Dolutegravir; lamivudine is a two-drug combination product that includes a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) and a nucleoside reverse transcriptase inhibitor (NRTI) in a single tablet that is administered once daily. This combination product constitutes a complete treatment regimen and is indicated for the treatment of HIV-1 infection in adults and pediatric patients 12 years and older weighing at least 25 kg with no antiretroviral treatment history or those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen and with no known or suspected substitutions associated with resistance to either drug. There is a potential for exacerbations of hepatitis B infection following lamivudine discontinuation in patients co-infected with hepatitis B and HIV.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer with or without food.
-Administer at least 2 hours before or 6 hours after taking cation-containing antacids or laxatives (i.e., magnesium, aluminum), sucralfate, oral calcium supplements, oral iron supplements, or buffered medications. Alternatively, may administer oral calcium and iron supplements concurrently if administered with food.
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.
Lactic acidosis and severe hepatotoxicity (i.e., fatal cases of hepatomegaly with steatosis) have been reported with the use of nucleoside reverse transcriptase inhibitors (e.g., lamivudine). Patients receiving treatment with a dolutegravir-containing regimen (including patients with no preexisting hepatic disease or other identifiable risk factors) have experienced elevated hepatic enzymes, hepatitis, and acute hepatic failure; in some cases, the drug-induced hepatotoxicity resulted in liver transplant. During clinical trials, Grade 3 to 4 elevations in hepatic enzymes (5-times or more ULN) were observed in up to 4% of dolutegravir; lamivudine recipients and Grade 2 elevations (less than 5-times ULN) were reported in up to 5% of patients. Also in trials, 1% of patients experienced Grade 3 to 4 hyperbilirubinemia (2.6-times or more ULN) and 3% had Grade 2 hyperbilirubinemia (less than 2.6-times ULN). Monitor for signs and symptoms of hepatotoxicity. Treatment should be discontinued if a patient develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity, including hepatomegaly and steatosis even in the absence of marked elevated transaminases.
There have been postmarketing reports of severe acute hepatitis B exacerbation in patients with HBV and HIV coinfection following the discontinuation of lamivudine therapy; close monitoring of clinical signs and symptoms, including laboratory monitoring, are recommended for several months following discontinuation. Typically, HBV exacerbation is associated with a return of HBV DNA and increases in ALT concentrations. Usually this exacerbation is self-limited; however, some fatalities have been reported. The causal relationship of discontinuation of lamivudine to the recurrence of HBV infection is not known. There is insufficient evidence to determine whether re-initiation of therapy alters the course of posttreatment exacerbations of hepatitis.
Hypersensitivity reactions were reported in less than 1% of patients receiving dolutegravir during clinical trials, and cases of anaphylactoid reactions and urticaria have been reported during postmarketing use of the drug. Signs and symptoms associated with dolutegravir hypersensitivity include severe rash, fever, malaise, tiredness, arthralgia, myalgia, oral lesions, conjunctivitis, angioedema, facial edema, hepatitis, eosinophilia, and breathing difficulty or wheezing. Patients developing these signs and symptoms should discontinue use of dolutegravir as soon as a hypersensitivity reaction is suspected. A delay in diagnosis of dolutegravir hypersensitivity can result in the drug being continued or reintroduced, leading to more severe and potentially life-threatening hypersensitivity reactions.
