Dolutegravir; rilpivirine is a two-drug combination of dolutegravir, a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), and rilpivirine, a HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI), is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components. Potential side effects associated with treatment include severe skin reactions, hepatotoxicity, and depressive disorders.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Administer orally with a meal.
Depressive disorders (including depressed mood, dysphoria, major depression, mood alteration, negative thoughts, suicidal ideation, and suicide attempts/completion) were reported by less than 2% of rilpivirine and dolutegravir recipients during clinical trials. These events were observed primarily in patients with a preexisting history of depression or other psychiatric illness. Health care providers are advised to counsel patients on the potential for severe depressive episodes. Instruct patients to seek immediate medical attention if depressive symptoms develop during treatment; treatment with dolutegravir; rilpivirine may need to be discontinued. Other psychiatric adverse events expereinced by less than 2% of rilpivirine treated patients included insomnia or sleep disorders, abnormal dreams, and anxiety.
Neurologic adverse events reported by recipients of dolutegravir; rilpivirine during clinical trials included headache (2%), dizziness (less than 2%), and somnolence or fatigue (less than 2%).
Pruritus and rash (unspecified) have been reported by less than 2% of patients receiving dolutegravir; rilpivirine during clinical trials. In addition, the dolutegravir component has been associated with hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Postmarketing use of rilpivirine has also been associated with the development of hypersensitivity and severe skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS). Immediately discontinue use and initiate appropriate therapy if signs or symptoms of a hypersensitivity reaction develop (e.g., severe rash or rash accompanied by fever, malaise, fatigue, muscle or joint pain, blisters or peeling skin, oral lesions, conjunctivitis, facial edema, hepatotoxicity, eosinophilia, angioedema, or difficulty breathing). Delay in stopping treatment may result in a life-threatening reaction.
During clinical trials, elevated hepatic enzymes were observed in up to 2% of patients receiving dolutegravir; rilpivirine. Specifically, Grade 2 (2.5 to 5 x ULN) and Grade 3 to 4 (more than 5 x ULN) increases in ALT occurred in 2% and less than 1% of drug recipients, respectively. In addition, less than 1% of patients developed both Grade 2 and Grade 3 to 4 increases in AST. Hyperbilirubinemia, defined as a Grade 2 (1.6 to 2.5 x ULN) increase in total bilirubin, was also reported in 2% of patients. Other hepatobiliary disorders experienced by less than 2% of dolutegravir; rilpivirine treated patients during clinical trials included hepatitis, cholecystitis, and cholelithiasis. Acute hepatic failure has been noted during postmarketing use. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
Adrenocortical insufficiency has been associated with rilpivirine treatment. Pooled data from clinical trials, showed patients treated with rilpivirine for 96 weeks developed a 0.69 mcg/dL (-1.12, 0.27) decrease in basal cortisol concentrations from baseline, compared to a 0.02 mcg/dL (-0.48, 0.44) decrease in the efavirenz group. In patients receiving rilpivirine, 7.3% developed an abnormal 250 micrograms ACTH stimulation test compared with 3.2% of patients receiving comparator (efavirenz). Despite the altered cortisol concentrations, no serious adverse events, deaths, or treatments discontinuations were attributed to adrenal insufficiency. The significance of the higher abnormal rate of 250 micrograms ACTH stimulation test in patients receiving rilpivirine is not known.
Dolutegravir and rilpivirine have been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 148 weeks. At weeks 48 and 148, the mean change from baseline was 0.093 mg/dL (range: -0.3 to 0.58 mg/dL) and 0.112 mg/dL (range: -0.24 to 0.81 mg/dL), respectively. Glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis, and renal impairment were reported by less than 2% of patients during clinical trials. In addition, nephrotic syndrome has been noted during postmarketing use of rilpivirine. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
Laboratory abnormalities observed in patients treated with dolutegravir; rilpivirine during clinical trials include hyperglycemia (more than 125 mg/dL; up to 4%), increased creatine kinase (at least 6-times ULN; up to 1%), increased lipase (more than 1.5-times ULN; 2% to 5%).
During clinical trials, 2% of patients receiving dolutegravir; rilpivirine experienced diarrhea or nausea. Other gastrointestinal adverse events experienced by less than 2% of drug recipients included abdominal pain, decreased appetite, flatulence, and vomiting. Weight gain has been reported with dolutegravir in postmarketing surveillance. Data from postmarketing trials found treatment-naive patients who started an integrase inhibitor-containing regimen (such as dolutegravir; rilpivirine) gained more weight than patients who began a protease inhibitor- or NNRTI-based regimen. Among agents within the integrase inhibitor class, the mean increase in weight from baseline was similar for dolutegravir and bictegravir (approximately 3.5 kg) and lower for elvitegravir. It is unknown whether the increase in weight is reversible upon treatment discontinuation.
Myositis was reported by less than 2% of patients receiving treatment with dolutegravir; rilpivirine during clinical trials. Cases of arthralgia and myalgia have been noted in postmarketing reports. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
Preliminary data from an ongoing observational study found an increased incidence of teratogenesis (specifically, neural tube birth defects involving the brain, spine and spinal cord) in infants born to mothers who received dolutegravir at the time of becoming pregnant or early in the 1st trimester. No cases have been identified in babies born to women starting dolutegravir later in pregnancy; however, the FDA continues to investigate the safety risk and will update the public when more information is available. The FDA advises health care providers and patients to report all side effects involving dolutegravir, or other medicines, to the FDA MedWatch Program.
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.
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.
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 dolutegravir; rilpivirine 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, and polymyositis) may also develop; the time to onset is variable and may occur months after treatment initiation.
Administration of dolutegravir; rilpivirine is contraindicated in patients with a history of dolutegravir or rilpivirine hypersensitivity. Cases of hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction (e.g., liver injury) have been reported with dolutegravir in less than 1% of drug recipients. In patients receiving rilpivirine, severe skin and hypersensitivity reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during the postmarketing period. In some cases these skin reactions were accompanied by constitutional findings (i.e., fever) or organ dysfunction (i.e., elevated hepatic enzymes). Health care providers are advised to closely monitor the clinical status of patients, including laboratory parameters and liver function tests, during treatment. Immediately discontinue dolutegravir; rilpivirine and initiate appropriate therapy in any patient who develops signs of hypersensitivity reactions, such as serious rash or rash accompanied with fever, fatigue, general malaise, muscle or joint aches, blisters or peeling of skin, oral lesions, conjunctivitis, hepatitis, facial edema, angioedema, difficulty breathing, or eosinophilia. Failure to promptly discontinue therapy may result in a life-threatening reaction.
Dolutegravir; rilpivirine is primarily metabolized and eliminated by the liver; however, no dosage adjustments are required for patients with mild or moderate hepatic impairment (Child-Pugh A or B). Use of the drug is not recommended for patients with severe hepatic disease (Child-Pugh C) as the effects have not been studied in this population. Cases of hepatotoxicity, including elevated hepatic enzymes, hepatitis, and acute liver failure, have been reported in patients receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or identifiable risk factors. Drug-induced liver injury requiring liver transplant has also been reported with dolutegravir-containing treatment regimens. Monitor patients for hepatotoxicity during treatment. In addition, cautious administration is also recommended for patients with hepatitis. In general, the safety profile in patients with hepatitis coinfection is similar to patients without hepatitis coinfection. However, as compared with data from patients without hepatitis, a higher percentage of patients with hepatitis experienced elevated AST and ALT. Patients who present with HIV infection should be screened for hepatitis B virus (HBV) coinfection to assure appropriate treatment. 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 requires 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.
Dolutegravir; rilpivirine plasma concentrations are decreased in patients with severe renal impairment and caution is advised when administering the drug to patients with renal failure (CrCl less than 30 mL/min) and/or end-stage renal disease. Use in this patient population may result in loss of therapeutic effect and development of resistance. In addition, due to greater frequency of decreased renal, hepatic, or cardiac function and of concomitant disease or other drug therapy, caution is advised when administering the drug to geriatric patients. Clinical studies of dolutegravir; rilpivirine did not include sufficient numbers of patients aged 65 years or over to determine whether they respond differently from younger patients.
Cautious administration is recommended for patients with hepatitis and HIV coinfection. In general, the safety profiles of patients with and without hepatitis C coinfection were similar; however, as compared with data from patients without hepatitis, a higher percentage of patients with hepatitis C experienced elevated AST and ALT. 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 a history of depression or other psychiatric illness may be at increased risk for psychiatric adverse events. During clinical trials, psychiatric orders were the most common adverse event leading to discontinuation of dolutegravir; rilpivirine (2% of patients receiving dolutegravir; rilpivirine vs. less than 1% on the current antiretroviral regimen). Depression, suicidal ideation, attempt, behavior, or completion was reported in less than 2% of patients. These events were observed primarily in patients with a pre-existing history of depression or other psychiatric illness. Prior to initiating therapy, inform patients of the potential for psychiatric adverse events. Additionally, instruct patients to seek immediate medical evaluation if severe depressive symptoms develop during therapy.
The safety and efficacy of dolutegravir; rilpivirine have not been established in neonates, infants, children, or adolescents.
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. Dolutegravir; rilpivirine as a complete regimen should not be initiated in pregnant patients or patients who are trying to become pregnant. However, it may be appropriate to continue use of this drug in patients who become pregnant while virally suppressed on this regimen. If dolutegravir; rilpivirine is used during pregnancy, frequently monitor viral loads (i.e., every 1 to 2 months). Data from the Antiretroviral Pregnancy Registry (APR), which includes 874 first trimester exposures to dolutegravir and 668 rilpivirine first trimester exposures, 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. The first trimester birth defect rates for dolutegravir and rilpivirine are 3.3% (95% CI: 2.2 to 4.7) and 2.1% (95% CI: 1.2 to 3.5), respectively. 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 delivery. 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 the 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 dolutegravir; rilpivirine; 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). Although there is no information regarding the effects of dolutegravir on breast-fed infants or milk production, available data show dolutegravir is found in breast milk at concentrations about 3% of those observed in maternal plasma. No data are available regarding the presence of rilpivirine in human breast milk. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.
