbital: (Major) Coadministration of darunavir with barbiturates is not recommended as there is a potential for decreased darunavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate; barbiturates as a class are CYP3A4 inducers. Most reports of clinically significant drug interactions occurring with the barbiturates have involved phenobarbital, a known potent CYP3A4 inducer.
Segesterone Acetate; Ethinyl Estradiol: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with segesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. (Major) Studies evaluating use of darunavir (boosted with either ritonavir or cobicistat) with ethinyl estradiol have not been conducted; therefore, an alternative (non-hormonal) method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethinyl estradiol. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with darunavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns. (Minor) Coadministration of segesterone and strong CYP3A4 inhibitors such as darunavir may increase the serum concentration of segesterone.
Selective serotonin reuptake inhibitors: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and cobicistat due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If cobicistat is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of cobicistat. Selpercatinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selpercatinib exposure by 133%. (Major) Avoid coadministration of selpercatinib and darunavir due to the risk of increased selpercatinib exposure which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Monitor ECGs for QT prolongation more frequently. If darunavir is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of darunavir. Selpercatinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selpercatinib exposure by 133%.
Selumetinib: (Major) Avoid coadministration of selumetinib and cobicistat due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If cobicistat is discontinued, resume the original selumetinib dose after 3 elimination half-lives of cobicistat. Selumetinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%. (Major) Avoid coadministration of selumetinib and darunavir due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If darunavir is discontinued, resume the original selumetinib dose after 3 elimination half-lives of darunavir. Selumetinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Semaglutide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Sertraline: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4. (Moderate) Use caution when coadministering darunavir with sertraline, as decreased SSRI concentrations may be seen. If sertraline is coadministered with darunavir, carefully titrate the dose of sertraline based on a clinical assessment of antidepressant response.
Sildenafil: (Major) Sildenafil is contraindicated for use with cobicistat when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold. (Major) Sildenafil is contraindicated for use with darunavir when used for pulmonary arterial hypertension (PAH). If used for erectile dysfunction, the dose of sildenafil should not exceed 25 mg in 48 hours with increased monitoring for adverse reactions during times of coadministration. Concurrent use is expected to substantially increase the sildenafil plasma concentrations and may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
Silodosin: (Contraindicated) Concurrent use of silodosin and cobicistat is contraindicated due to increased plasma concentrations of silodosin resulting in an increase of treatment-related adverse reactions. Cobicistat is a strong inhibitor of CYP3A4 and a P-glycoprotein (P-gp) inhibitor. Silodosin is a CYP3A4 and P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased silodosin exposure by 2.9-fold to 3.2-fold. (Major) Silodosin is extensively metabolized by hepatic cytochrome P450 3A4. In theory, drugs that inhibit CYP3A4 such as anti-retroviral protease inhibitors may cause significant increases in silodosin plasma concentrations.
Simvastatin: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (Contraindicated) The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Siponimod: (Moderate) Concomitant use of siponimod and cobicistat may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod. (Moderate) Concomitant use of siponimod and darunavir may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the exposure of siponimod.
Sirolimus: (Major) Avoid concomitant use of sirolimus and cobicistat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold. (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Sitagliptin: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Sodium Phenylbutyrate; Taurursodiol: (Major) Avoid coadministration of sodium phenylbutyrate; taurursodiol and cobicistat. Concomitant use may increase plasma concentrations of sodium phenylbutyrate; taurursodiol. Sodium phenylbutyrate; taurursodiol is an OATP1B3 substrate and cobicistat is an OATP1B3 inhibitor.
Sofosbuvir: (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
Sofosbuvir; Velpatasvir: (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP. (Moderate) Monitor for velpatasvir-related adverse events when administering velpatasvir with cobicistat. In an interaction study, use of these drugs together resulted in a 50% increase in velpatasvir exposure; however, because data have not correlated velpatasvir exposure with toxicity, no dose adjustments are recommended. Velpatasvir is a substrate of P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP1B1), Breast Cancer Resistance Protein (BCRP), and CYP3A; cobistat is an inhibitor of P-gp, OATP1B1, BCRP, and CYP3A4.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP. (Moderate) Monitor for velpatasvir-related adverse events when administering velpatasvir with cobicistat. In an interaction study, use of these drugs together resulted in a 50% increase in velpatasvir exposure; however, because data have not correlated velpatasvir exposure with toxicity, no dose adjustments are recommended. Velpatasvir is a substrate of P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP1B1), Breast Cancer Resistance Protein (BCRP), and CYP3A; cobistat is an inhibitor of P-gp, OATP1B1, BCRP, and CYP3A4.
Solifenacin: (Major) If coadministered with cobicistat, do not exceed a 5 mg daily dose of solifenacin in adults; do not exceed the initial starting dose in pediatric patients. The plasma concentrations of solifenacin may be elevated when administered concurrently with cobicistat. Monitor for excessive anticholinergic effects. Solifenacin is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased solifenacin exposure by 2.7-fold. (Major) If coadministered with darunavir, do not exceed a 5 mg daily dose of solifenacin in adults; do not exceed the initial starting dose in pediatric patients. The plasma concentrations of solifenacin may be elevated when administered concurrently with darunavir. Monitor for excessive anticholinergic effects. Solifenacin is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased solifenacin exposure by 2.7-fold.