Less than 2% of patients receiving dolutegravir; lamivudine during clinical trials developed myositis. Other musculoskeletal adverse events associated with postmarketing use of the drug include arthralgia, myalgia, muscle weakness, rhabdomyolysis, and elevated creatine phosphokinase (CPK) concentrations. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
Neurologic adverse events associated with dolutegravir; lamivudine treatment during clinical trials include headache (3%), fatigue (2%), anxiety (2%), asthenia (2%), malaise (2%), insomnia (2%), dizziness (1%), and somnolence (less than 2%). Psychiatric disorders, including abnormal dreams, depression, and suicidal ideation, attempt, behavior, or completion were noted in less than 2% of drug recipients; however, these events were observed primarily in patients with a pre-existing history of depression or other psychiatric illness. Paresthesias and peripheral neuropathy have been reported with one or more of the individual components in postmarketing use. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
During clinical trials, weight gain (3%), nausea (2%), and diarrhea (2%) were experienced by patients receiving treatment with dolutegravir; lamivudine. Other gastrointestinal adverse events reported by less than 2% of drug recipients included abdominal pain or discomfort, flatulence, and vomiting. During postmarketing use, cases of pancreatitis, redistribution or accumulation of body fat, and weight gain have been noted. Data from postmarketing trials found treatment-naive patients who started an integrase inhibitor-containing regimen (such as dolutegravir; lamivudine) 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.
Pruritus was reported by less than 2% of patients receiving dolutegravir; lamivudine during clinical trials. Cases of alopecia have been noted during postmarketing use. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
During clinical trials, less than 2% of patients receiving treatment with dolutegravir; lamivudine developed anemia, neutropenia, or thrombocytopenia. Additionally, anemia (including pure red cell aplasia and severe anemia progressing on therapy) has been noted during postmarketing use of the drug. Due to the voluntary nature of postmarketing reports, neither a frequency nor a definitive causal relationship can be established.
During clinical trials, recipients of dolutegravir; lamivudine experienced a mean increase in serum creatinine concentrations of 0.144 mg/dL over baseline, and less than 2% developed renal impairment. The change in serum creatinine was observed within the first 4 weeks of treatment and remained stable through 144 weeks. This increase occurs as a result of dolutegravir inhibiting tubular secretion of creatinine without affecting renal glomerular function. Other laboratory abnormalities observed in recipients of dolutegravir; lamivudine during clinical trials included elevated creatine kinase (10-times or more ULN, 8%; less than 10-times ULN, 5%), elevated lipase (3-times or more ULN, 3%; less than 3-times ULN, 7%), hypophosphatemia (less than 1.4 mg/dL, 1%; 1.4 to less than 2 mg/dL, 11%), and hyperglycemia (more than 250 mg/dL, 1%; 126 to 250 mg/dL, 11%). Drug recipients also experienced a mean increase in total cholesterol and triglycerides concentrations over baseline of 15 mg/dL and 10 mg/dL, respectively.
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.
Screen all patients who present with HIV infection for hepatitis B virus (HBV) coinfection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection should be started on a fully suppressive 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 given 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 coinfected patients should continue treatment indefinitely with the goal of maximal HIV suppression and prevention of HBV relapse. It should also be noted that following discontinuation of lamivudine in patients with HBV and HIV coinfection, some patients experienced clinical or laboratory evidence of hepatitis B exacerbation, which has been fatal in some cases. This reaction may be more severe in patients with decompensated hepatic disease. Thus, HBV and HIV coinfected patients should have transaminase concentrations monitored every 6 weeks for the first 3 months after stopping dolutegravir; lamivudine, 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 hepatitis and HIV coinfected patients to avoid consuming alcohol, and offer vaccinations against hepatitis A and hepatitis B as appropriate.
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.
Dolutegravir; lamivudine is not recommended for used in patients with severe hepatic disease (Child-Pugh C), and should be used with caution in persons with known risk factors for liver disease (e.g., alcoholism). 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 other identifiable risk factors. Drug-induced liver injury requiring liver transplant has been reported with use of dolutegravir; lamivudine in combination with abacavir. Monitor patients for hepatotoxicity during treatment. Additionally, hepatotoxicity or lactic acidosis, including fatal cases, has been associated with nucleoside analog therapy, including lamivudine. Obesity may be a risk factor, and most of these cases have occurred in females. It is unknown if pregnant women are at increased risk for this syndrome; however, because being pregnant itself can mimic some of the early symptoms of the lactic acid and hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant women receiving nucleoside analogs should have liver function tests and serum electrolytes assessed more frequently during the last trimester and any new symptoms should be evaluated thoroughly. Treatment should be discontinued 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 increases in transaminases.
