Dolutegravir-lamivudine Oral

Dolutegravir sodium and lamivudine (dolutegravir/lamivudine) is a fixed-combination antiretroviral agent containing dolutegravir (a human immunodeficiency virus integrase strand transfer inhibitor [INSTI]) and lamivudine (an HIV nucleoside reverse transcriptase inhibitor [NRTI]).[1]

Brand Name: Dovato
Classes: HIV Integrase Inhibitors (8:18.08.12), HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (8:18.08.20)

Table of Contents

Uses

Treatment of HIV Infection

The fixed combination of dolutegravir sodium and lamivudine (dolutegravir/lamivudine) is used as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naive (have not previously received antiretroviral therapy) adults or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or lamivudine.[1][2][12][14][15]

Dolutegravir and lamivudine are available as a fixed-combination preparation (dolutegravir/lamivudine), and as separate single-entity products.[1][236] Refer to the full prescribing information for the single-entity products for information on specific uses.[219][236]

Clinical Experience

Antiretroviral-naive Adults

Efficacy of dolutegravir/lamivudine for the treatment of HIV-1 infection in antiretroviral-naive adults is supported by data from 2 identically designed, randomized, double-blind, phase 3 noninferiority trials (GEMINI-1; NCT02831673 and GEMINI-2; NCT02831764).[1][2] Pooled 48-week data from these studies indicated that a 2-drug regimen of dolutegravir and lamivudine is noninferior to a 3-drug regimen of dolutegravir, emtricitabine, and tenofovir disoproxil fumarate (TDF) in antiretroviral-naive adults.[1][2] Pooled 96-week data from GEMINI-1 and GEMINI-2 confirmed these results and indicated long-term noninferiority of the 2-drug regimen of dolutegravir and lamivudine compared with the 3-drug regimen.[3]

GEMINI-1 and GEMINI-2 included a total of 1433 adults with HIV-1 infection who had received no prior antiretroviral treatment and had plasma HIV-1 RNA levels of 1000-500,000 copies/mL, no evidence of hepatitis B virus (HBV) infection, and no major HIV mutations associated with resistance to HIV NRTIs, HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs), or HIV protease inhibitors (PIs) at initial screening.[1][2] Patients were randomized 1:1 to receive a 2-drug regimen of single-entity dolutegravir and single-entity lamivudine (dolutegravir 50 mg and lamivudine 300 mg) once daily or a 3-drug regimen of single-entity dolutegravir and the fixed combination of emtricitabine and TDF (dolutegravir 50 mg, emtricitabine 200 mg, and TDF 300 mg) once daily.[1][2] The primary efficacy end point in both trials was the proportion of patients in the intention-to-treat (ITT) population with plasma HIV-1 RNA levels <50 copies/mL at 48 weeks.[1][2] Pooled analysis of the ITT populations indicated that study participants had a median age of 33 years, 15% were female, 69% were white, 9% were CDC stage 3 (acquired immunodeficiency syndrome [AIDS]), 20% had baseline plasma HIV-1 RNA levels >100,000 copies/mL, and the median CD4+ T-cell count was 432 cells/mm3 (8% had CD4+ T-cell counts of <=200 cells/mm3); patient characteristics were similar in both studies.[1][2]

At 48 weeks, pooled data for the ITT populations in GEMINI-1 and GEMINI-2 indicated that 91% of patients receiving the 2-drug regimen and 93% of those receiving the 3-drug regimen had plasma HIV-1 RNA levels <50 copies/mL.[1][2] When results were stratified by baseline CD4+ T-cell count, the response rate (i.e., plasma HIV-1 RNA levels <50 copies/mL) was lower in patients with baseline CD4+ T-cell counts of <=200 cells/mm3 (pooled response rate was 79% in those receiving the 2-drug regimen and 93% in those receiving the 3-drug regimen) compared with the response rate in patients with higher baseline CD4+ T-cell counts (pooled response rate was 93% in both treatment groups).[1][2]