Health care providers are advised to use caution when co-administering dolutegravir; rilpivirine with medications that have the potential to cause QT prolongation and torsade de pointes. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) administered to healthy subjects have resulted in prolongation of the QT interval. Further, use dolutegravir; rilpivirine with caution in patients with cardiac disease or other conditions that may increase the risk of QT prolongation including cardiac arrhythmias, congenital long QT syndrome, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances. Females, geriatric patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation.
Starting an integrase inhibitor-containing regimen (such as dolutegravir; rilpivirine) in treatment-naive patients has been associated with weight gain. Predictors and mechanisms for the increase in weight are still unclear; however, the weight gain appears to disproportionately affect females, Hispanic patients, and Black patients (particularly Black women). It is unknown whether the increase in weight is associated with significant cardio-metabolic risks or if it is reversible upon treatment discontinuation.
Counsel drug recipients about the potential reproductive risk and contraception requirements associated with dolutegravir therapy. Preliminary study data identified a small increase in the incidence of neural tube birth defects (involving the brain, spine, and spinal cord) in infants born to mothers who received dolutegravir around the time of conception (periconception exposure). If the decision to use dolutegravir in a woman of childbearing age is made, the patient should be informed of the potential risk for birth defects, undergo pregnancy testing before initiating treatment, and be counseled on contraception requirements (i.e., consistent use of effective birth control). Males of reproductive potential should also be counseled on contraception requirements.
HIV guidelines recommend consideration be given to avoiding use of rilpivirine-containing regimens in patients with pre-existing psychiatric illnesses or prolongation of the QTc interval.
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:
-Dolutegravir; rilpivirine may replace the current retroviral regimen in patients who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to either dolutegravir or rilpivirine.
-Dolutegravir; rilpivirine has not been studied in treatment-naive patients and is not recommended for use as initial therapy.
-Dolutegravir; rilpivirine as a complete regimen is not recommended for routine use in pregnant patients and patients who are trying to become pregnant. However, it may be appropriate to continue use of this drug in patients who become pregnant while virally suppressed on this regimen.
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 adults who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components:
-for the treatment of human immunodeficiency virus (HIV) infection without concurrent rifabutin:
Oral dosage:
Adults: 1 tablet (dolutegravir 50 mg; rilpivirine 25 mg) PO once daily with a meal.
-for the treatment of human immunodeficiency virus (HIV) infection with concurrent rifabutin:
Oral dosage:
Adults: 1 tablet (dolutegravir 50 mg; rilpivirine 25 mg) plus an additional 25 mg tablet of rilpivirine (total daily rilpivirine dose of 50 mg) PO once daily with a meal. When rifabutin coadministration is stopped, reduce rilpivirine dose to 25 mg PO once daily with a meal.
Maximum Dosage Limits:
-Adults
dolutegravir 50 mg/day PO; rilpivirine 25 mg/day PO; rilpivirine 50 mg/day PO when administered with rifabutin.
-Geriatric
dolutegravir 50 mg/day PO; rilpivirine 25 mg/day PO; rilpivirine 50 mg/day PO when administered with rifabutin.
-Adolescents
Safety and efficacy have not been established.
-Children
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
Dosage adjustments are not required for mild to moderate hepatic impairment (Child-Pugh Class A and B); dolutegravir or rilpivirine have not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Patients with Renal Impairment Dosing
Dosage adjustments are not required for mild to moderate renal impairment (CrCl greater than or equal to 30 mL/min). Use with caution in patients with severe renal impairment or end-stage renal disease (CrCl less than 30 mL/min) and monitor carefully for adverse effects.
*non-FDA-approved indication
Abrocitinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with abrocitinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and abrocitinib is a P-gp inhibitor.
Acalabrutinib: (Moderate) Coadministration of acalabrutinib and dolutegravir may increase dolutegravir exposure and increase the risk of dolutegravir toxicity. Acalabrutinib is an inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Dolutegravir is a BCRP transporter substrate in vitro.
Adagrasib: (Major) Avoid concomitant use of adagrasib and rilpivirine due to the potential for increased rilpivirine exposure and additive risk for QT/QTc prolongation and torsade de pointes (TdP). If use is necessary, monitor for rilpivirine-related adverse effects and consider taking additional steps to minimize the risk for QT prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring. Rilpivirine is a CYP3A substrate and adagrasib is a strong CYP3A inhibitor. Both medications have been associated with QT interval prolongation, however, the degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with adagrasib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor.
Adefovir: (Major) Patients who are concurrently taking adefovir (a nucleotide analog) with antiretrovirals (i.e., anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs)) 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).
Alfuzosin: (Moderate) Caution is advised when administering rilpivirine with alfuzosin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation and alfuzosin may also prolong the QT interval in a dose-dependent manner.
Alogliptin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Aluminum Hydroxide: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain magnesium and calcium which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing gastrointestinal medications such as magnesium hydroxide. The chemical structure of these GI drugs that contain polyvalent cations, such as magnesium hydroxide, can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing gastrointestinal medications such as magnesium hydroxide. The chemical structure of these GI drugs that contain polyvalent cations, such as magnesium hydroxide, can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain aluminum which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain magnesium which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Amiodarone: (Major) Concomitant use of amiodarone and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after drug discontinuation. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with amiodarone. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and amiodarone is a P-gp inhibitor.
Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with rilpivirine. Amisulpride causes dose- and concentration- dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Amobarbital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include rilpivirine.
Antacids: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Apalutamide: (Contraindicated) Concurrent use of apalutamide and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Apalutamide is a strong inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with apalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Apalutamide is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
Apomorphine: (Moderate) Exercise caution when administering apomorphine concomitantly with rilpivirine since concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure.
Aprepitant, Fosaprepitant: (Moderate) Use caution if dolutegravir and aprepitant, fosaprepitant are used concurrently and monitor for an increase in dolutegravir-related adverse effects for several days after administration of a multi-day aprepitant regimen. Dolutegravir is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and may increase plasma concentrations of dolutegravir. 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. (Moderate) Use caution if rilpivirine and aprepitant, fosaprepitant are used concurrently and monitor for an increase in rilpivirine-related adverse effects for several days after administration of a multi-day aprepitant regimen. Rilpivirine is 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 increase plasma concentrations of rilpivirine. 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: (Moderate) Concomitant use of aripiprazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Armodafinil: (Moderate) Close clinical monitoring is advised when administering armodafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathways of these drugs. Armodafinil is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with armodafinil; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Armodafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Arsenic Trioxide: (Major) Concurrent use of arsenic trioxide and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If possible, rilpivirine should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. TdP and complete atrioventricular block have been reported. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Artemether; Lumefantrine: (Major) Concurrent use of rilpivirine and artemether; lumefantrine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment. Administration of artemether; lumefantrine is associated with prolongation of the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as artemether. In addition to avoiding drug interactions, the potential for torsade de pointes (TdP) can be reduced by avoiding the use of QT prolonging drugs in patients at substantial risk for TdP. Consider ECG monitoring if rilpivirine must be used with or after artemether; lumefantrine treatment.
Asciminib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with asciminib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and asciminib is a BCRP inhibitor.
Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer of asenapine, the drug should be avoided in combination with other agents also known to have this effect. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as asenapine.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Aspirin, ASA; Omeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Atazanavir: (Moderate) Caution is warranted when atazanavir is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and uridine glucuronyltransferase (UGT). Atazanavir is an inhibitor of CYP3A4 and UGT1A1. (Moderate) Close clinical monitoring is advised when administering atazanavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Atazanavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Atazanavir; Cobicistat: (Moderate) Caution is warranted when atazanavir is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and uridine glucuronyltransferase (UGT). Atazanavir is an inhibitor of CYP3A4 and UGT1A1. (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 atazanavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Atazanavir is an inhibitor 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.
Atomoxetine: (Moderate) Concomitant use of atomoxetine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Azithromycin: (Major) Concomitant use of rilpivirine and azithromycin increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with rilpivirine. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Berotralstat: (Moderate) Coadministration of rilpivirine with berotralstat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and berotralstat is a moderate CYP3A4 inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with berotralstat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and berotralstat is a moderate CYP3A inhibitor.
Bexarotene: (Moderate) Close clinical monitoring is advised when administering bexarotene with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bexarotene is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with bexarotene; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Bexarotene is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at three times the maximum recommended dose.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at three times the maximum recommended dose.
Bosentan: (Moderate) Close clinical monitoring is advised when administering bosentan with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Bosentan is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with bosentan; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Bosentan is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Brigatinib: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with brigatinib is necessary. Dolutegravir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
Buprenorphine: (Major) Concomitant use of rilpivirine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Buprenorphine; Naloxone: (Major) Concomitant use of rilpivirine and buprenorphine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Butalbital; Acetaminophen: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Butalbital; Acetaminophen; Caffeine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Cabozantinib: (Minor) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with cabozantinib is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
Calcium Acetate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium Carbonate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir. (Moderate) Coadministration with famotidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of famotidine for at least 12 hours before and at least 4 hours after administering rilpivirine. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Calcium Carbonate; Simethicone: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Calcium Chloride: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium Gluconate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Calcium; Vitamin D: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Canagliflozin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Cannabidiol: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with cannabidiol. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and cannabidiol is a P-gp inhibitor.