Sonidegib: (Major) Avoid concomitant use of sonidegib and cobicistat as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Cobicistat is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively. (Major) Avoid concomitant use of sonidegib and darunavir as increased sonidegib plasma are expected, resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Darunavir is a strong CYP3A4 inhibitor and may significantly increase the level of the CYP3A4 substrate, sonidegib. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of sonidegib by 2.2-fold and 1.5-fold, respectively.
Sorafenib: (Moderate) Monitor for an increase in darunavir-related adverse reactions if coadministration with sorafenib is necessary. Darunavir may be a P-glycoprotein (P-gp) substrate. Sorafenib inhibits P-gp in vitro and may increase the concentrations of concomitantly administered drugs that are P-gp substrates.
Sotorasib: (Moderate) Coadministration of cobicistat with sotorasib may result in decreased plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Coadministration of darunavir with sotorasib may result in decreased plasma concentrations of darunavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Darunavir is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Sparsentan: (Major) Avoid concomitant use of sparsentan and cobicistat. Concomitant use may increase sparsentan exposure and the risk for sparsentan-related adverse effects. Sparsentan is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased sparsentan overall exposure by 174%. (Major) Avoid concomitant use of sparsentan and darunavir. Concomitant use may increase sparsentan exposure and the risk for sparsentan-related adverse effects. Sparsentan is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased sparsentan overall exposure by 174%.
St. John's Wort, Hypericum perforatum: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer. (Contraindicated) Coadministration of St. John's Wort, Hypericum perforatum with cobicistat is contraindicated. St. John's Wort induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. St. John's Wort in all forms, including teas, should be avoided.
Stiripentol: (Moderate) Consider a dose adjustment of darunavir when coadministered with stiripentol. Coadministration may alter plasma concentrations of darunavir resulting in an increased risk of adverse reactions and/or decreased efficacy. Darunavir is a sensitive CYP3A4 substrate. In vitro data predicts inhibition or induction of CYP3A4 by stiripentol potentially resulting in clinically significant interactions.
Streptogramins: (Moderate) Caution is warranted when cobicistat is administered with dalfopristin; quinupristin as there is a potential for elevated cobicistat concentrations. Quinupristin is a CYP3A4 inhibitor and cobicistat is substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with dalfopristin; quinupristin as there is a potential for elevated concentrations of darunavir. Quinupristin is a CYP3A4 inhibitor; darunavir is a substrate of CYP3A4.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if cobicistat must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like cobicistat can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If cobicistat is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil. (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if protease inhibitors must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of protease inhibitors is necessary. If protease inhibitors is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a CYP3A inhibitor like protease inhibitors can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If protease inhibitors is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulfonylureas: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Sunitinib: (Major) Avoid coadministration of cobicistat with sunitinib if possible due to increased sunitinib exposure, which may increase the risk of QT prolongation. If concomitant use is unavoidable, monitor the QT interval more frequently and consider reducing the daily dose of sunitinib to a minimum of 37.5 mg for patients with GIST or RCC, and to a minimum of 25 mg for patients with pNET. Sunitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%. (Major) Avoid coadministration of darunavir with sunitinib if possible due to increased sunitinib exposure, which may increase the risk of QT prolongation. If concomitant use is unavoidable, monitor the QT interval more frequently and consider reducing the daily dose of sunitinib to a minimum of 37.5 mg for patients with GIST or RCC, and to a minimum of 25 mg for patients with pNET. Sunitinib is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to sunitinib and its primary active metabolite by 51%.
Suvorexant: (Major) Coadministration of suvorexant and cobicistat is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold. (Major) Coadministration of suvorexant and darunavir is not recommended due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate. Darunavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
Tacrolimus: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentration if coadministration with darunavir is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Consider a tacrolimus dose reduction to 0.5 mg to 1 mg once per week when coadministered with a protease inhibitor. In one study, the tacrolimus half-life increased to 10.6 days in one patient and 20.6 days in another following coadministration of tacrolimus and another protease inhibitor combination. Up to 80% reductions in tacrolimus dosages and 7-fold increase in dosage intervals were needed when tacrolimus was coadministered with protease inhibitors in studies. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; darunavir is a strong CYP3A4 inhibitor. (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with cobicistat is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; cobicistat is a strong CYP3A4 inhibitor.
Tadalafil: (Major) Avoid coadministration of tadalafil and cobicistat for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of cobicistat for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A. Potent inhibitors of CYP3A, such as cobicistat, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of darunavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of darunavir therapy. Stop tadalafil at least 24 hours prior to starting darunavir. After at least 1 week of darunavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and darunavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if concomitant use of cobicistat is necessary. Concomitant use may increase talazoparib exposure. Talazoparib is a P-gp and BCRP substrate; cobicistat is a P-gp and BCRP inhibitor.