Pooled data from another prespecified secondary analysis of GEMINI-1 and GEMINI-2 performed at 144 weeks indicated that the 2-drug regimen of dolutegravir and lamivudine remained noninferior to the 3-drug regimen of dolutegravir and the fixed combination of emtricitabine and TDF.[1][3] At 144 weeks, 82% of patients receiving the 2-drug regimen and 84% of patients receiving the 3-drug regimen still had plasma HIV-1 RNA levels <50 copies/mL.[1][3] The adjusted mean change in CD4+ T-cell count from baseline at week 144 was 302 cells/mm3 in those receiving dolutegravir and lamivudine and 300 cells/mm3 in those receiving dolutegravir and the fixed combination of emtricitabine and TDF.[1] At week 144, treatment-emergent substitutions associated with resistance to dolutegravir or NRTIs were not detected in any patients in either treatment arm.[1]

Antiretroviral-experienced Adults

Efficacy of dolutegravir/lamivudine for the treatment of HIV-1 infection in antiretroviral-experienced adults is primarily supported by data from a randomized, open-label, phase 3 trial (TANGO; NCT03446573).[1][12] In the TANGO trial, 741 previously treated HIV-infected adults who were virologically suppressed for more than 6 months on a 3-drug antiretroviral regimen that included tenofovir alafenamide (TAF; i.e., TAF and emtricitabine in conjunction with an HIV INSTI, NNRTI, or boosted PI) and had no history of virologic failure and no evidence of resistance to INSTIs or NRTIs were randomized 1:1 to switch to a 2-drug regimen of dolutegravir and lamivudine (fixed-combination tablet containing dolutegravir 50 mg/lamivudine 300 mg once daily) or continue their current TAF-based regimen.[1][12] Patients with HBV coinfection were excluded.[12] The primary endpoint was the proportion of patients with plasma HIV-1 RNA >=50 copies/mL (virologic nonresponse) at week 48.[1]

At baseline, the median age was 39 years; 8% of patients were female, 21% were non-white, 5% were CDC stage 3 (AIDS), and 98% had baseline CD4+ T-cell counts >=200 cells/mm3.[1] Most patients were on an INSTI-based, TAF-based regimen prior to study enrollment, and the median length of antiretroviral treatment prior to study enrollment was 2.8 years in the dolutegravir/lamivudine group and 2.9 years in the group continuing their TAF-based regimen.[1] The 48-week data indicated that a switch to a 2-drug regimen of dolutegravir/lamivudine in virologically suppressed patients was noninferior to continued treatment with a 3-drug TAF-based regimen.[1][12] The rate of virologic nonresponse was <1% in both treatment arms at week 48.[1] At week 144, switching to dolutegravir/lamivudine remained noninferior to continuation of a TAF-based regimen; the proportion of patients with virologic nonresponse was 0.3% in the dolutegravir/lamivudine group and 1.3% in the group of patients continuing a TAF-based regimen.[1][14] Treatment outcomes were similar across subgroups by age, sex, race, baseline CD4+ T-cell count, baseline third-agent class (PI, INSTI, or NNRTI), CDC HIV disease stage, and countries.[1] The median change from baseline in CD4+ T-cell count at week 144 was 36 cells/mm3 in the dolutegravir/lamivudine group and 35 cells/mm3 in the group of patients continuing a TAF-based regimen.[1]