Capivasertib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with capivasertib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a substrate of UGT1A1; capivasertib is an UGT1A1 inhibitor.
Capmatinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with capmatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and capmatinib is a P-gp inhibitor.
Carbamazepine: (Contraindicated) Coadministration of carbamazepine and rilpivirine is contraindicated due to the potential for loss of virologic response and possible resistance to rilpivirine or the class of non-nucleoside reverse transcriptase inhibitors (NNRTIs). Rilpivirine is a CYP3A4 substrate and carbamazepine is a strong CYP3A4 inducer. (Major) When possible, avoid concurrent use of dolutegravir with carbamazepine in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with carbamazepine. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and carbamazepine is an inducer of CYP3A4.
Carvedilol: (Moderate) Increased concentrations of dolutegravir may occur if it is coadministered with carvedilol; exercise caution. Carvedilol is a P-glycoprotein (P-gp) inhibitor and dolutegravir is a P-gp substrate in vitro.
Cenobamate: (Moderate) Close clinical monitoring is advised when administering cenobamate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Cenobamate is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Ceritinib: (Major) Avoid coadministration of ceritinib with rilpivirine if possible due to the risk of QT prolongation; plasma concentrations of rilpivirine may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Rilpivirine is a CYP3A4 substrate that has been associated with QT prolongation at supratherapeutic doses (75 to 300 mg per day). Ceritinib is a strong CYP3A4 inhibitor that has also been associated with concentration-dependent QT prolongation. Coadministration with another strong CYP3A4 inhibitor increased the AUC of rilpivirine by 1.49-fold. (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with ceritinib is necessary. Dolutegravir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor.
Chloramphenicol: (Moderate) Close clinical monitoring is advised when administering chloramphenicol with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Chloramphenicol is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Chloroquine: (Major) Avoid coadministration of chloroquine with rilpivirine due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Chlorpromazine: (Major) Concurrent use of chlorpromazine and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Phenothiazines have also been associated with QT prolongation and/or TdP. This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine.
Chromium: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Cimetidine: (Moderate) Coadministration with cimetidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of H2 receptor antagonist for at least 12 hours before and at least 4 hours after administering rilpivirine.
Ciprofloxacin: (Moderate) Concomitant use of ciprofloxacin and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Cisapride: (Contraindicated) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Because of the potential for torsades de pointes, use of cisapride with rilpivirine is contraindicated.
Citalopram: (Major) Concomitant use of rilpivirine and citalopram increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Clarithromycin: (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Class IA Antiarrhythmics: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Clobazam: (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with clobazam; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Clobazam is a weak inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Clofazimine: (Moderate) Concomitant use of clofazimine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Clozapine: (Moderate) Caution is advised when administering rilpivirine with clozapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death.
Cobicistat: (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) 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.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of promethazine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Codeine; Promethazine: (Moderate) Concomitant use of promethazine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Conivaptan: (Moderate) Coadministration of rilpivirine with conivaptan may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and conivaptan is a moderate CYP3A inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with conivaptan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and P-gp substrate and conivaptan is a moderate CYP3A and P-gp inhibitor.
Crizotinib: (Major) Avoid coadministration of crizotinib with rilpivirine due to the risk of QT prolongation; exposure to rilpivirine may also increase. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib is a moderate CYP3A inhibitor that has been associated with concentration-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation; rilpivirine is also a CYP3A4 substrate.
Dabrafenib: (Major) The concomitant use of dabrafenib and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Dabrafenib is a moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate.
Daclatasvir: (Moderate) Systemic exposure of dolutegravir, a P-glycoprotein (P-gp) substrate, may be increased when administered concurrently with daclatasvir, a P-gp inhibitor. Taking these drugs together could increase or prolong the therapeutic effects of dolutegravir; monitor patients for potential adverse effects.
Dalfampridine: (Moderate) Concurrent treatment with OCT2 inhibitors, such as dolutegravir, may cause increased exposure to dalfampridine. Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dolutegravir concurrently with dalfampridine should be considered against the risk of seizures.
Danazol: (Moderate) Close clinical monitoring is advised when administering danazol with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Danicopan: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with danicopan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and danicopan is a P-gp and BCRP inhibitor.
Dapagliflozin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Daridorexant: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with daridorexant. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and daridorexant is a P-gp inhibitor.
Darolutamide: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with darolutamide is necessary. Dolutegravir is a BCRP substrate and darolutamide is a BCRP inhibitor.
Darunavir: (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.
Darunavir; Cobicistat: (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.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (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.
Dasatinib: (Moderate) Caution is advised when administering rilpivirine with dasatinib as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Delavirdine: (Major) Coadministration of delavirdine and rilpivirine is not recommended. If they are coadministered, close clinical monitoring is advised due to the increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Delavirdine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Desflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Deutetrabenazine: (Moderate) Caution is advised when administering rilpivirine with deutetrabenazine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
Dexamethasone: (Contraindicated) Concurrent use of dexamethasone (more than 1 dose) and rilpivirine is contraindicated. Concomitant use may decrease the exposure and efficacy of rilpivirine leading to potential development of viral resistance. Rilpivirine is a CYP3A substrate and dexamethasone is an inducer of CYP3A4.
Dexlansoprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Dexmedetomidine: (Moderate) Concomitant use of dexmedetomidine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Dextromethorphan; Quinidine: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Didanosine, ddI: (Moderate) While no dosage adjustments are required, because didanosine, ddI is administered on an empty stomach and rilpivirine is given with food, do not give didanosine within at least two hours before or at least four hours after rilpivirine.
Diltiazem: (Moderate) Close clinical monitoring is advised when administering diltiazem with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Diltiazem is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Disopyramide: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Dofetilide: (Contraindicated) Concurrent use of dolutegravir with dofetilide is contraindicated due of the potential for serious and life-threatening adverse events, such as QT prolongation and torsade de pointes (TdP). Dolutegravir inhibits the renal organic cation transporter OCT2, dofetilide is eliminated via this transporter. If coadministered, the plasma concentration of dofetilide may increase. (Major) Coadministration of dofetilide and rilpivirine is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Dolasetron: (Moderate) Administer dolasetron with caution in combination with rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
Donepezil: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Dronedarone: (Contraindicated) Concurrent use of dronedarone and rilpivirine is contraindicated. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Duvelisib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with duvelisib. Coadministration may increase the exposure of dolutegravir. Dolutegravir is a CYP3A substrate; duvelisib is a moderate CYP3A inhibitor.
Efavirenz: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP). (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP). (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Coadministration of efavirenz and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Efavirenz is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. In addition, both drugs have been associated with prolongation of the QT interval. Use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP). (Major) When possible, avoid concurrent use of dolutegravir with efavirenz or efavirenz-containing products (e.g., efavirenz; emtricitabine; tenofovir) in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with efavirenz. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and efavirenz is an inducer of CYP3A4.
Elacestrant: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with elacestrant. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a substrate of BCRP and P-gp and elacestrant is a BCRP and P-gp inhibitor.
Elagolix: (Major) The concomitant use of elagolix and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Elagolix is a weak to moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with elagolix; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Elagolix is a weak to moderate inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Elagolix; Estradiol; Norethindrone acetate: (Major) The concomitant use of elagolix and rilpivirine may lead to decreased rilpivirine concentrations and loss of virologic response. Consider use of an alternative agent. If concomitant use of these agents is unavoidable, monitor patients for loss of rilpivirine efficacy. Elagolix is a weak to moderate CYP3A4 inducer and rilpivirine is a moderately sensitive CYP3A4 substrate. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with elagolix; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Elagolix is a weak to moderate inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Eliglustat: (Moderate) Caution is advised when administering rilpivirine with eliglustat as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (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) 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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (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) 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.
Empagliflozin; Linagliptin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Empagliflozin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Enasidenib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with enasidenib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Encorafenib: (Major) Concomitant use of encorafenib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP) and may decrease rilpivirine exposure and efficacy. Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Monitor for altered response to rilpivirine and consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Rilpivirine is a CYP3A substrate, encorafenib is a strong CYP3A inducer, and both medications have been associated with QT/QTc prolongation. Coadministration with another strong CYP3A inducer decreased rilpivirine exposure by approximately 80%. Although specific recommendations are unavailable for use with encorafenib, coadministration with other strong CYP3A inducers is contraindicated. (Moderate) Monitor for increased toxicity or decreased efficacy of dolutegravir if coadministered with encorafenib. Concurrent use may increase or decrease the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A and BCRP substrate and encorafenib is a strong CYP3A inducer and BCRP inhibitor. The net effect on dolutegravir exposure is unknown.
Entrectinib: (Major) Avoid coadministration of entrectinib with rilpivirine due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Enzalutamide: (Contraindicated) Concurrent use of enzalutamide and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Enzalutamide is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with enzalutamide; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Enzalutamide is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
Erdafitinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with erdafitinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and erdafitinib is a P-gp inhibitor.
Eribulin: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as eribulin. ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
Ertugliflozin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Erythromycin: (Major) Close clinical monitoring is advised when administering erythromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events, including QT prolongation. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Erythromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as erythromycin.
Escitalopram: (Moderate) Concomitant use of escitalopram and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Eslicarbazepine: (Contraindicated) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. CYP3A4 is primarily responsible for the metabolism of rilpivirine. The related anticonvulsants, carbamazepine and oxcarbazepine are contraindicated in combination with rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. Although not specifically mentioned by the manufacturer of rilpivirine, it may be prudent to avoid coadministration of eslicarbazepine and rilpivirine given the potential for an interaction based on the pharmacokinetic parameters of the drugs.
Esomeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Etrasimod: (Moderate) Concomitant use of etrasimod and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. Etrasimod has a limited effect on the QT/QTc interval at therapeutic doses but may cause bradycardia and atrioventricular conduction delays which may increase the risk for TdP in patients with a prolonged QT/QTc interval.
Etravirine: (Major) Coadministration of dolutegravir with etravirine should be avoided, unless also administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. When administered with etravirine (a CYP3A4 inducer), the plasma concentration of dolutegravir (a CYP3A4 substrate) is significantly reduced; however, this effect is diminished by the presence of one of the above mentioned protease inhibitors. (Major) Coadministration of etravirine and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. If they are coadministered, close clinical monitoring is advised due to the potential for rilpivirine treatment failure. Predictions about the interaction can be made based on metabolic pathways. Etravirine is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Famotidine: (Moderate) Coadministration with famotidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of famotidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
Fedratinib: (Moderate) Monitor for increased rilpivirine adverse effects if administered with fedratinib. Coadministration may increase rilpivirine exposure. Rilpivirine is a CYP3A4 substrate; fedratinib is a moderate CYP3A4 inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with fedratinib. Coadministration may increase the exposure of dolutegravir. Dolutegravir is a CYP3A substrate; fedratinib is a moderate CYP3A inhibitor.
Ferric Maltol: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Fexinidazole: (Major) Concomitant use of fexinidazole and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with rilpivirine as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Flecainide: (Major) Concomitant use of rilpivirine and flecainide increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Fluconazole: (Contraindicated) Concurrent use of fluconazole and rilpivirine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Fluconazole is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of rilpivirine. These drugs used in combination may result in elevated rilpivirine plasma concentrations, causing an increased risk for adverse events, such as QT prolongation. Additionally, fluconazole has been associated with prolongation of the QT interval; do not use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as rilpivirine.
Fluoxetine: (Moderate) Concomitant use of fluoxetine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Fluphenazine: (Minor) Caution is advised when administering rilpivirine with fluphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Fluphenazine is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Flutamide: (Moderate) Close clinical monitoring is advised when administering flutamide with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Flutamide is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. In addition, fluvoxamine is a moderate inhibitor of CYP3A4 and rilpivirine is a CYP3A4 substrate. Coadministration may result in increased rilpivirine plasma concentrations.
Fosamprenavir: (Major) Avoid concurrent use of dolutegravir and fosamprenavir boosted with ritonavir in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For INSTI-naive adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with fosamprenavir/ritonavir. Use of these drugs together results in decreased dolutegravir plasma concentrations. (Moderate) Coadministration of rilpivirine with fosamprenavir may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and fosamprenavir is a moderate CYP3A inhibitor.
Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as rilpivirine. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosphenytoin: (Contraindicated) Concurrent use of phenytoin or fosphenytoin and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenytoin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Avoid concurrent use of dolutegravir with phenytoin or fosphenytoin, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenytoin is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Fostamatinib: (Moderate) Monitor for dolutegravir toxicities that may require dolutegravir dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a CYP3A4, BCRP, or P-gp substrate may increase the concentration of the CYP3A4, BCRP, or P-gp substrate. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a CYP3A4 and BCRP inhibitor; dolutegravir is a substrate for CYP3A4, BCRP, and P-gp. Coadministration of fostamatinib with a sensitive CYP3A4 substrate increased the substrate AUC by 64% and Cmax by 113%. Coadministration of fostamatinib with another BCRP substrate increased the substrate AUC by 95% and Cmax by 88%. Coadministration of fostamatinib with another P-gp substrate increased the substrate AUC by 37% and Cmax by 70%.
Fostemsavir: (Moderate) Caution is advised when administering rilpivirine with fostemsavir due to the potential for QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with fostemsavir. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and fostemsavir is a BCRP inhibitor.
Futibatinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with futibatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP and P-gp substrate and futibatinib is a P-gp and BCRP inhibitor.
Gemifloxacin: (Moderate) Caution is advised when administering rilpivirine with gemifloxacin as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and rilpivirine together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Gilteritinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with gilteritinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and rilpivirine is necessary. Gilteritinib has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Glasdegib: (Major) Avoid coadministration of glasdegib with rilpivirine due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Glipizide; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Glyburide; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
Granisetron: (Moderate) Use granisetron with caution in combination with rilpivirine due to the risk of QT prolongation. Granisetron has been associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Grapefruit juice: (Moderate) Close clinical monitoring is advised when administering grapefruit juice with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Grapefruit juice is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Halogenated Anesthetics: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Haloperidol: (Moderate) Caution is advised when administering rilpivirine with haloperidol as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
Hydroxychloroquine: (Major) Concomitant use of rilpivirine and hydroxychloroquine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Hydroxyzine: (Moderate) Concomitant use of hydroxyzine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Ibuprofen; Famotidine: (Moderate) Coadministration with famotidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of famotidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with dolutegravir, a CYP3A substrate, as dolutegravir toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. (Moderate) Coadministration of rilpivirine with idelalisib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and idelalisib is a strong CYP3A inhibitor.
Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Imatinib: (Moderate) Close clinical monitoring is advised when administering imatinib, STI-571 with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Imatinib is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Indinavir: (Moderate) Close clinical monitoring is advised when administering indinavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Indinavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with rilpivirine due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Interferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents 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.
Interferon Alfa-n3: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents 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.
Interferon Beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents 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.
Interferon Beta-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents 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.
Interferon Gamma-1b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents 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.
Interferons: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents 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.
Iron Salts: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Iron: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with dolutegravir may result in increased serum concentrations of dolutegravir. Dolutegravir is a substrate of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp); isavuconazole, the active moiety of isavuconazonium, is an inhibitor of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are used together. (Moderate) Concomitant use of isavuconazonium with rilpivirine may result in increased serum concentrations of rilpivirine. Rilpivirine is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Concurrent use of rifampin and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifampin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) When possible, avoid concurrent use of dolutegravir with rifampin in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with rifampin. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and rifampin is an inducer of CYP3A4.
Isoniazid, INH; Rifampin: (Contraindicated) Concurrent use of rifampin and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifampin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) When possible, avoid concurrent use of dolutegravir with rifampin in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with rifampin. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and rifampin is an inducer of CYP3A4.
Itraconazole: (Moderate) Caution is advised when administering itraconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to itraconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and itraconazole, a strong CYP3A4 inhibitor, are both associated with QT prolongation; rilpivirine dosage adjustments are not recommended. In addition, concurrent use of rilpivirine decreased exposure to another azole antifungal. A similar interaction may occur with itraconazole. (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministered with itraconazole. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is an in vitro substrate of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); itraconazole inhibits both P-gp and BCRP.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with rilpivirine due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Ketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and rilpivirine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of rilpivirine, further increasing the risk for adverse effects. Rilpivirine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
Lansoprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with rilpivirine. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Lasmiditan: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with lasmiditan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and lasmiditan is a P-gp inhibitor.
Lefamulin: (Major) Avoid coadministration of lefamulin with rilpivirine as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Lenacapavir: (Moderate) Coadministration of rilpivirine with lenacapavir may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with lenacapavir. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A, P-gp, and BCRP substrate and lenacapavir is a moderate CYP3A, P-gp, and BCRP inhibitor.
Leniolisib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with leniolisib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and leniolisib is a BCRP inhibitor.
Lenvatinib: (Major) Avoid coadministration of lenvatinib with rilpivirine due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of dolutegravir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Dolutegravir is partially metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. (Moderate) A clinically relevant increase in the plasma concentration of rilpivirine may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Rilpivirine is primarily metabolized by CYP3A4. 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.
Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
Levofloxacin: (Moderate) Concomitant use of levofloxacin and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Levoketoconazole: (Contraindicated) Avoid concomitant use of ketoconazole and rilpivirine due to an increased risk for torsade de pointes (TdP) and QT/QTc prolongation. Concomitant use may also increase the exposure of rilpivirine, further increasing the risk for adverse effects. Rilpivirine is a CYP3A substrate and ketoconazole is a strong CYP3A inhibitor.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Linagliptin; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Lithium: (Moderate) Concomitant use of lithium and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with rilpivirine due to the potential for additive QT prolongation. Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of torsade de pointes. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Lonafarnib: (Moderate) Coadministration of rilpivirine with lonafarnib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with lonafarnib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-gp substrate and lonafarnib is a P-gp and strong CYP3A4 inhibitor.
Loperamide: (Moderate) Caution is advised when administering rilpivirine with loperamide as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Loperamide; Simethicone: (Moderate) Caution is advised when administering rilpivirine with loperamide as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest.
Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with rilpivirine due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Lorlatinib: (Moderate) Close clinical monitoring is advised when administering lorlatinib with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Lorlatinib is a moderate CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with lorlatinib. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate as well as a substrate of P-glycoprotein (P-gp). Lorlatinib is a moderate CYP3A4 inducer and a P-gp inducer.
Lumacaftor; Ivacaftor: (Contraindicated) Concomitant use of lumacaftor; ivacaftor and rilpivirine is contraindicated, as significant decreases in rilpivirine plasma concentrations may occur. This may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Rilpivirine is primarily metabolize by CYP3A, and lumacaftor is a strong CYP3A inducer. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with lumacaftor; ivacaftor; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Dolutegravir is partially metabolized by CYP3A and, in vitro, is a substrate for the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp.