Talimogene Laherparepvec: (Major) Consider the risks and benefits of treatment with talimogene laherparepvec before administering acyclovir or other antivirals to prevent or manage herpetic infection. Talimogene laherparepvec is a live, attenuated herpes simplex virus that is sensitive to acyclovir; coadministration with antiviral agents may cause a decrease in efficacy.
Tamsulosin: (Major) Concurrent use of tamsulosin and cobicistat is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is metabolized by CYP3A4 and CYP2D6 hepatic enzymes. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. (Major) Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided.
Tasimelteon: (Moderate) Caution is recommended during concurrent use of tasimelteon and darunavir. Because tasimelteon is partially metabolized via CYP3A4, use with CYP3A4 inhibitors, such as darunavir, may increase exposure to tasimelteon with the potential for adverse reactions.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with cobicistat as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold. (Major) Avoid coadministration of tazemetostat with darunavir as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telmisartan; Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Temsirolimus: (Major) Avoid coadministration of cobicistat with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of cobicistat before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. (Major) Avoid coadministration of darunavir with temsirolimus due to increased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus); exposure to darunavir may also be increased. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. Allow a washout period of approximately 1 week after discontinuation of darunavir before increasing temsirolimus to its original dose. Temsirolimus is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not significantly affect temsirolimus exposure, but increased the AUC and Cmax of sirolimus by 3.1-fold and 2.2-fold, respectively. Darunavir is also a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use may lead to increased concentrations of darunavir.
Tenofovir Alafenamide: (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
Tenofovir Alafenamide: (Moderate) The plasma concentrations of tenofovir may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the drug transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transport protein (OATP1B1/1B3). Tenofovir alafenamide is a substrate for all three transporters.
Tenofovir Disoproxil Fumarate: (Moderate) Pharmacokinetic parameters (AUC, Cmax, Cmin) of tenofovir, PMPA are elevated when administered in combination with darunavir and ritonavir. The clinical significance of this interaction has not been established, and dosage adjustments are not recommended. Monitor the patients closely for tenofovir-related adverse events.
Terbinafine: (Moderate) Caution is advised when administering terbinafine with cobicistat. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of both drugs. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is an inhibitor of CYP2D6 and is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4. Cobicistat is a substrate of CYP2D6 and an inhibitor of CYP3A4. Monitor patients for adverse reactions if these drugs are coadministered. Topical terbinafine formulations would not be expected to interact. (Moderate) Due to the risk for terbinafine related adverse effects, caution is advised when coadministering darunavir. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may increase the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; darunavir is an inhibitor of this enzyme. Monitor patients for adverse reactions if these drugs are coadministered.
Tetrabenazine: (Moderate) The plasma concentrations of tetrabenazine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is a CYP2D6 inhibitor, while tetrabenazine is a CYP2D6 substrate.
Tezacaftor; Ivacaftor: (Major) If cobicistat and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If darunavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with cobicistat; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor/ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); cobicistat is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with darunavir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); darunavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Theophylline, Aminophylline: (Moderate) Caution is warranted when cobicistat is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor. (Moderate) Caution is warranted when darunavir is administered with theophylline; aminophylline as there is a potential for elevated theophylline concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Theophylline is a substrate of CYP3A4; darunavir is a CYP3A4 inhibitor.
Thiazolidinediones: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
Thioridazine: (Contraindicated) Cobicistat is a mild inhibitor of CYP2D6 and the use of thioridazine concomitantly with CYP2D6 inhibitors is contraindicated due to the possible risk of QT prolongation and subsequent arrhythmias, or other serious side effects, occurring from elevated serum concentrations of thioridazine. (Major) Decreased thioridazine doses may be required when coadministered with darunavir/ritonavir. Darunavir/ritonavir is expected to decrease the hepatic metabolism of the thioridazine, resulting in increased thioridizine concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and cobicistat if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; cobicistat is a strong CYP3A4 inhibitor. (Major) Avoid the concomitant use of thiotepa and darunavir if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; darunavir is a strong CYP3A4 inhibitor.
Tiagabine: (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate. (Moderate) The plasma concentrations of tiagabine may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while tiagabine is a CYP3A4 substrate.
Ticagrelor: (Major) Avoid coadministration of ticagrelor with cobicistat due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold. (Major) Avoid coadministration of ticagrelor with darunavir due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions. Ticagrelor is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by 7.32-fold.
Timolol: (Moderate) A dose decrease may be needed for timolol when administered with darunavir/ritonavir as serum concentrations for timolol may be increased. Caution is warranted and clinical monitoring is recommended. (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as timolol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advised.
Tinidazole: (Major) The plasma concentrations of tinidazole may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while tinidazole is a CYP3A4 substrate. (Moderate) The plasma concentrations of tinidazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while tinidazole is a CYP3A4 substrate.