Avoid use of dolutegravir, lamivudine in patients with renal failure (CrCl less than 30 mL/min). Dolutegravir plasma concentrations are decreased in patients with renal failure, as compared to healthy controls; therefore, use of the drug in this patient population may result in loss of therapeutic effect and development of resistance. Conversely, lamivudine exposures may be increased in patients with renal impairment (CrCl between 30 and 49 mL/min). Monitor these patients for lamivudine-related hematologic toxicities. If new or worsening neutropenia or anemia develops, substitute the use of dolutegravir; lamivudine with the individual drug components to allow for a lamivudine renal dose adjustment.
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; lamivudine 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.
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.
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; lamivudine 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; lamivudine 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 5,613 lamivudine 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 lamivudine are 3.3% (95% CI: 2.2 to 4.7) and 3.1% (95% CI: 2.6 to 3.6), respectively. Nucleoside reverse transcriptase inhibitors (NRTIs) are known to induce mitochondrial dysfunction. An association of mitochondrial dysfunction in infants and in-utero antiretroviral exposure has been suggested, but not established. While the development of severe or fatal mitochondrial disease in exposed infants appears to be extremely rare, more intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised. Nucleoside analogs have been associated with the development of lactic acidosis, especially during pregnancy. It is unclear if pregnancy augments the incidence of lactic acidosis/hepatic steatosis in patients receiving nucleoside analogs. However, because pregnancy itself can mimic some early symptoms of the lactic acid/hepatic steatosis syndrome or be associated with other significant disorders of liver metabolism, clinicians need to be alert for early diagnosis of this syndrome. Pregnant patients receiving nucleoside analogs should have liver function tests and serum electrolytes assessed more frequently during the last trimester of pregnancy and any new symptoms should be evaluated thoroughly. 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; lamivudine; 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 or lamivudine 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. Lamivudine was also found to be secreted in human breast milk during a study involving 20 breast-feeding women with HIV who were administered either 300 mg of lamivudine twice daily as a single agent (n = 10) or lamivudine 150 mg twice daily in combination with zidovudine (n = 10). The mean breast milk concentrations of lamivudine in the respective groups were similar at 1.22 mg/L (range less than 0.5 to 6.09 mg/L) and 0.9 mg/L (range less than 0.5 to 8.2 mg/L). Other antiretroviral mediations whose passage into human breast milk have been evaluated include nevirapine, zidovudine, and nelfinavir.
Starting an integrase inhibitor-containing regimen (such as dolutegravir; lamivudine) 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.
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 infection:
-Dolutegravir; lamivudine is a recommended initial treatment regimen for most adults and adolescents with HIV-1, except for individuals:
--with pre-treatment HIV RNA greater than 500,000 copies/mL
-with hepatitis B virus (HBV) coinfection
-who need to start treatment before results of RT genotypic resistance testing and HBV testing are available
-who have a history of using long-acting cabotegravir as pre-exposure prophylaxis and need to start treatment before results of INSTI genotypic resistance testing are available
-Dolutegravir; lamivudine 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 treatment-naive persons or those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components:
Oral dosage:
Adults: 50 mg dolutegravir; 300 mg lamivudine PO once daily.
Children and Adolescents 12 to 17 years weighing 25 kg or more: 50 mg dolutegravir; 300 mg lamivudine PO once daily.
Maximum Dosage Limits:
-Adults
dolutegravir 50 mg/day PO; lamivudine 300 mg/day PO.
-Geriatric
dolutegravir 50 mg/day PO; lamivudine 300 mg/day PO.
-Adolescents
dolutegravir 50 mg/day PO; lamivudine 300 mg/day PO.
-Children
12 years weighing 25 kg or more: dolutegravir 50 mg/day PO; lamivudine 300 mg/day PO.
1 to 11 years or weighing less than 25 kg: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Mild to moderate hepatic impairment (Child-Pugh A or B): No dosage adjustment is needed.
Severe hepatic impairment (Child-Pugh C): Use is not recommended as studies have not been conducted in this population.