Lumacaftor; Ivacaftor: (Contraindicated) Concomitant use of lumacaftor; ivacaftor and rilpivirine is contraindicated, as significant decreases in rilpivirine plasma concentrations may occur. This may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Rilpivirine is primarily metabolize by CYP3A, and lumacaftor is a strong CYP3A inducer. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with lumacaftor; ivacaftor; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Dolutegravir is partially metabolized by CYP3A and, in vitro, is a substrate for the P-glycoprotein (P-gp) drug transporter. Lumacaftor is a strong CYP3A inducer; in vitro data suggest lumacaftor; ivacaftor may also induce and/or inhibit P-gp.
Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as rilpivirine. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Magnesium Citrate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing laxatives such as magnesium citrate. The chemical structure contains polyvalent cations which can bind dolutegravir in the GI tract. Taking magnesium citrate simultaneously may result in reduced bioavailability of dolutegravir.
Magnesium Hydroxide: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing gastrointestinal medications such as magnesium hydroxide. The chemical structure of these GI drugs that contain polyvalent cations, such as magnesium hydroxide, can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Magnesium Salts: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain magnesium and calcium which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking cation-containing antacids. The chemical structure of these antacids contain magnesium which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Maprotiline: (Moderate) Caution is advised when administering rilpivirine with maprotiline as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
Maribavir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with maribavir. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and maribavir is a P-gp and BCRP inhibitor.
Mavacamten: (Moderate) Coadministration of rilpivirine with mavacamten may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A substrate and mavacamten is a moderate CYP3A inducer. (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with mavacamten. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A substrate and mavacamten is a moderate CYP3A inducer.
Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Meropenem: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with meropenem. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and meropenem is a P-gp inhibitor.
Meropenem; Vaborbactam: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with meropenem. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and meropenem is a P-gp inhibitor.
Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Metformin; Repaglinide: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Metformin; Saxagliptin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Metformin; Sitagliptin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Methadone: (Major) Close clinical monitoring is advised with coadministration. Use of these drugs together may cause the plasma concentration of methadone to decrease, thereby resulting in decreased methadone efficacy. No dose adjustments are required when initiating concurrent treatment; however, the maintenance dose of methadone may need to be adjusted in some patients. In addition, due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with methadone. A careful assessment of treatment risks versus benefits should be conducted prior to coadministration. When initiating concurrent treatment no dose adjustments are required; however, the dose of methadone may need to be adjusted during maintenance therapy. Methadone is considered to be associated with an increased risk for QT prolongation and TdP, especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also been associated with prolongation of the QT interval.
Methohexital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Metronidazole: (Moderate) Concomitant use of metronidazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at three times the maximum recommended dose.
Midostaurin: (Major) The concomitant use of midostaurin and rilpivirine may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with midostaurin. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and midostaurin is a BCRP inhibitor.
Mifepristone: (Major) Avoid use together if possible due to the risk of elevated rilpivirine exposure and a combined risk for QT prolongation. Consider alternatives to rilpivirine when coadministered with a drug with a known risk of QT prolongation and torsade de pointes (TdP), such as mifepristone when it is used for chronic hormonal conditions, such as Cushing's syndrome. Mifepristone is an inhibitor of CYP3A4; rilpivirine is a CYP3A4 substrate. Coadministration is likely to increase rilpivirine plasma concentrations. Monitor for rilpivirine-related side effects, including rash, mood changes or depression, fast, irregular heart rate, and hepatotoxicity. To minimize the risk of QT prolongation, the lowest effect dose of mifepristone should always be used.
Mirtazapine: (Moderate) Concomitant use of mirtazapine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Mitapivat: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with mitapivat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and mitapivat is a P-gp inhibitor.
Mitotane: (Major) Concomitant use of mitotane with rilpivirine should be undertaken with caution due to potential decreased rilpivirine concentrations, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. The use of rilpivirine is contraindicated with other specific strong CYP3A inducers, including carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, and St John's wort. Mitotane is a strong CYP3A4 inducer and rilpivirine is a CYP3A4 substrate. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with mitotane; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Mitotane is a strong CYP3A inducer and dolutegravir is partially metabolized by this isoenzyme.
Mobocertinib: (Major) Concomitant use of mobocertinib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Modafinil: (Moderate) Close clinical monitoring is advised when administering modafinil with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Modafinil is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with modafinil; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Modafinil is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Momelotinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with momelotinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and momelotinib is a BCRP inhibitor.
Moxifloxacin: (Major) Concurrent use of rilpivirine and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Moxifloxacin has also been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded.
Nafcillin: (Moderate) Close clinical monitoring is advised when administering nafcillin with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Naproxen; Esomeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Nefazodone: (Moderate) Close clinical monitoring is advised when administering nefazodone with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nefazodone is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Nelfinavir: (Moderate) Close clinical monitoring is advised when administering nelfinavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Nelfinavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Neratinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with neratinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
Nevirapine: (Major) Avoid concurrent use of nevirapine and dolutegravir. Concomitant use may decrease plasma concentrations of dolutegravir and there are insufficient data to make dosing recommendations. Dolutegravir is a CYP3A substrate and nevirapine is a weak CYP3A inducer. (Major) Coadministration of nevirapine and rilpivirine is not recommended as the combined use of two NNRTIs has not been shown to be beneficial. Concomitant use may also cause a significant decrease in rilpivirine plasma concentrations and, thus, a loss of therapeutic effect. Rilpivirine is a CYP3A substrate and nevirapine is a weak CYP3A inducer.
Nicardipine: (Moderate) Close clinical monitoring is advised when administering nicardipine with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Nicardipine is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Nilotinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval, such as rilpivirine. Nilotinib is a moderate inhibitor of CYP3A4 and rilpivirine is a substrate of CYP3A4; administering these drugs together may result in increased rilpivirine levels. If the use of rilpivirine is necessary, hold nilotinib therapy. If these drugs are used together, consider a rilpivirine dose reduction and monitor patients for toxicity (e.g., QT interval prolongation).
Nirogacestat: (Moderate) Coadministration of rilpivirine with nirogacestat may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with nirogacestat. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and nirogacestat is a moderate CYP3A inhibitor.
Nizatidine: (Moderate) Coadministration with nizatidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of nizatidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Ofloxacin: (Moderate) Concomitant use of ofloxacin and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Olanzapine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Olanzapine; Fluoxetine: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval. (Moderate) Concomitant use of fluoxetine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Olanzapine; Samidorphan: (Moderate) Caution is advised when administering rilpivirine with olanzapine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Limited data, including some case reports, suggest that olanzapine may also be associated with a significant prolongation of the QTc interval.
Omeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Omeprazole; Amoxicillin; Rifabutin: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Increase the dose of rilpivirine to 50 mg PO once daily when coadministered with rifabutin. When rifabutin coadministration is stopped, decrease the rilpivirine dose to 25 mg PO once daily. Coadministration of rilpivirine with rifabutin may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Omeprazole; Sodium Bicarbonate: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine. (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Ondansetron: (Major) Concomitant use of rilpivirine and ondansetron increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. Do not exceed 16 mg of IV ondansetron in a single dose; the degree of QT prolongation associated with ondansetron significantly increases above this dose. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Oritavancin: (Major) Rilpivirine is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of rilpivirine may be reduced if these drugs are administered concurrently. (Moderate) Dolutegravir plasma concentrations may be reduced when administered concurrently with oritavancin; thereby increasing the risk for HIV treatment failures or the development of viral-resistance. Data are insufficient to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Dolutegravir is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer.
Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with rilpivirine as concurrent use may increase the risk of QT prolongation. Osilodrostat is associated with dose-dependent QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Osimertinib: (Major) Avoid coadministration of rilpivirine with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase dolutegravir plasma concentrations. Dolutegravir is a BCRP and P-glycoprotein (P-gp) substrate and osimertinib is a BCRP and P-gp inhibitor.
Oteseconazole: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with oteseconazole. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of rilpivirine with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Supratherapeutic doses of rilpivirine (75 to 300 mg per day) have caused QT prolongation. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have also been reported with oxaliplatin use in postmarketing experience.
Oxcarbazepine: (Contraindicated) Concurrent use of oxcarbazepine and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Oxcarbazepine is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Avoid concurrent use of dolutegravir with oxcarbazepine, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Oxcarbazepine is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Ozanimod: (Major) In general, do not initiate ozanimod in patients taking rilpivirine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Pacritinib: (Major) Concomitant use of pacritinib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with pacritinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP and P-gp substrate; pacritinib is a BCRP and P-gp inhibitor.
Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
Panobinostat: (Major) The co-administration of panobinostat with rilpivirine or emtricitabine; rilpivirine; tenofovir is not recommended; QT prolongation has been reported with panobinostat and rilpivirine. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve.
Pantoprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Pasireotide: (Moderate) Use caution when using pasireotide in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Pazopanib: (Major) Concurrent use of pazopanib and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If these drugs must be continued, closely monitor the patient for QT interval prolongation. Pazopanib has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. In addition, pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and rilpivirine, a CYP3A4 substrate, may cause an increase in systemic concentrations of rilpivirine.
Peginterferon Alfa-2a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents 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.
Peginterferon Alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents 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.
Peginterferon beta-1a: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents 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.
Pentamidine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with pentamidine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Pentamidine has also been associated with QT prolongation.
Pentobarbital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Perphenazine: (Minor) Caution is advised when administering rilpivirine with perphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Perphenazine; Amitriptyline: (Minor) Caution is advised when administering rilpivirine with perphenazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Perphenazine is also associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Pexidartinib: (Moderate) Coadministration of rilpivirine with pexidartinib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer. (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with pexidartinib. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer.