Tipranavir: (Contraindicated) Use of tipranavir with cobicistat plus either atazanavir or darunavir is not recommended, as pharmacokinetic data are not available to provide appropriate dosage recommendations. Use of tipranavir with either atazanavir; cobicistat or darunavir; cobicistat may lead to loss of antiretroviral efficacy and development of resistance. Tipranavir is a substrate/inhibitor of CYP3A4, an inhibitor of CYP2D6, and a substrate of P-glycoprotein (P-gp). Cobicistat is a substrate/inhibitor of both CYP2D6 and CYP3A4 as well as an inhibitor of P-gp, and atazanavir and darunavir are CYP3A4 substrates.
Tirzepatide: (Moderate) New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with cobicistat is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%. (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with darunavir is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with cobicistat. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with cobicistat. Cobicistat is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold. (Major) A dosage reduction of tofacitinib is necessary if coadministered with darunavir. In patients receiving 5 mg or less twice daily, reduce to once daily dosing; in patients receiving 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving 22 mg once daily of the extended-release (XR) formulation, switch to 11 mg XR once daily; in patients receiving 11 mg XR once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib exposure is increased when coadministered with darunavir. Darunavir is a strong CYP3A4 inhibitor; tofacitinib is a CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Tolterodine: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with cobicistat. Concurrent use may increase tolterodine exposure. Cobicistat is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers. (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with darunavir. Concurrent use may increase tolterodine exposure. Darunavir is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Tolvaptan: (Contraindicated) The concomitant use of tolvaptan and cobicistat is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors. (Contraindicated) The concomitant use of tolvaptan and darunavir is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; darunavir is a strong inhibitor of CYP3A4. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
Topiramate: (Moderate) Caution is warranted when cobicistat is administered with topiramate as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Cobicistat is a substrate of CYP3A4. (Moderate) Caution is warranted when darunavir is administered with topiramate as there is a potential for decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Darunavir is a substrate of CYP3A4.
Topotecan: (Major) Avoid coadministration of cobicistat with oral topotecan due to increased topotecan exposure; cobicistat may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP); cobicistat is a P-gp and BCRP inhibitor. Following escalating doses of a dual inhibitor of BCRP and P-gp, the AUC of topotecan lactone and total topotecan increased by approximately 2.5-fold compared to topotecan alone. Coadministration of a dual P-gp/BCRP inhibitor with intravenous topotecan increased total topotecan exposure by 1.2-fold and exposure to topotecan lactone by 1.1-fold.
Toremifene: (Major) Avoid coadministration of cobicistat with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%. (Major) Avoid coadministration of darunavir with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner, and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with cobicistat due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone. (Major) Avoid the concomitant use of trabectedin with darunavir due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Tramadol: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. (Major) Concurrent use of tramadol with darunavir may decrease the CYP3A4 and CYP2D6 metabolism of tramadol; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Tramadol; Acetaminophen: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. (Major) Concurrent use of tramadol with darunavir may decrease the CYP3A4 and CYP2D6 metabolism of tramadol; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Trandolapril; Verapamil: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Complex interactions can be expected with coadministered with diltiazem or verapamil, as both are substrates and inhibitors of CYP3A4. (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as verapamil, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised.
Trazodone: (Major) Avoid coadministration of trazodone with cobicistat due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone. (Major) Avoid coadministration of trazodone with darunavir due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
Triamcinolone: (Moderate) Cobicistat may inhibit the CYP3A4 metabolism of triamcinolone, resulting in increased plasma triamcinolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving another strong CYP3A4 inhibitor with triamcinolone, resulting in systemic corticosteroid effects including, but not limited to, Cushing syndrome and adrenal suppression. Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Consider using an alternative treatment to triamcinolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). In some patients, a corticosteroid dose adjustment may be needed. If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal. (Moderate) Darunavir may inhibit the CYP3A4 metabolism of triamcinolone, resulting in increased plasma triamcinolone concentrations and reduced serum cortisol concentrations. There have been reports of clinically significant drug interactions in patients receiving another strong CYP3A4 inhibitor with triamcinolone, resulting in systemic corticosteroid effects including, but not limited to, Cushing syndrome and adrenal suppression. Consider the benefit-risk of concomitant use and monitor for systemic corticosteroid side effects. Consider using an alternative treatment to triamcinolone, such as a corticosteroid not metabolized by CYP3A4 (i.e., beclomethasone or prednisolone). In some patients, a corticosteroid dose adjustment may be needed. If corticosteroid therapy is to be discontinued, consider tapering the dose over a period of time to decrease the potential for withdrawal.