An additional phase 3, randomized, open-label, noninferiority trial (SALSA; NCT04021290) examined the efficacy of switching to dolutegravir/lamivudine compared with continuing various 3- or 4-drug antiretroviral regimens in 493 virologically suppressed adults with HIV-1.[15] Patients were eligible for enrollment if they had an undetectable viral load for >=6 months prior to screening and were stable on their first or second antiretroviral regimen for >=3 months prior to screening.[15] Any prior switch in therapy must not have occurred due to suspected or established treatment failure.[15] Acceptable stable antiretroviral regimens were those that included 2 NRTIs plus an INSTI, NNRTI, or PI.[15] The primary endpoint was the proportion of patients with plasma HIV-1 RNA >=50 copies/mL at week 48.[15] At baseline, the median age was 45 years; 39% of patients were female, 19% were African American, and 14% were Asian.[15] At 48 weeks, switching to dolutegravir/lamivudine was found to be noninferior to continuing the current antiretroviral regimen; the proportion of patients with HIV-1 RNA >=50 copies/mL was 0.4% in the dolutegravir/lamivudine group and 1.2% in the group of patients continuing their baseline regimen.[15]

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.[200][201][202] Antiretroviral therapy is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.[200][201][202] The primary goals of antiretroviral therapy are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.[200][202] While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.[200][201][202] Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.[200][201][202]

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.[200][201] In both treatment-naive adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an INSTI, an NNRTI, or a PI with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).[200][201][202] Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.[200][201][202] In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.[200]

Dolutegravir/lamivudine is a co-formulation of an INSTI (dolutegravir) and an NRTI (lamivudine).[200] In the 2023 HHS adult and adolescent HIV treatment guideline, dolutegravir/lamivudine is listed among recommended initial regimens for most people with HIV; however, it is not recommended for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom antiretroviral therapy is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available.[200]

In the 2023 HHS pediatric HIV treatment guideline, dolutegravir/lamivudine is not a recommended regimen for children with HIV; data are insufficient to support the use of 2-drug regimens in children at this time.[201]

In the 2023 HHS perinatal HIV treatment guideline, dolutegravir is included in various antiretroviral regimens.[202] Dolutegravir/lamivudine is not recommended for antiretroviral-naive pregnant patients due to lack of data in this patient population; however, if a pregnant patient presents to care on dolutegravir/lamivudine and demonstrates successful maintenance of viral suppression, they can continue the 2-drug regimen with more frequent viral load monitoring (every 1-2 months throughout pregnancy).[202]

Dosage And Administration

General

Pretreatment Screening

Perform testing for hepatitis B virus (HBV) infection prior to initiation of dolutegravir/lamivudine.[1]Perform pregnancy testing in individuals of reproductive potential prior to initiation of dolutegravir/lamivudine.[1]

Patient Monitoring

Monitor for hepatotoxicity during treatment with dolutegravir/lamivudine.[1]Closely monitor hepatic function with both clinical and laboratory follow-up for at least several months after discontinuing treatment with dolutegravir/lamivudine in patients who are coinfected with HBV and human immunodeficiency virus type 1 (HIV-1).[1]Monitor closely for lactic acidosis and severe hepatomegaly with steatosis in patients with known risk factors for liver disease.[1]Monitor for hematologic toxicities in patients with a sustained creatinine clearance between 30-49 mL/minute who receive dolutegravir/lamivudine.[1]

Administration

The fixed combination dolutegravir/lamivudine is administered orally once daily with or without food.[1]

Store dolutegravir/lamivudine tablets below 30°C.[1]

Dosage

Fixed-combination tablets of dolutegravir/lamivudine contain dolutegravir sodium and lamivudine; dosages are expressed in terms of dolutegravir and lamivudine, respectively.[1]

Each fixed-combination tablet of dolutegravir/lamivudine contains 50 mg of dolutegravir and 300 mg of lamivudine.[1]

Adult Dosage

Treatment of HIV-1 Infection

For the treatment of human immunodeficiency virus type 1 (HIV-1) infection, the recommended dosage of dolutegravir/lamivudine is 1 tablet (50 mg of dolutegravir and 300 mg of lamivudine) once daily.[1]