Phenobarbital: (Contraindicated) Concurrent use of phenobarbital and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenobarbital is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Avoid concurrent use of dolutegravir with phenobarbital, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenobarbital is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Contraindicated) Concurrent use of phenobarbital and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenobarbital is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Avoid concurrent use of dolutegravir with phenobarbital, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenobarbital is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Phentermine; Topiramate: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. 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. Dolutegravir is partially metabolized by this isoenzyme. (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Phenytoin: (Contraindicated) Concurrent use of phenytoin or fosphenytoin and rilpivirine is contraindicated. When these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Phenytoin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Avoid concurrent use of dolutegravir with phenytoin, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Phenytoin is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Coadministration may increase the risk for QT prolongation.
Pimozide: (Contraindicated) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP) and coadministration with other drugs associated with a possible risk for QT prolongation and TdP, such as rilpivirine, should be avoided.
Pioglitazone; Metformin: (Major) If these drugs are used in combination, the total daily dose of metformin must not exceed 1,000 mg/day. Dolutegravir may increase exposure to metformin. Increased exposure to metformin may increase the risk for hypoglycemia, gastrointestinal side effects, and potentially increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use of dolutegravir with metformin. Close monitoring of blood glucose and patient clinical status (gastrointestinal side effects, renal function, electrolytes and acid-base balance) is recommended. When stopping dolutegravir, the metformin dose may need to be adjusted. In drug interaction studies, dolutegravir increased both the Cmax and AUC of metformin when metformin 500 mg PO twice daily was coadministered. Dolutegravir inhibits common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2]/multidrug and toxin extrusion [MATE1 and MATE2k]).
Pirtobrutinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with pirtobrutinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and pirtobrutinib is a P-gp and BCRP inhibitor.
Pitolisant: (Major) Avoid coadministration of pitolisant with rilpivirine as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Polysaccharide-Iron Complex: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Ponesimod: (Major) In general, do not initiate ponesimod in patients taking rilpivirine due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Posaconazole: (Contraindicated) Concurrent use of posaconazole and rilpivirine is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of ripivirine. These drugs used in combination may result in elevated rilpivirine plasma concentrations, causing an increased risk for rilpivirine-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as rilpivirine.
Pretomanid: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with pretomanid. Concurrent use may increase the exposure of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and pretomanid is a P-gp and BCRP inhibitor.
Primaquine: (Moderate) Exercise caution when administering primaquine in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Primaquine is associated with QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Primidone: (Major) Avoid concurrent use of dolutegravir with primidone, as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. Primidone is metabolized to phenobarbital, which is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme. (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Procainamide: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Prochlorperazine: (Minor) Caution is advised when administering rilpivirine with prochlorperazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Prochlorperazine is also associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Promethazine: (Moderate) Concomitant use of promethazine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Promethazine; Dextromethorphan: (Moderate) Concomitant use of promethazine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Promethazine; Phenylephrine: (Moderate) Concomitant use of promethazine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Propafenone: (Major) Concomitant use of rilpivirine and propafenone increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Proton pump inhibitors: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Pyridoxine, Vitamin B6: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Quetiapine: (Major) Concomitant use of rilpivirine and quetiapine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Quinidine: (Major) Rilpivirine should be used cautiously with Class IA antiarrhythmics (disopyramide, procainamide, quinidine). Class IA antiarrhythmics are associated with QT prolongation and torsades de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Quinine: (Major) Concurrent use of quinine and rilpivirine should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. In addition, concentrations of rilpivirine may be increased with concomitant use of quinine. Rilpivirine is a CYP3A4 substrate and quinine is a CYP3A4 inhibitor.
Quizartinib: (Major) Concomitant use of quizartinib and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Rabeprazole: (Contraindicated) Concurrent use of proton pump inhibitors and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Proton pump inhibitors inhibit secretion of gastric acid by proton pumps thereby increasing the gastric pH; for optimal absorption, rilpivirine requires an acidic environment. Coadministration of a proton pump inhibitor and rilpivirine may result in decreased rilpivirine absorption/serum concentrations, which could cause impaired virologic response to rilpivirine.
Ranitidine: (Moderate) Coadministration with ranitidine may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of ranitidine for at least 12 hours before and at least 4 hours after administering rilpivirine.
Ranolazine: (Moderate) Caution is advised when administering rilpivirine with ranolazine as concurrent use may increase the risk of QT prolongation; rilpivirine exposure may also increase. Rilpivirine is a CYP3A4 substrate; supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Ranolazine is a moderate CYP3A4 inhibitor that is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs concurrent use may result in additive QT prolongation.
Regorafenib: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with regorafenib is necessary. Dolutegravir is a BCRP substrate and regorafenib is a BCRP inhibitor.
Relugolix: (Moderate) Caution is advised when administering rilpivirine with relugolix. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Relugolix; Estradiol; Norethindrone acetate: (Moderate) Caution is advised when administering rilpivirine with relugolix. Androgen deprivation therapy (i.e., relugolix) may prolong the QT/QTc interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Repotrectinib: (Moderate) Coadministration of rilpivirine with repotrectinib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer. (Moderate) Monitor for decreased efficacy of dolutegravir if coadministered with repotrectinib. Concurrent use may decrease the plasma concentrations of dolutegravir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Dolutegravir is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer.
Ribavirin: (Major) The concomitant use of ribavirin and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. 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: (Major) Avoid coadministration of ribociclib with rilpivirine due to an increased risk for QT prolongation. Systemic exposure of rilpivirine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day), a CYP3A4 substrate, have also caused QT prolongation. Concomitant use may increase the risk for QT prolongation. (Moderate) Use caution if coadministration of ribociclib with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with rilpivirine due to an increased risk for QT prolongation. Systemic exposure of rilpivirine may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor that has been shown to prolong the QT interval in a concentration-dependent manner. Supratherapeutic doses of rilpivirine (75 to 300 mg per day), a CYP3A4 substrate, have also caused QT prolongation. Concomitant use may increase the risk for QT prolongation. (Moderate) Use caution if coadministration of ribociclib with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Ribociclib is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
Rifabutin: (Major) Increase the dose of rilpivirine to 50 mg PO once daily when coadministered with rifabutin. When rifabutin coadministration is stopped, decrease the rilpivirine dose to 25 mg PO once daily. Coadministration of rilpivirine with rifabutin may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and rifabutin is a moderate CYP3A4 inducer.
Rifampin: (Contraindicated) Concurrent use of rifampin and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifampin is a potent inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) When possible, avoid concurrent use of dolutegravir with rifampin in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with rifampin. Use of these drugs together may result in decreased dolutegravir plasma concentrations. Dolutegravir is a CYP3A4 substrate and rifampin is an inducer of CYP3A4.
Rifapentine: (Contraindicated) Concurrent use of rifapentine and rilpivirine is contraindicated; when these drugs are coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Rifapentine is a strong CYP3A4 inducer, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Do not administer rifapentine and dolutegravir together in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance who are receiving twice daily doses of dolutegravir. Additionally, avoid use of once daily rifapentine in any patient receiving dolutegravir. However, once weekly doses of rifapentine may be administered with caution to treatment-naive or treatment-experienced, but INSTI-naive patients receiving once daily dolutegravir. Monitor for virologic efficacy if these drugs are administered concurrently. In a drug interaction study, administration of rifapentine (900 mg once weekly) decreased the AUC and trough concentration of dolutegravir by 26% and 47%, respectively. Dolutegravir is a CYP3A and UGT1A substrate and rifapentine is a strong CYP3A and UGT1A inducer.
Risperidone: (Moderate) Use risperidone and rilpivirine together with caution due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Ritlecitinib: (Moderate) Coadministration of rilpivirine with ritlecitinib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with ritlecitinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with rilpivirine as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Ropeginterferon alfa-2b: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents 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.
Saquinavir: (Contraindicated) Concurrent use or switching form rilpivirine to saquinavir boosted with ritonavir without a washout period of at least 2 weeks is contraindicated. Taking these drugs together is expected to increase rilpivirine concentrations and increase the risk for QT prolongation and torsade de pointes (TdP). Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. Before administering saquinavir boosted with ritonavir, perform a baseline ECG and carefully follow monitoring recommendations.
Secobarbital: (Moderate) Close clinical monitoring is advised when administering barbiturates with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Barbiturates are inducers of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with rilpivirine is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with selpercatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and selpercatinib is a P-gp inhibitor.
Sertraline: (Moderate) Concomitant use of sertraline and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose. The degree of QT prolongation associated with sertraline is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 2 times the maximum recommended dose.
Sevoflurane: (Major) Halogenated anesthetics should be used cautiously and with close monitoring with rilpivirine. Halogenated anesthetics can prolong the QT interval. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval.
Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving rilpivirine due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Sodium Bicarbonate: (Moderate) Concurrent administration of rilpivirine and antacids may significantly decrease rilpivirine plasma concentrations, potentially resulting in treatment failure. To decrease the risk of virologic failure, avoid use of antacids for at least 2 hours before and at least 4 hours after administering rilpivirine.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing iron if given under fasting conditions. When taken with food, dolutegravir and supplements containing iron can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with taurursodiol. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and taurursodiol is a P-gp and BCRP inhibitor.
Sodium Stibogluconate: (Moderate) Concomitant use of sodium stibogluconate and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Solifenacin: (Moderate) Caution is advised when administering rilpivirine with solifenacin as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Solifenacin has also been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported with postmarketing use, although causality was not determined. This should be taken into consideration when prescribing solifenacin to patients taking other drugs that are associated with QT prolongation.
Sorafenib: (Major) Avoid coadministration of sorafenib with rilpivirine due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation. (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with sorafenib is necessary. Dolutegravir is a P-glycoprotein (P-gp) and UGT1A1 substrate. Sorafenib inhibits both P-gp and UGT1A1 in vitro, and may increase the concentrations of concomitantly administered drugs that are P-gp or UGT1A1 substrates.