Triazolam: (Contraindicated) Coadministration of triazolam, a primary CYP3A4 substrate, with strong CYP3A4 inhibitors, such as cobicistat, is contraindicated by the manufacturer of triazolam due to the risk for increased and prolonged sedation and respiratory depression. Concurrent use is expected to produce large increases in systemic exposure to triazolam, with the potential for serious adverse effects. (Contraindicated) Coadministration of triazolam, a primary CYP3A4 substrate, with strong CYP3A4 inhibitors, such as protease inhibitors, is contraindicated by the manufacturer of triazolam due to the risk for increased and prolonged sedation and respiratory depression. Concurrent use is expected to produce large increases in systemic exposure to triazolam, with the potential for serious adverse effects.
Tricyclic antidepressants: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Trimipramine: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Tucatinib: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with tucatinib as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with tucatinib. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
Ubrogepant: (Contraindicated) Coadministration of ubrogepant and cobicistat is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor resulted in a 9.7-fold increase in the exposure of ubrogepant. (Contraindicated) Coadministration of ubrogepant and darunavir is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor resulted in a 9.7-fold increase in the exposure of ubrogepant.
Ulipristal: (Minor) Concomitant use of ulipristal and cobicistat may increase the plasma concentration of ulipristal resulting in an increased risk for ulipristal-related adverse events; however, this is not likely to be significant for single-dose emergency contraceptive use. Ulipristal is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ulipristal overall exposure by 5.9-fold and increased the overall exposure if ulipristal's active metabolite, monodemethyl-ulipristal acetate, by 2.4-fold. (Minor) Concomitant use of ulipristal and darunavir may increase the plasma concentration of ulipristal resulting in an increased risk for ulipristal-related adverse events; however, this is not likely to be significant for single-dose emergency contraceptive use. Ulipristal is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ulipristal overall exposure by 5.9-fold and increased the overall exposure if ulipristal's active metabolite, monodemethyl-ulipristal acetate, by 2.4-fold.
Umeclidinium: (Moderate) Caution is warranted when darunavir is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6.
Umeclidinium; Vilanterol: (Moderate) Caution is warranted when cobicistat is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Cobicistat is an inhibitor of CYP3A4, CYP2D6, and P-gp inhibitor. (Moderate) Caution is warranted when darunavir is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4 and CYP2D6. Darunavir is an inhibitor of CYP3A4 and CYP2D6.
Upadacitinib: (Major) During concomitant use of upadacitinib and cobicistat reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold. (Major) During concomitant use of upadacitinib and darunavir reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Valbenazine: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with cobicistat is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor, and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold. (Major) The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as darunavir. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Valproic Acid, Divalproex Sodium: (Major) Caution is warranted when cobicistat is administered with valproic acid as there is a potential for altered concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; cobicistat is a CYP3A4 substrate. (Major) Caution is warranted when darunavir is administered with valproic acid as there is a potential for altered concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Valproic acid is a weak inhibitor and inducer (in vitro) of CYP3A4; darunavir is a CYP3A4 substrate.
Valsartan: (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP.
Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP.
Vamorolone: (Major) Decrease the vamorolone dose to 4 mg/kg once daily (max: 200 mg) and monitor for adverse effects if concomitant use with cobicistat is necessary. Concomitant use may increase vamorolone exposure and the risk for vamorolone-related adverse effects. Vamorolone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased vamorolone overall exposure by 44%. (Major) Decrease the vamorolone dose to 4 mg/kg once daily (max: 200 mg) and monitor for adverse effects if concomitant use with darunavir is necessary. Concomitant use may increase vamorolone exposure and the risk for vamorolone-related adverse effects. Vamorolone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased vamorolone overall exposure by 44%.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with cobicistat due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 72-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10 to 16-fold. (Major) Do not use vardenafil orally disintegrating tablets with darunavir due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 72-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; darunavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and cobicistat; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with cobicistat cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%. (Major) Avoid the concomitant use of vemurafenib and darunavir; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with darunavir cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Venetoclax: (Major) Coadministration of cobicistat with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of cobicistat. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a CYP3A4 (strong) and P-gp inhibitor Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies, while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78% in a drug interaction study. (Major) Coadministration of darunavir with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose 2 to 3 days after discontinuation of darunavir. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day 1, 20 mg on day 2, 50 mg on day 3, then 100 mg/day starting on day 4. Venetoclax is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies.
Venlafaxine: (Moderate) Monitor for adverse effects when administering venlafaxine with cobicistat. There is a potential for elevated venlafaxine and cobicistat concentrations if these drugs are given together. Venlafaxine and cobicistat are substrates and inhibitors of CYP2D6. In addition, venlafaxine is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A4.
Verapamil: (Moderate) As darunavir is a CYP3A substrate and inhibitor, interactions with calcium-channel blockers may occur. Complex interactions can be expected with coadministered with diltiazem or verapamil, as both are substrates and inhibitors of CYP3A4. (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as verapamil, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate dose reductions are advised.
Vilazodone: (Major) Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, the manufacturer of vilazodone recommends that the daily dose not exceed 20 mg/day during concurrent use of a strong CYP3A4 inhibitor, such as darunavir. The original vilazodone dose can be resumed when the CYP3A4 inhibitor is discontinued. (Major) Do not exceed a vilazodone dose of 20 mg once daily if coadministration with cobicistat is necessary; the original dose of vilazodone can be resumed if cobicistat is discontinued. Vilazodone is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vilazodone exposure by 50%.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with cobicistat is necessary. Vinblastine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with darunavir is necessary. Vinblastine is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor.