Treatment of HIV-1 Infection in Adults Receiving Carbamazepine or Rifampin

If dolutegravir/lamivudine is used for the treatment of HIV-1 infection in adults receiving carbamazepine or rifampin, patients should receive 1 tablet of the fixed combination (50 mg of dolutegravir and 300 mg of lamivudine) once daily and a 50-mg tablet of single-entity dolutegravir once daily given 12 hours after the fixed-combination tablet.[1]

Special Populations

Hepatic Impairment

Dosage adjustment of dolutegravir/lamivudine is not necessary in adults with mild or moderate hepatic impairment (Child-Pugh class A or B).[1]

Dolutegravir/lamivudine is not recommended in patients with severe hepatic impairment (Child-Pugh class C).[1]

Renal Impairment

Dolutegravir/lamivudine is not recommended in patients with creatinine clearances <30 mL/minute.[1]

Geriatric Patients

The manufacturer makes no specific dosage recommendations for dolutegravir/lamivudine in geriatric patients, but recommends caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.[1]

Cautions

Contraindications

Prior hypersensitivity to dolutegravir or lamivudine.[1]Concomitant use with dofetilide because of the potential for serious and/or life-threatening adverse effects resulting from increased dofetilide plasma concentrations.[1]

Warnings/Precautions

Warnings

HIV and Hepatitis B Virus Coinfection

A boxed warning regarding the risk of lamivudine-resistant strains of hepatitis B virus (HBV) in patients coinfected with human immunodeficiency virus type 1 (HIV-1) and exacerbations of HBV is included in the prescribing information of dolutegravir/lamivudine.[1] Test all patients with HIV-1 infection for HBV prior to or when initiating dolutegravir/lamivudine.[1] Lamivudine-resistant strains of HBV have emerged in patients coinfected with HBV and HIV-1 who were receiving lamivudine-containing antiretroviral regimens.[1] In patients with HIV-1 and HBV coinfection, severe acute exacerbations of HBV infection, including liver decompensation and liver failure, have occurred following discontinuance of lamivudine-containing regimens.[1] Such reactions could occur following discontinuance of dolutegravir/lamivudine.[1] Some experts state that a 2-drug antiretroviral regimen of dolutegravir and lamivudine should not be used in patients coinfected with HBV.[200] The manufacturer states that if a decision is made to use dolutegravir/lamivudine in patients coinfected with HIV-1 and HBV, consider appropriate additional treatment for chronic HBV infection; alternatively, consider a different antiretroviral regimen.[1] Closely monitor hepatic function with clinical and laboratory follow-up for at least several months after dolutegravir/lamivudine is discontinued in patients coinfected with HIV-1 and HBV.[1] If appropriate, initiation of HBV treatment may be warranted, especially in patients with advanced liver disease or cirrhosis.[1]

Other Warnings and Precautions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., rash, constitutional findings, and, sometimes, organ dysfunction including liver injury) have been reported in patients receiving dolutegravir.[1] These adverse effects were reported in <1% of patients receiving dolutegravir in phase 3 clinical trials.[1]

Discontinue dolutegravir/lamivudine immediately if signs or symptoms of hypersensitivity reactions occur (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing).[1] Monitor clinical status, including liver aminotransferase concentrations, and initiate appropriate therapy.[1]

Delay in stopping dolutegravir/lamivudine treatment or other suspect agents after onset of a hypersensitivity reaction may result in a life-threatening reaction.[1]

Hepatotoxicity

Adverse hepatic effects have been reported in patients receiving dolutegravir-containing regimens.[1]

Patients with underlying HBV or hepatitis C virus (HCV) may be at increased risk for development or worsening of serum aminotransferase elevations.[1] In some patients receiving a dolutegravir-containing regimen, serum aminotransferase elevations were consistent with immune reconstitution syndrome or HBV reactivation, particularly in the setting where HBV treatment had been discontinued.[1]

Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure, also have been reported in patients receiving dolutegravir-containing regimens who had no preexisting hepatic disease or other identifiable risk factors.[1] Drug-induced liver injury leading to liver transplantation has been reported with the fixed combination of abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine).[1]