Sotalol: (Major) Concomitant use of sotalol and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Sotorasib: (Moderate) Coadministration of rilpivirine with sotorasib may result in decreased plasma concentrations of rilpivirine, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Rilpivirine is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer. (Moderate) Monitor for decreased efficacy or increased toxicity of dolutegravir if coadministered with sotorasib. Concurrent use may alter the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4, BCRP, and P-gp substrate; sotorasib is a moderate CYP3A4 inducer and a BCRP and P-gp inhibitor.
Sparsentan: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with sparsentan. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp and BCRP substrate and sparsentan is a P-gp and BCRP inhibitor.
St. John's Wort, Hypericum perforatum: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and rilpivirine is contraindicated. When coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. St. John's wort appears to be an inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Avoid concurrent use of dolutegravir with St. John's Wort, Hypericum perforatum as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. St. John's Wort is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Sucralfate: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking sucralfate. The chemical structure of sucralfate contains aluminum, which can bind dolutegravir in the GI tract. Taking these drugs simultaneously may result in reduced bioavailability of dolutegravir.
Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with rilpivirine. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Sunitinib can prolong the QT interval.
Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with rilpivirine. Tacrolimus may prolong the QT interval and cause torsade de pointes (TdP). Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Tafamidis: (Moderate) Caution is advised with the coadministration of tafamidis and dolutegravir as coadministration may increase the plasma concentrations of dolutegravir increasing the risk of adverse effects. Dolutegravir is a substrate of the breast cancer resistance protein (BCRP) and tafamidis is a BCRP inhibitor.
Tamoxifen: (Moderate) Concomitant use of tamoxifen and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Tedizolid: (Moderate) If possible, stop use of dolutegravir temporarily during treatment with oral tedizolid. If coadministration cannot be avoided, closely monitor for dolutegravir-associated adverse events. Dolutegravir plasma concentrations may be increased when dolutegravir is administered concurrently with oral tedizolid. Dolutegravir is a in vitro substrate of the Breast Cancer Resistance Protein (BCRP); oral tedizolid inhibits BCRP in the intestine.
Telavancin: (Moderate) Caution is advised when administering rilpivirine with telavancin as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Telavancin has also been associated with QT prolongation.
Temsirolimus: (Moderate) Monitor for an increase in dolutegravir-related adverse reactions if coadministration with temsirolimus is necessary. Dolutegravir is a P-glycoprotein (P-gp) substrate and temsirolimus is a P-gp inhibitor. Concomitant use is likely to lead to increased concentrations of dolutegravir.
Tepotinib: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with tepotinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and tepotinib is a P-gp inhibitor.
Tetrabenazine: (Major) Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer of tetrabenazine recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc such as rilpivirine.
Thioridazine: (Contraindicated) Thioridazine is associated with a well-established risk of QT prolongation and TdP. Thioridazine is considered contraindicated for use along with rilpivirine which, when combined with thioridazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension.
Ticagrelor: (Moderate) Close clinical monitoring for adverse events is advised when administering rilpivirine with ticagrelor. Use of these drugs together may result in elevated rilpivirine plasma concentrations. Ticagrelor is a weak inhibitor of the hepatic isoenzyme CYP3A4 and drug transporter P-glycoprotein (P-gp). Rilpivirine is primarily metabolized by CYP3A4.
Tipranavir: (Major) When possible, avoid concurrent use of dolutegravir and tipranavir boosted with ritonavir in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. For treatment-naive or treatment-experienced, but INSTI-naive, adult and pediatric patients, the dose of dolutegravir should be increased to twice daily when administered with tipranavir/ritonavir. Use of these drugs together results in decreased dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT), P-glycoprotein (P-gp), and CYP3A4 (minor). Tipranavir is an inducer of P-gp and inhibitor of CYP3A4; while ritonavir is an inducer of UGT, an inhibitor of P-gp, and a mixed inducer/inhibitor of CYP3A4. (Moderate) Close clinical monitoring is advised when administering the combination of tipranavir and ritonavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Tipranavir and ritonavir are inhibitors of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Tolterodine: (Moderate) Caution is advised when administering rilpivirine with tolterodine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Tolterodine has been associated with dose-dependent prolongation of the QT interval, especially in poor CYP2D6 metabolizers.
Topiramate: (Moderate) Caution is warranted when dolutegravir is administered with topiramate as there is a potential for decreased dolutegravir concentrations. 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. Dolutegravir is partially metabolized by this isoenzyme. (Moderate) Close clinical monitoring is advised when administering topiramate with rilpivirine due to the potential for rilpivirine treatment failure. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Topiramate is an inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in decreased rilpivirine serum concentrations and impaired virologic response.
Toremifene: (Major) Avoid coadministration of rilpivirine with toremifene if possible due to the risk of additive 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 has been shown to prolong the QTc interval in a dose- and concentration-related manner. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Trandolapril; Verapamil: (Moderate) Close clinical monitoring is advised when administering verapamil with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Verapamil is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Trazodone: (Major) Concomitant use of trazodone and rilpivirine increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Triclabendazole: (Moderate) Concomitant use of triclabendazole and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Trifluoperazine: (Minor) Caution is advised when administering rilpivirine with trifluoperazine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Trifluoperazine is also associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving rilpivirine as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Androgen deprivation therapy may also prolong the QT/QTc interval.
Tucatinib: (Moderate) Coadministration of rilpivirine with tucatinib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with tucatinib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-glycoprotein (P-gp) substrate and tucatinib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Vandetanib: (Major) Avoid coadministration of vandetanib with rilpivirine due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have also caused QT prolongation.
Vardenafil: (Moderate) Concomitant use of vardenafil and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Vemurafenib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with vemurafenib. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Both vemurafenib and supratherapeutic doses of rilpivirine (75 to 300 mg/day) have been associated with QT prolongation. Also, rilpivirine is a CYP3A4 substrate, while vemurafenib is a CYP3A4 substrate and inducer. Therefore, decreased concentrations of rilpivirine and potential loss of virologic response may occur with concomitant use.
Venlafaxine: (Moderate) Concomitant use of venlafaxine and rilpivirine may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP. The degree of QT prolongation associated with rilpivirine is not clinically significant when administered within the recommended dosage range; QT prolongation has been described at 3 times the maximum recommended dose.
Verapamil: (Moderate) Close clinical monitoring is advised when administering verapamil with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Verapamil is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Vitamin D: (Moderate) Administer dolutegravir 2 hours before or 6 hours after taking supplements containing calcium if given under fasting conditions. When taken with food, dolutegravir and supplements containing calcium can be taken at the same time. Simultaneous administration under fasted conditions may result in reduced bioavailability of dolutegravir.
Voclosporin: (Moderate) Concomitant use of voclosporin and rilpivirine may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Both voclosporin and rilpivirine have been associated with QT prolongation at supratherapeutic doses. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with voclosporin. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a P-gp substrate and voclosporin is a P-gp inhibitor.
Vonoprazan: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Vonoprazan; Amoxicillin: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Vonoprazan; Amoxicillin; Clarithromycin: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy. (Major) Close clinical monitoring is advised when administering clarithromycin with rilpivirine due to an increased potential for rilpivirine-related adverse events. When possible, alternative antibiotics should be considered. Predictions about the interaction can be made based on metabolic pathways. Clarithromycin is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. Also, supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation; caution is advised when administering rilpivirine with other drugs that may prolong the QT or PR interval, such as clarithromycin.
Voriconazole: (Moderate) Caution is advised when administering voriconazole with rilpivirine due to the potential for additive effects on the QT interval, increased exposure to rilpivirine, and decreased exposure to voriconazole. Monitor for breakthrough fungal infections in patients receiving rilpivirine with an azole antifungal. Rilpivirine, a CYP3A4 substrate, and voriconazole, a strong CYP3A4 inhibitor, are both associated with QT prolongation; rilpivirine dosage adjustments are not recommended. In addition, concurrent use of rilpivirine decreased exposure to another azole antifungal. A similar interaction may occur with voriconazole. (Moderate) Use caution if coadministration of voriconazole with dolutegravir is necessary, as the systemic exposure of dolutegravir may be increased resulting in an increase in treatment-related adverse reactions. Voriconazole is a strong CYP3A4 inhibitor. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A.
Vorinostat: (Moderate) Caution is advised when administering rilpivirine with vorinostat. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Vorinostat therapy is also associated with a risk of QT prolongation.
Voxelotor: (Moderate) Coadministration of rilpivirine with voxelotor may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with voxelotor. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
Zafirlukast: (Moderate) Close clinical monitoring is advised when administering zafirlukast with rilpivirine due to an increased potential for rilpivirine-related adverse events. Although this interaction has not been studied, predictions can be made based on metabolic pathways. Zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations.
Ziprasidone: (Major) Concomitant use of ziprasidone and rilpivirine should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
Dolutegravir; rilpivirine is a combination antiretroviral agent containing an integrase strand transfer inhibitor (INSTI) and a non-nucleoside reverse transcriptase inhibitor (NNRTI). During clinical testing, neither dolutegravir nor rilpivirine were antagonistic to all tested antiretroviral agents or with each other.