Patients with Renal Impairment Dosing
CrCl 50 mL/minute or more: No dosage adjustment is needed.
CrCl 30 to 49 mL/minute: No dosage adjustment is needed, but monitor for lamivudine-related hematologic toxicities. If new or worsening neutropenia or anemia develops, discontinue use of the fixed-dose combination product and administer the individual components to allow for a lamivudine dose adjustment.
CrCl less than 30 mL/minute: Use not recommended.
*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: (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 with antiretrovirals (i.e., anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs)) 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).
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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.
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.
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.
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.
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.
Amiloride: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
Amiloride; Hydrochlorothiazide, HCTZ: (Moderate) Drugs that are actively secreted via cationic tubular secretion, such as amiloride, should be co-administered with caution with lamivudine since they could increase lamivudine plasma concentrations, and therefore lamivudine associated adverse reactions, via potential competition for renal cationic secretion.
Amiodarone: (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.
Apalutamide: (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.
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.
Armodafinil: (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.
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.
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.
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.
Belumosudil: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with belumosudil. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a BCRP, P-gp, and UGT1A1 substrate and belumosudil is a BCRP, P-gp, and UGT1A1 inhibitor.
Berotralstat: (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) 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.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Bortezomib: (Minor) Monitor patients for the development of peripheral neuropathy when receiving bortezomib in combination with other drugs that can cause peripheral neuropathy like lamivudine; the risk of peripheral neuropathy may be additive.
Bosentan: (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.
Cabozantinib: (Minor) Monitor for an increase in cabozantinib-related adverse reactions if coadministration with lamivudine is necessary. Cabozantinib is a Multidrug Resistance Protein 2 (MRP2) substrate and lamivudine is an MRP2 inhibitor. MRP2 inhibitors have the potential to increase plasma concentrations of cabozantinib; however, the clinical relevance of this interaction is unknown. (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.
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.
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.
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.
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.
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.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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: (Major) Avoid concomitant use of dolutegravir and carbamazepine in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. When used in other patients, increase the dose of dolutegravir to twice daily when administered with carbamazepine. For patients receiving dolutegravir-containing, fixed-dose combination product, give an additional dolutegravir 50 mg dose separated by 12 hours from the combination product. Concomitant use may decrease dolutegravir exposure. Dolutegravir is a CYP3A substrate and carbamazepine is a strong CYP3A inducer. Coadministration with carbamazepine decreased dolutegravir exposure by approximately 50%.
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) 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: (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.
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.
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.
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.
Conivaptan: (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.
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.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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; 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.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine. (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
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. (Moderate) Drugs that are actively secreted via cationic secretion, such as lamivudine, should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion.
Donepezil; Memantine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
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.
Echinacea: (Moderate) Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Efavirenz: (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) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine. (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) 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: (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: (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.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine. (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine. (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Emtricitabine: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Tenofovir alafenamide: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Do not coadminister lamivudine, 3TC-containing products and emtricitabine-containing products due to similarities between emtricitabine and lamivudine.
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: (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.
Enzalutamide: (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.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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.
Fedratinib: (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.
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.
Fosphenytoin: (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) 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.
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.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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.
Interferon Alfa-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Interferon Alfa-n3: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Interferon Beta-1a: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Interferon Beta-1b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Interferon Gamma-1b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Interferons: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
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.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of dolutegravir and rifampin in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. When used in other patients, increase the dose of dolutegravir to twice daily when administered with rifampin. For patients receiving a dolutegravir-containing, fixed-dose combination product, give an additional dolutegravir 50 mg dose separated by 12 hours from the combination product. Concomitant use may decrease dolutegravir exposure. Dolutegravir is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin decreased dolutegravir exposure by approximately 50%.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of dolutegravir and rifampin in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. When used in other patients, increase the dose of dolutegravir to twice daily when administered with rifampin. For patients receiving a dolutegravir-containing, fixed-dose combination product, give an additional dolutegravir 50 mg dose separated by 12 hours from the combination product. Concomitant use may decrease dolutegravir exposure. Dolutegravir is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin decreased dolutegravir exposure by approximately 50%.