Vincristine Liposomal: (Major) Avoid coadministration of vincristine with cobicistat due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
Vincristine: (Major) Avoid coadministration of vincristine with cobicistat due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Major) The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with cobicistat is necessary. Vinorelbine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with darunavir is necessary. Vinorelbine is a CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and cobicistat is contraindicated; concomitant use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold. (Contraindicated) Concomitant use of voclosporin and darunavir is contraindicated; concomitant use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and darunavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) The coadministration of darunavir with clarithromycin results in increased clarithromycin concentrations and decreased concentrations of the 14-hydroxy-clarithromycin metabolite. In patients with normal renal function, coadministration of these drugs is acceptable with no dosage adjustments. For patients with a creatinine clearance (CrCl) 30 to 60 ml/min, the dose of clarithromycin should be reduced by 50%; for patients with CrCl < 30 ml/min, the dose of clarithromycin should be reduced by 75%.
Vorapaxar: (Major) Avoid coadministration of vorapaxar with cobicistat due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known. (Moderate) Use caution during concurrent use of vorapaxar and darunavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with darunavir, a CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: (Major) Avoid concurrent use of voriconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increase plasma concentrations of cobicistat, atazanavir, and darunavir; effects on the voriconazole concentrations has not been determined. (Major) Coadministration of darunavir and voriconazole is not recommended unless the benefit outweighs the risk. Concurrent administration of darunavir with voriconazole has not been studied; however, there is the potential for a bi-directional inhibition between voriconazole and protease inhibitors. Additionally, administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%. Patients should be monitored for voriconazole toxicity and/or decreased antiretroviral efficacy during coadministration.
Voxelotor: (Moderate) Monitor for cobicistat-related adverse effects if coadministered with voxelotor as concurrent use may increase cobicistat exposure. Cobicistat is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. (Moderate) Monitor for increased darunavir-related adverse effects if coadministered with voxelotor. Concurrent use may result in increased plasma concentrations of darunavir. Darunavir is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with cobicistat is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. Cobicistat is a strong CYP3A4 inhibitor and the R-enantiomer of warfarin is a CYP3A4 substrate. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance. (Moderate) Monitor the INR and adjust the dose as necessary if warfarin is coadministered with darunavir. Concurrent use may increase the INR and the risk of bleeding. Darunavir is a CYP3A4 inhibitor and the R-enantiomer of warfarin is a 3A4 substrate. The S-enantiomer exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Zafirlukast: (Moderate) Caution is warranted when cobicistat is administered with zafirlukast as there is a potential for elevated concentrations of cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; cobicistat is a CYP3A4 substrate. (Moderate) Caution is warranted when darunavir is administered with zafirlukast as there is a potential for elevated concentrations of darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Zafirlukast inhibits CYP3A4; darunavir is a CYP3A4 substrate.
Zaleplon: (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as cobicistat, may decrease the clearance of zaleplon. Coadministration with a moderate CYP3A4 inhibitor increased zaleplon exposure by 20%. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability. (Moderate) Zaleplon is partially metabolized by CYP3A4, and concurrent use of strong CYP3A4 inhibitors, such as darunavir, may decrease the clearance of zaleplon. Routine dosage adjustments of zaleplon are not required. Dosage adjustments should be made on an individual basis according to efficacy and tolerability.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with cobicistat. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of cobicistat, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor. (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with darunavir. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of darunavir, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; darunavir is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor.
Zavegepant: (Major) Avoid concomitant use of zavegepant and cobicistat. Concomitant use may increase zavegepant exposure and the risk for zavegepant-related adverse effects. Zavegepant is an OATP1B3 substrate and cobicistat is an OATP1B3 inhibitor. Concomitant use with another OATP1B3 inhibitor increased zavegepant overall exposure by 2.3-fold.
Ziprasidone: (Major) The plasma concentrations of ziprasidone may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Darunavir is a CYP3A4 inhibitor, while ziprasidone is a CYP3A4 substrate. (Moderate) The plasma concentrations of ziprasidone may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as extrapyramidal symptoms and CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while ziprasidone is a CYP3A4 substrate.
Zolmitriptan: (Moderate) Caution is warranted when cobicistat is administered with zolmitriptan as there is a potential for elevated zolmitriptan concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Zolmitriptan is a substrate of CYP3A4; cobicistat is a CYP3A4 inhibitor. (Moderate) Caution is warranted when darunavir is administered with zolmitriptan as there is a potential for elevated zolmitriptan concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Zolmitriptan is a substrate of CYP3A4; darunavir is a CYP3A4 inhibitor.
Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with cobicistat is necessary. Zolpidem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%. (Moderate) Consider decreasing the dose of zolpidem if coadministration with protease inhibitors is necessary. Zolpidem is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
Zuranolone: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with cobicistat is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold. (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with darunavir is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and darunavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Mechanism of Action:-Darunavir: Darunavir inhibits HIV protease, an enzyme involved in the replication of HIV. It binds to the active site of HIV protease and inhibits the virus-specific processing of the viral gag-pol polyproteins in HIV infected cells, thus preventing formation of mature virions. During the later stages of the HIV growth cycle, the gag-pol gene products are first translated into polyproteins and become immature budding particles. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of a mature virion core and to activate reverse transcriptase for a new round of infection. Thus, protease is necessary for the production of mature virions. Protease inhibition renders the virus noninfectious. Because HIV protease inhibitors inhibit the HIV replication cycle after translation and before assembly, they are active in acutely and chronically infected cells, and in cells not normally affected by dideoxynucleoside reverse transcriptase inhibitors (i.e., monocytes and macrophages). Darunavir exhibits activity against both HIV-1 and HIV-2 strains. In cell culture, the EC50 (50% effective concentration) for these isolates ranges from 1.2 to 8.5 nM; however, the EC50 increases by a median factor of 5.4 in the presence of human serum.
-Cobicistat: Cobicistat is an inhibitor of CYP3A enzymes. It is used as a pharmacokinetic enhancer to increase the serum concentration of CYP3A substrates, such as darunavir. Cobicistat has no antiviral activity.
In vitro and in vivo HIV-1 isolates with reduced sensitivity to darunavir have been reported. An analysis of isolates from darunavir-resistant viruses has identified 22 mutations in the protease gene that encode for multiple amino acid substitutions; the most common substitutions are L10F, V32I, L33F, S37N, M46I, I47V, I50V, L63P, A71V, and I84V.
While cross-resistance among protease inhibitors has been observed, darunavir displays a less than 10-fold decreased susceptibility against 90% of HIV-1 isolates resistant to amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and/or tipranavir. Cross-resistance between darunavir and the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), the non-nucleoside reverse transcriptase inhibitors (NNRTIs), or the fusion inhibitor is unlikely because of the different viral targets involved.
Darunavir; cobicistat tablets are administered orally.
-Cobicistat: Cobicistat is extensively plasma protein bound (97% to 98%), with a mean blood to plasma ratio of 0.5. The majority of cobicistat metabolism is mediated by CYP3A enzymes with a minor amount of metabolism occurring via the CYP2D6 enzyme. Cobicistat is eliminated via the feces (86.2%) and urine (8.2%), with a terminal plasma half-life of approximately 4 hours.
-Darunavir: Darunavir is approximately 95% bound to plasma proteins, specifically alpha-1-acid glycoprotein (AAG). The primary route of metabolism is oxidative via CYP3A to inactive metabolites. In order to achieve effective plasma concentrations, the drug is coadministered (boosted) with a pharmacokinetic enhancer (i.e., ritonavir or cobicistat). These pharmacokinetic enhancers inhibit CYP3A metabolism, thereby increasing darunavir concentrations. In healthy volunteers, approximately 80% of a single dose (400 mg, with ritonavir 100 mg) is excreted in the feces, and approximately 14% is recovered in the urine. Unchanged darunavir accounted for approximately 41% and 8% of the administered dose in feces and urine, respectively. The terminal elimination half-life, when administered with cobicistat, is approximately 7 hours.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, P-gp, BCRP, MATE1, OATP1B1, and OATP1B3
Darunavir is a substrate and inhibitor of CYP3A4. Coadministration with CYP3A inducers may decrease darunavir plasma concentrations; coadministration with CYP3A inhibitors may increase plasma concentrations. Darunavir is also an inhibitor of CYP2D6.
Cobicistat is a significant substrate of CYP3A, with a minor amount being metabolized by CYP2D6. Cobicistat also inhibits both CYP3A and CYP2D6 and is an inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), human multidrug and toxic extrusion 1 (MATE1), organic anion transporter polypeptide (OATP1B1), and OATP1B3. Concomitant administration with CYP3A4 inducers may lead to a loss of virologic efficacy and possible resistance.
-Route-Specific Pharmacokinetics
Oral Route
In healthy subjects, the darunavir; cobicistat combination tablet produced darunavir exposures that were similar to those observed with the darunavir 800 mg tablet plus a cobicistat 150 mg tablet, administered as single entities. In another study, patients with HIV who were administered darunavir 800 mg with either 100 mg of ritonavir or 150 mg of cobicistat (single entities) produced similar darunavir exposures.
-Darunavir: When administered with cobicistat, the maximum plasma concentration of darunavir is achieved within approximately 4 to 4.5 hours. Administration with a high-fat meal increases the maximum plasma concentration (Cmax) and exposure (AUC) of darunavir by 127% and 70%, respectively.
-Cobicistat: When administered with darunavir, the maximum plasma concentration of cobicistat is achieved within approximately 4 to 5 hours. Administration with a high-fat meal does not alter the AUC of cobicistat.