Monitor for hepatotoxicity in patients receiving dolutegravir/lamivudine.[1]

Fetal/Neonatal Morbidity and Mortality

Data from an observational study in Botswana showed an association between dolutegravir and an increased risk of neural tube defects when the drug is administered at the time of conception and during early pregnancy.[1][10]

Because there is only a limited understanding of reported types of neural tube defects associated with dolutegravir use, inform individuals of reproductive potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with dolutegravir/lamivudine.[1] Assess the risks and benefits of dolutegravir/lamivudine and discuss with the patient to determine if an alternative should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester.[1]

Perform pregnancy testing in individuals of reproductive potential before initiation of dolutegravir/lamivudine, and counsel them on the consistent use of effective contraception.[1]

Dolutegravir/lamivudine may be considered during the second and third trimesters of pregnancy if expected benefits justify potential risks to the pregnant woman and fetus.[1]

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis (sometimes fatal) have been reported in patients receiving nucleoside analogs, including lamivudine.[1] These cases were reported most frequently in women; obesity also may be a risk factor.[1]

Monitor closely if dolutegravir/lamivudine is used in patients with known risk factors for liver disease.[1]

Discontinue dolutegravir/lamivudine in patients who develop clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (e.g., hepatomegaly and steatosis even in the absence of markedly increased serum aminotransferase concentrations).[1]

Drug Interactions

Concomitant use of dolutegravir/lamivudine and certain other drugs may result in known or potentially clinically important drug interactions, some of which may lead to loss of therapeutic effect of dolutegravir/lamivudine and possible development of resistance or result in greater exposures of the concomitant drug.[1]

Consider the potential for drug interactions prior to and during dolutegravir/lamivudine therapy; review concomitant drugs during dolutegravir/lamivudine therapy and monitor the patient for adverse effects.[1]

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with multiple-drug antiretroviral therapy, including dolutegravir/lamivudine.[1] During the initial phase of treatment, HIV-infected patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium infection, cytomegalovirus [CMV], Pneumocystis jirovecii, tuberculosis); such responses may necessitate further evaluation and treatment.[1]

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of antiretroviral therapy.[1]

Use of Fixed Combinations

When dolutegravir/lamivudine is used, consider the cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination.[1]

Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.[1]

Specific Populations

Pregnancy

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to dolutegravir/lamivudine during pregnancy.[1] Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting http://www.apregistry.com/.[1][202]

Dolutegravir crosses the placenta.[1] In a clinical trial conducted in Uganda and South Africa in pregnant women receiving dolutegravir 50 mg once daily in the last trimester, the ratio of median dolutegravir concentration in fetal umbilical cord to that in maternal peripheral plasma was 1.21 (range, 0.51-2.11).[1] Lamivudine readily crosses the placenta and concentrations of the drug were generally similar in maternal, neonatal, and umbilical cord serum samples.[1]

Human data regarding use of dolutegravir/lamivudine in pregnant women are insufficient to definitively assess a drug-associated risk for birth defects and miscarriage associated with the fixed combination.[1] Based on prospective reports to the APR of 842 exposures to dolutegravir during pregnancy resulting in live births, the prevalence of defects in live births was 3.3% and 4.8% following first-trimester and second-/third-trimester exposures, respectively, in comparison to the background birth defect rate of 2.7% in the US reference population.[1] Based on prospective reports to the APR of over 12,000 exposures to lamivudine during pregnancy resulting in live births (including over 5300 exposures in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the US reference population.[1]