Dolutegravir: Dolutegravir inhibits the catalytic activity of HIV integrase, which is an HIV encoded enzyme required for viral replication. Integrase is one of the three HIV-1 enzymes required for viral replication. Integration of HIV into cellular DNA is a multi-step process. First, the assembly of integrase in a stable complex with the viral DNA occurs. Second, the terminal dinucleotides from each end of the viral DNA are removed by endonucleolytic processing. Lastly, the viral DNA 3' ends are covalently linked to the cellular (target) DNA by strand transfer. The last 2 processes, which are catalytic, require integrase to be appropriately assembled on a specific viral DNA substrate. Inhibition of integrase by dolutegravir prevents the covalent insertion, or integration, of unintegrated linear HIV DNA into the host cell genome preventing the formation of the HIV provirus. The provirus is required to direct the production of progeny virus, so inhibiting integration prevents propagation of the viral infection.
Cell culture studies have observed up to a 4-fold decrease in dolutegravir susceptibility in wild-type HIV-1 strains with the following amino acid substitutions: E92Q, G118R, S153F, S153Y, G193E, and R263K. In cross-resistance studies, single INSTI-resistant substitutions (T66K, I151L, and S153Y) and multiple INSTI-resistant substitutions (T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, R, or K, Q148R/N155H, T97A/G140S/Q148, E138/G140/Q148) have conferred a greater than 2-fold decrease in dolutegravir susceptibility.
Rilpivirine: Rilpivirine is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI). Unlike nucleoside reverse transcriptase inhibitors (NRTIs), it does not compete for binding nor does it require phosphorylation to be active. Rilpivirine binds directly to a site on reverse transcriptase that is distinct from where NRTIs bind. This binding causes disruption of the enzyme's active site thereby blocking RNA-dependent and DNA-dependent DNA polymerase activities. Human cellular DNA polymerase alpha, beta, and gamma are not inhibited by rilpivirine.
Data from cell cultures and clinical studies suggested reduced rilpivirine susceptibility when any of the following amino acid substitutions are present at baseline: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, or M230L. Cross-resistance has been observed among NNRTIs. Single NNRTI substitutions K101P, Y181I, and Y181V confer 52-times, 15-times, and 12-times decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I show 6.7-times reduced rilpivirine susceptibility compared to 2.8-times for E138K alone. The K103N substitution does not produce reduced rilpivirine susceptibility by itself; however, when combined with L100I, susceptibility is reduced by 7-times.
Avoid the use of rilpivirine in patients with HIV-2, as HIV-2 is intrinsically resistant to NNRTIs. To identify the HIV strain, The Centers for Disease Control and Prevention guidelines for HIV diagnostic testing recommend initial HIV testing using an HIV-1/HIV-2 antigen/antibody combination immunoassay and subsequent testing using an HIV-1/HIV-2 antibody differentiation immunoassay.
Dolutegravir; rilpivirine is administered orally.
-Dolutegravir: Dolutegravir is approximately 99% bound to human plasma protein, with a blood-to-plasma ratio of 0.5. Metabolism occurs via UDP-glucuronosyltransferase (UGT)1A1 (major) and by the hepatic isoenzyme CYP3A (minor). The terminal half-life is approximately 14 hours, with more than half of the total dose (53%) excreted unchanged in the feces. Excretion in the urine accounts 31% of the total dose; however, less than 1% of the renally eliminated drug is unchanged.
-Rilpivirine: Rilpivirine is approximately 99% bound to human plasma protein, predominantly to albumin. The blood-to-plasma ratio for rilpivirine is 0.7. Metabolism occurs primarily via oxidation by the hepatic isoenzyme CYP3A4. The terminal elimination half-life is approximately 50 hours with excretion occurring predominately through the feces. Following administration of a single oral dose, an average of 85% is eliminated via the feces and 6.5% is excreted in the urine. Metabolites account for the majority of the excretion with only 25% of an administered dose excreted as unchanged rilpivirine (25% in feces, less than 1% in urine).
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, UGT1A1, UGT1A3, UGT1A9, P-gp, BCRP, OCT2, MATE1
Rilpivirine is primarily metabolized via oxidation by CYP3A4. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A4. Dolutegravir is also an in vitro substrate for the enzymes UGT1A3 and UGT1A9, and transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Dolutegravir inhibits the renal organic cation transporter (OCT2) and potentially the multidrug and toxin extrusion transporter (MATE1). In addition, the drug is an in vitro inhibitor of the renal organic anion transporters OAT1 and OAT3; however, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir, which is a substrate of OAT1 and OAT3.
-Route-Specific Pharmacokinetics
Oral Route
-Dolutegravir: The absolute bioavailability of dolutegravir is unknown. Peak plasma concentrations are obtained 3 to 4 hours following an oral dose, with steady-state concentrations achieved within 5 days. Administration with food increases the extent and slows the rate of absorption, although there are no restrictions regarding administration with or without food. When given with a low-, moderate-, and high-fat meal, the AUC is increased by 33%, 41%, and 66%, respectively; the Cmax is increased by 46%, 52%, and 67%, respectively; and the Tmax is prolonged from 2 hours (under fasting conditions) to 3 hours, 4 hours, and 5 hours, respectively. At doses more than 50 mg/day, dolutegravir exhibits non-linear pharmacokinetics, with increasing doses producing less than proportional increases in plasma concentrations. An evaluation of the drugs steady-state pharmacokinetics found doses of 50 mg once daily produced an AUC of 53.6 mcg x hour/mL, where as dose of 50 mg twice daily produced an AUC of only 75.1 mcg x hour/mL.
-Rilpivirine: The absolute oral bioavailability of rilpivirine is unknown; however, the time to reach maximum plasma concentrations (Tmax) is approximately 4 to 5 hours. Compared to fasting conditions, exposure (AUC) is increased by 40% when administered with a normal caloric (533 kcal) or high fat, high caloric meal (928 kcal). Administering with only a protein-rich nutritional drink decreases exposure by 50% when compared with fed conditions.
-Special Populations
Hepatic Impairment
-Dolutegravir: Moderate hepatic impairment (Child-Pugh B) does not produce a clinically relevant effect on the pharmacokinetics of dolutegravir. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh C).
-Rilpivirine: When compared against matched controls, rilpivirine exposures (AUC) are increased by 47% in patients with mild hepatic impairment (Child-Pugh Class A) and 5% in patients with moderate hepatic impairment (Child-Pugh Class B). Pharmacokinetic parameters have not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Renal Impairment
-Dolutegravir: Mild to moderate renal impairment does not produce a clinically relevant effect on the pharmacokinetics of dolutegravir. However, an evaluation of the pharmacokinetic parameters in 8 patients with severe renal impairment (CrCl less than 30 mL/minute) found the AUC, Cmax, and C24 were decreased by 40%, 23%, and 43%, respectively, when compared to patients with normal renal function. Data are inadequate to recommend appropriate dosing of dolutegravir in patients requiring dialysis.
-Rilpivirine: Analysis of rilpivirine pharmacokinetics indicate that exposure (AUC) in patients with mild renal impairment is comparable to the exposure observed in patients with normal renal function. There is limited information available regarding the pharmacokinetics in patients with moderate to severe renal impairment or in patients with end-stage renal disease. Caution and close monitoring are recommended for patients with severe renal impairment or end-stage renal disease. It is not likely that hemodialysis or peritoneal dialysis will remove rilpivirine from plasma because a large percentage of circulating drug is bound to plasma proteins.
Other
UGT1A1 Polymorphism
A meta-analysis of healthy patients, found individuals with UGT1A1 genotypes that result in poor dolutegravir metabolism (n = 7) had a 32% lower clearance and 46% higher drug exposure when compared to individuals with UGT1A1 genotypes that are associated with normal metabolism (n = 41).
Pregnancy
-Dolutegravir: In a pharmacokinetic study of 29 pregnant patients, dolutegravir plasma concentrations were lower during pregnancy than during the postpartum period. Specifically, systemic exposure (AUC) was reduced by 21% during pregnancy and trough concentrations were reduced by 34% in the third trimester; however, trough concentrations were still well above the 90% effective concentration of 0.064 mcg/mL. Another study involving 15 pregnant patients showed similar results with the AUC and Cmin being decreased by 14% and 26%, respectively, during pregnancy as compared to postpartum. Dolutegravir has also been shown to cross the placenta. In a study of 15 patients who received dolutegravir 50 mg once daily during the last trimester of pregnancy, the ratio of median dolutegravir concentration in fetal umbilical cord to that in maternal peripheral plasma was 1.21 (range, 0.51 to 2.11).
-Rilpivirine: In a study of 80 rilpivirine recipients (second trimester, n = 19; third trimester, n = 31; postpartum, n = 30), reductions in systemic drug exposure (AUC) and trough concentrations (Cmin) were observed during pregnancy as compared to postpartum. Median Cmin values recorded during the second trimester, third trimester, and postpartum period were 65 ng/mL, 56 ng/mL, and 81 ng/mL, respectively. The median AUC value in the third trimester was 1.70 ng x hr/mL, compared to 2.39 ng x hr/mL during postpartum. Despite the lower AUC values during pregnancy, more than 90% of women in both the second and third trimesters achieved the target concentration of 0.88 ng x hr/mL. Similar results were observed in another study, where exposure to rilpivirine was 30% to 40% lower during pregnancy (second and third trimesters) than during the postpartum period. In this study, the mean Cmin values observed during the second trimester (n = 15), third trimester (n = 13), and postpartum period (n = 11) were 54.3 ng/mL, 52.9 ng/mL, and 84 ng/mL, respectively. The mean AUCs during the second and third trimesters were 1,792 and 1,762 ng x hour/mL, respectively, compared to the postpartum AUC of 2,714 ng x hour/mL. These reductions in exposures are not considered clinically relevant in patients who are virologically suppressed; therefore, no dosage adjustments are recommended. Rilpivirine is more than 99% bound to plasma proteins during pregnancy and the postpartum period and has moderate to high placental transfer to the fetus.