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.
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.
Lenacapavir: (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.
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.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Lonafarnib: (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.
Lorlatinib: (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: (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: (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.
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.
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.
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) 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.
Memantine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
Midostaurin: (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.
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: (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.
Modafinil: (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.
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.
Nirogacestat: (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.
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.
Oritavancin: (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.
Orlistat: (Moderate) According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs). Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Osimertinib: (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.
Oxcarbazepine: (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.
Pacritinib: (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.
Peginterferon Alfa-2a: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Peginterferon Alfa-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Peginterferon beta-1a: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Pexidartinib: (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: (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: (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.
Phenytoin: (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.
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]). (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Cationic drugs that are eliminated by renal tubular secretion, such as lamivudine, may decrease metformin elimination by competing for common renal tubular transport systems.
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.
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.
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.
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.
Procainamide: (Moderate) Cationic drugs that are eliminated by renal tubular secretion such as procainamide may compete with lamivudine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of the response to lamivudine and/or procainamide is recommended to individualize dosage. In selected individuals, procainamide serum concentration monitoring may be appropriate.
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.
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.
Repotrectinib: (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: (Moderate) Use lamivudine with ribavirin and interferon with caution and closely monitor for hepatic decompensation and anemia. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh greater than 6). Hepatic decompensation (some fatal) has occurred in HCV/HIV coinfected patients who received both ribavirin/interferon and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) therapies. In addition, ribavirin has been shown in cell culture to inhibit phosphorylation of lamivudine, which could lead to decreased antiretroviral activity; however, while ribavirin inhibits the phosphorylation reactions required to activate lamivudine, no evidence of a pharmacokinetic or pharmacodynamic interaction has been observed.
Ribociclib: (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: (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.
Rifampin: (Major) Avoid concomitant use of dolutegravir and rifampin in integrase strand transfer inhibitor (INSTI)-experienced patients with INSTI-associated resistance substitutions or clinically suspected INSTI resistance. When used in other patients, increase the dose of dolutegravir to twice daily when administered with rifampin. For patients receiving a dolutegravir-containing, fixed-dose combination product, give an additional dolutegravir 50 mg dose separated by 12 hours from the combination product. Concomitant use may decrease dolutegravir exposure. Dolutegravir is a CYP3A substrate and rifampin is a strong CYP3A inducer. Coadministration with rifampin decreased dolutegravir exposure by approximately 50%.
Rifapentine: (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.
Ritlecitinib: (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.
Ropeginterferon alfa-2b: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Selpercatinib: (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.
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.
Sorafenib: (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.
Sorbitol: (Major) Avoid coadministration of lamivudine oral solution and sorbitol if possible due to sorbitol dose-dependent reduction in lamivudine exposure. An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol. Consider more frequent monitoring of viral load when treating with lamivudine oral solution. In a drug interaction study in 16 healthy adult patients, coadministration of a single 300 mg dose of lamivudine oral solution with sorbitol 3.2 g, 10.2 g, or 13.4 g resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC24 and 28%, 52%, and 55% in the Cmax of lamivudine.
Sotorasib: (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: (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.
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.
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.
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.
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.
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.
Trospium: (Moderate) Trospium is eliminated by active tubular secretion and has the potential for pharmacokinetic interactions with other drugs that are eliminated by active tubular secretion including lamivudine. In theory, coadministration of trospium with lamivudine may increase the serum concentrations of trospium or lamivudine due to competition for the drug elimination pathway.
Tucatinib: (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.
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) 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.
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.
Voxelotor: (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.
Dolutegravir; lamivudine is active against infections caused by human immunodeficiency virus type 1 (HIV-1). Lamivudine is a nucleoside analog that works by inhibiting HIV reverse transcriptase, while dolutegravir works by inhibiting the catalytic activity of HIV integrase.