Interim analyses from an observational birth outcome surveillance study in Botswana (Tsepamo study) showed an increased risk of neural tube defects associated with use of dolutegravir-containing regimens at the time of conception and during early pregnancy compared with use of antiretroviral regimens that did not contain dolutegravir.[1][10] Based on these findings, the manufacturer states to advise individuals of reproductive potential, including those actively trying to become pregnant, of the potential risk of neural tube defects.[1] Assess the risks and benefits of dolutegravir/lamivudine and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester.[1] A benefit-risk assessment should consider factors such as the feasibility of switching to a different regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant versus the risk of neural tube defects.[1] Use of dolutegravir/lamivudine may be considered during the second and third trimesters of pregnancy if expected benefits justify potential risks to the pregnant woman and fetus.[1]

The Health and Human Services (HHS) Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission reports that more recent data from Botswana indicate that the prevalence of neural tube defects in infants born to pregnant women with HIV receiving dolutegravir at conception is no longer statistically different than in those receiving other antiretrovirals.[202] The HHS states that data are not available regarding use of 2-drug regimens for the treatment of HIV-1 infection during pregnancy and, therefore, a 2-drug regimen of dolutegravir/lamivudine is not recommended as a complete treatment regimen in antiretroviral-naive or antiretroviral-experienced pregnant women or women of reproductive potential trying to conceive.[202]

Lactation

Dolutegravir and lamivudine are distributed into human milk.[1] It is not known whether dolutegravir/lamivudine or its components affect human milk production or affect the breast-fed infant.[1]

The Centers for Disease Control and Prevention and the HHS state that HIV-infected women should not breast-feed infants.[1][202] This is because of the potential for HIV-1 transmission in HIV-negative infants, development of viral resistance in HIV-positive infants, and adverse reactions in the breast-fed infant.[1]

Females and Males of Reproductive Potential

Perform pregnancy testing in all individuals of reproductive potential before initiation of dolutegravir/lamivudine.[1]

In individuals of reproductive potential currently on dolutegravir/lamivudine who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing dolutegravir/lamivudine and discuss with the patient if an alternative treatment should be considered.[1]

Advise individuals of reproductive potential to consistently use effective contraception during dolutegravir/lamivudine therapy.[1]

Pediatric Use

The safety and efficacy of dolutegravir/lamivudine have not been established in pediatric patients.[1]

Geriatric Use

Clinical trials of dolutegravir/lamivudine did not include a sufficient number of patients >=65 years of age to determine whether they respond differently compared with younger patients.[1]

Use dolutegravir/lamivudine with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.[1]

Hepatic Impairment

Dosage adjustment of dolutegravir/lamivudine is not necessary in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).[1]

Dolutegravir has not been studied in patients with severe hepatic impairment (Child-Pugh class C); therefore, dolutegravir/lamivudine is not recommended in those with severe hepatic impairment.[1]

Renal Impairment

Dolutegravir/lamivudine is not recommended in patients with creatinine clearances <30 mL/minute because dolutegravir/lamivudine is a fixed-dose combination preparation and dosage of its components cannot be adjusted individually.[1] Use single-entity dolutegravir and single-entity lamivudine in patients with creatinine clearances <30 mL/minute if a reduction of lamivudine dosage is required in such patients.[1]

Patients with a creatinine clearance between 30-49 mL/minute receiving dolutegravir/lamivudine may experience a 1.6-3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance >=50 mL/minute.[1] Patients with a sustained creatinine clearance between 30-49 mL/minute who receive dolutegravir/lamivudine should be monitored for hematologic toxicities.[1] If new or worsening neutropenia or anemia develop, adjust the dosage of lamivudine per the prescribing information for lamivudine.[1] If lamivudine dose adjustment is indicated, discontinue dolutegravir/lamivudine and use single-entity dolutegravir and single-entity lamivudine to construct the treatment regimen.[1]

Common Adverse Effects

Adverse effects reported in 2% or more of patients receiving dolutegravir/lamivudine include headache, nausea, diarrhea, insomnia, fatigue, and anxiety.[1][2]

Drug Interactions

The following drug interactions are based on studies using the individual components of the fixed combination of dolutegravir and lamivudine (dolutegravir/lamivudine) or are predicted to occur with the fixed combination.[1] When dolutegravir/lamivudine is used, consider interactions associated with both drugs in the fixed combination.[1]