-Special Populations
Hepatic Impairment
Darunavir; cobicistat has not been studied in patients with hepatic impairment and is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C).
-Darunavir: Darunavir is primarily metabolized by the liver. Steady-state pharmacokinetic parameters were similar after multiple dose administration (darunavir 600 mg, with ritonavir 100 mg, twice daily) to subjects with normal hepatic function (n = 16), mild hepatic impairment (Child-Pugh Class A, n = 8), and moderate hepatic impairment (Child-Pugh Class B, n = 8). Darunavir was not studied in patients with severe hepatic impairment; use in this patient population is not recommended. Hepatitis B and/or C co-infection does not appear to have a significant effect on the exposure of darunavir.
-Cobicistat: Cobicistat is primarily metabolized and eliminated by the liver. No clinically relevant differences in cobicistat pharmacokinetic parameters were observed between patients with moderate hepatic impairment (Child-Pugh Class B) and healthy patients. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied.
Renal Impairment
Use of darunavir; cobicistat has not been evaluated in patients with renal impairment.
-Darunavir: Darunavir pharmacokinetic parameters are not significantly affected in patients with moderate renal impairment (CrCl 30 to 60 mL/minute, n = 20). There are no pharmacokinetic data available in patients with severe renal impairment or end-stage renal disease. As darunavir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
-Cobicistat: In a pharmacokinetic study of cobicistat in uninfected subjects with severe renal impairment (CrCl less than 30 mL/minute), no clinically relevant differences in cobicistat pharmacokinetics were observed. The effect of cobicistat on serum creatinine was investigated in a trial of patients with normal renal function (estimated glomerular filtration rate [eGFR] 80 mL/minute or more; n = 12) and mild-to-moderate renal impairment (eGFR 50 to 79 mL/minute; n = 18). A statistically significant change in eGFR from baseline was observed after 7 days of treatment with cobicistat 150 mg in patients with normal renal function (-9.9 +/- 13.1 mL/minute) and mild-to-moderate renal impairment (-11.9 +/- 7 mL/minute). No statistically significant changes in eGFR were observed compared to baseline 7 days after cobicistat was discontinued. The actual GFR, as determined by the clearance of the probe drug iohexol, was not altered from baseline after treatment of cobicistat in these patients, indicating that cobicistat inhibits tubular secretion of creatinine without affecting the actual GFR.
Pediatrics
Available pharmacokinetic data for the different components of darunavir; cobicistat indicates that there were no clinically relevant differences in exposure between adults and pediatric patients weighing at least 40 kg. In pediatric patients aged 12 to 17 years, weighing at least 40 kg who received darunavir 800 mg coadministered with cobicistat 150 mg (n = 7), geometric mean darunavir Cmax values were similar between adults and pediatric patients (8.34 mcg/mL vs. 7.32 mcg/mL). Geometric mean darunavir AUC and Cmin values were 77.22 mcg x hr/mL and 0.68 mcg/mL, respectively. These values were 15% and 32% lower, with geometric mean ratios of 0.85 (90% CI: 0.64 to 1.13) and 0.68 (90% CI: 0.3 to 1.55) in pediatric patients relative to adults, respectively. These differences were not considered clinically significant. Geometric mean AUC, Cmax, and Cmin cobicistat values in pediatric patients were 8.33 mcg x hr/mL, 1.1 mcg/mL, and 0.02 mcg/mL, respectively. These values were comparable to those observed in adults.
Geriatric
Darunavir pharmacokinetic parameters in elderly patients (65 to 75 years) do not significantly differ compared to those in younger adult patients.
Gender Differences
There are no clinically important pharmacokinetic differences observed with darunavir or cobicistat due to gender.
Ethnic Differences
There are no clinically relevant pharmacokinetic differences observed with darunavir or cobicistat due to race.
Other
Pregnancy
-Darunavir: Pharmacokinetic studies involving women in the second and third trimesters of pregnancy have shown reductions in serum darunavir concentrations, ranging from 17% to 35%, with both the once- and twice-daily dosing regimens. However, patients receiving twice-daily dosing achieved trough concentrations (Cmin) that were similar to those observed during postpartum; whereas, those treated with once-daily dosing had Cmin values that were reduced by 32% to 50%. As a result, HIV guidelines recommend the use of the twice-daily dosing regimen during pregnancy. Darunavir has low placental transfer to the fetus. Data from 5 small studies (involving between 6 and 14 subjects each), found the mean ratio of darunavir concentration in cord blood to that in maternal delivery plasma ranged from 13% to 24%.
-Cobicistat: When compared to postpartum drug exposures (AUC), total AUC to cobicistat are significantly lower during the second and third trimesters of pregnancy [0.37 (0.17; 0.79) and 0.51 (0.33; 0.80), respectively]. Similarly, women in the second and third trimesters also have significantly lower trough concentrations [0.17 (0.05; 0.61) and 0.17 (0.04; 0.74), respectively].