-Lamivudine: In vitro activity has been assessed in a number of cell lines where lamivudine showed anti-HIV activity in all virus-cell infections tested. Intracellular phosphorylation produces the 5'-triphosphate metabolite, lamivudine triphosphate (3TC-TP). This active metabolite inhibits reverse transcriptase and viral DNA synthesis. 3TC-TP also inhibits cellular DNA polymerase.
-Dolutegravir: Antiviral activity results from inhibition of HIV integrase, 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.
Antiviral drug resistance is a problem in the treatment of HIV infection. Lamivudine has demonstrated decreased susceptibility to viruses with certain viral mutations, including M184V and M184I. Decreases in dolutegravir susceptibility have been observed in HIV-1 with the following amino acid substitutions: E92Q, G118R, S153F, S153Y, G193E, and R263K. Combination therapy targets different points in the life cycle of HIV, reducing the ability of HIV to mutate to drug-resistant strains.
Dolutegravir; lamivudine is administered orally.
-Lamivudine: Once in systemic circulation, lamivudine is 36% bound to plasma protein and has a blood-to-plasma ratio of 1.1 to 1.2. The parent drug is not significantly metabolized, with most of the oral dose (approximately 70%) being excreted unchanged in the urine by active organic cationic secretion. The elimination half-life is 13 to 19 hours.
-Dolutegravir: Dolutegravir is highly bound (approximately 99%) to human plasma protein, with a blood-to-plasma ratio of 0.44 to 0.54. 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 for 31% of the total dose; however, less than 1% of the renally eliminated drug is unchanged.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, UGT1A1, UGT1A3, UGT1A9, P-gp, BCRP, OCT2, MATE1
Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A4. Dolutegravir is a substrate, in vitro, for the enzymes UGT1A3 and UGT1A9. It is also a substrate, in vitro, for the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). It is an inhibitor of the renal organic cation transporter OCT2 and the multidrug and toxin extrusion transporter MATE1. Lamivudine is a substrate of P-gp and BCRP.
-Route-Specific Pharmacokinetics
Oral Route
-Lamivudine: Absorption is rapid, with a mean absolute bioavailability of approximately 86%. Peak plasma concentrations are obtained 1 hour after an oral dose. Food has no significant effect on systemic exposure.
-Dolutegravir: The absolute bioavailability is unknown. Peak plasma concentrations are obtained 2.5 hours after an oral dose, with steady-state concentrations achieved within 5 days. Food has no significant effect on systemic exposure.
-Special Populations
Hepatic Impairment
-Lamivudine: Lamivudine pharmacokinetics are not altered by hepatic dysfunction.
-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).
Renal Impairment
-Lamivudine: Total clearance of lamivudine decreases as creatinine clearance decreases; therefore, exposure (AUC), Cmax, and half-life increase with diminishing renal function. Hemodialysis increases clearance; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single dose. The hemodialysis extraction ratio is approximately 53% to 65%. Continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis have negligible effects on lamivudine clearance. After correction of dose for creatinine clearance, no additional dose modification is necessary after routine hemodialysis or peritoneal dialysis. It is not known if continuous (24-hour) hemodialysis can remove lamivudine.
-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. Dolutegravir has not been adequately studied in patients requiring dialysis.
Pediatrics
In adolescents 12 to 17 years receiving dolutegravir; lamivudine, the exposures of dolutegravir and lamivudine were higher compared to adults; however, the differences in exposure were not considered clinically significant. Lamivudine and dolutegravir exposures were within the observed ranges at the recommended doses in adults and pediatrics receiving the individual components of dolutegravir; lamivudine.
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).
-Lamivudine: Although population pharmacokinetic modeling suggests the oral clearance of lamivudine is increased by 22% during pregnancy, limited data from 2 studies involving 36 pregnant women (16 at 36 weeks, 20 at 38 weeks gestation) found the pharmacokinetic parameters of lamivudine to be similar to those observed in non-pregnant and postpartum adults. No change in dose is indicated. In addition, placental transfer of lamivudine results in amniotic fluid drug concentrations that are 3.9-fold (1.2- to 12.8-fold) greater than maternal serum levels.