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Cytochrome P-450 (CYP) isoenzyme 3A plays a minor role in the metabolism of dolutegravir;[1] lamivudine is not metabolized by CYP isoenzymes to any clinically important extent.[1][219]

In vitro studies indicate that dolutegravir does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A and does not induce CYP1A2, 2B6, or 3A4.[1]

Concomitant use of dolutegravir and drugs that induce CYP3A may decrease dolutegravir plasma concentrations and decrease therapeutic effects of the drug.[1] Concomitant use with drugs that inhibit CYP3A may increase dolutegravir plasma concentrations.[1]

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferases

Dolutegravir is metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A1, and in vitro studies indicate the drug also is a substrate for UGT1A3 and UGT1A9.[1]

Dolutegravir does not inhibit UGT1A1 or UGT2B7 in vitro.[1]

Pharmacokinetic interactions are possible if dolutegravir is used with inducers of UGT1A1, 1A3, or 1A9 (decreased plasma concentrations of dolutegravir and decreased therapeutic effects of the drug) or with inhibitors of these enzymes (increased plasma concentrations of dolutegravir).[1]

Drugs Affecting or Affected by P-glycoprotein Transport

Dolutegravir is a substrate of the P-glycoprotein (P-gp) transport system in vitro; dolutegravir does not inhibit P-gp-mediated transport in vitro.[1]

Pharmacokinetic interactions are possible if dolutegravir is used with inducers of P-gp (decreased plasma concentrations of dolutegravir and decreased therapeutic effects of the drug) or with inhibitors of P-gp (increased plasma concentrations of dolutegravir).[1]

Although lamivudine is a substrate of P-gp,[1][219] concomitant use with P-gp inhibitors is unlikely to affect lamivudine concentrations.[219] Lamivudine does not inhibit P-gp in vitro[1] and is not expected to affect the pharmacokinetics of drugs that are P-gp substrates.[219]

Drugs Affecting or Affected by Bile Salt Export Pump

Dolutegravir does not inhibit the bile salt export pump (BSEP) in vitro.[1]

Drugs Affecting or Affected by Breast Cancer Resistance Protein

Dolutegravir is a substrate of breast cancer resistance protein (BCRP) in vitro; dolutegravir does not inhibit BCRP in vitro.[1]

Pharmacokinetic interactions are possible if dolutegravir is used with inducers of BCRP (decreased plasma concentrations of dolutegravir and decreased therapeutic effects of the drug) or with inhibitors of BCRP (increased plasma concentrations of dolutegravir).[1]

Although lamivudine is a substrate of BCRP,[1][219] concomitant use with BCRP inhibitors is unlikely to affect lamivudine concentrations.[219] Lamivudine does not inhibit BCRP in vitro[1] and is not expected to affect the pharmacokinetics of drugs that are BCRP substrates.[219]

Drugs Affecting or Affected by Multidrug and Toxin Extrusion Transporter

Dolutegravir inhibits multidrug and toxin extrusion transporter (MATE) 1 in vitro.[1]

Concomitant use of dolutegravir may increase plasma concentrations of drugs eliminated by MATE1 (e.g., dofetilide, metformin).[1]

Lamivudine is a substrate of MATE1 and MATE2-K in vitro.[219] Although inhibitors of MATE1 or MATE2-K may increase lamivudine concentrations, this effect is not considered clinically important.[219] Lamivudine does not inhibit MATE1 or MATE2-K in vitro and is not expected to affect the pharmacokinetics of drugs that are MATE-1 or MATE2-K substrates.[219]

Drugs Affecting or Affected by Multidrug Resistance Protein

Dolutegravir does not inhibit multidrug resistance protein (MRP) 2 or MRP4 in vitro.[1]

Drugs Affecting or Affected by Organic Anion Transporters

In vitro, dolutegravir inhibits renal organic anion transporter (OAT) 1 and OAT3.[1] In vivo, dolutegravir does not alter plasma concentrations of OAT1 or OAT3 substrates (e.g., tenofovir, aminohippurate).[1]

Dolutegravir does not inhibit hepatic organic anion transporter polypeptide (OATP) 1B1 or OATP1B3 in vitro; dolutegravir is not a substrate of OATP1B1 or 1B3 in vitro.[1]

Lamivudine does not inhibit OATP1B1/3 in vitro[1] and is not expected to affect the pharmacokinetics of drugs that are OATP1B1/3 substrates.[219]

Drugs Affecting or Affected by Organic Cation Transporters

In vitro, dolutegravir inhibits renal organic cation transporter (OCT) 2; dolutegravir does not inhibit OCT1 in vitro.[1]

Dolutegravir may increase plasma concentrations of drugs eliminated by OCT2 (e.g., dalfampridine, dofetilide, metformin).[1]

Lamivudine is a substrate of OCT2 in vitro.[219] Although inhibitors of OCT2 may increase lamivudine concentrations, this effect is not considered clinically important.[219] Lamivudine does not inhibit OCT1, OCT2, or OCT3 in vitro[1] and is not expected to affect the pharmacokinetics of drugs that are OCT1, OCT2, or OCT3 substrates.[219]

Anticonvulsants

Carbamazepine

Concomitant use of carbamazepine (300 mg twice daily) and dolutegravir (50 mg once daily) decreases peak plasma concentrations and area under the plasma concentration-time curve (AUC) of dolutegravir.[1]

If carbamazepine and dolutegravir/lamivudine are used concomitantly, administer a 50-mg dose of single-entity dolutegravir once daily 12 hours after the usual daily dose of dolutegravir/lamivudine.[1]

Oxcarbazepine, Phenobarbital, and Phenytoin

Possible pharmacokinetic interactions if oxcarbazepine, phenobarbital, or phenytoin is used concomitantly with dolutegravir (decreased dolutegravir concentrations).[1]

Avoid concomitant use of oxcarbazepine, phenobarbital, or phenytoin and dolutegravir/lamivudine since data are insufficient to make dosage recommendations.[1]

Antimycobacterial Agents

Rifabutin

Rifabutin does not have a clinically important effect on the pharmacokinetics of dolutegravir.[1]

Rifampin

Concomitant use of rifampin and dolutegravir decreases plasma concentrations and AUC of dolutegravir.[1]

If rifampin and dolutegravir/lamivudine are used concomitantly, administer a 50-mg dose of single-entity dolutegravir once daily 12 hours after the usual daily dose of dolutegravir/lamivudine.[1]

Rifapentine

Clinically important decreases in dolutegravir plasma concentrations are expected if rifapentine and dolutegravir are used concomitantly.[200]

Rifapentine and dolutegravir should not be used concomitantly.[200]

Antiretroviral Agents

Dolutegravir/lamivudine is a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in certain adults, and the manufacturer states that concomitant use with other antiretroviral agents is not recommended.[1]

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and lamivudine.[1]

Calcium, Iron, Multivitamins, and Other Preparations Containing Polyvalent Cations

Calcium, Iron, and Multivitamins

Concomitant administration of oral calcium supplements, oral iron preparations, or other oral supplements containing calcium or iron (e.g., multivitamins) and dolutegravir in the fasted state may decrease absorption of dolutegravir resulting in decreased plasma concentrations and AUC of the drug.[1]

Administer dolutegravir/lamivudine at least 2 hours before or 6 hours after oral supplements containing calcium or iron.[1] Alternatively, if dolutegravir/lamivudine is administered with food, the drug can be used concomitantly with oral supplements containing calcium or iron.[1]

Preparations Containing Polyvalent Cations

Concomitant administration of drugs containing polyvalent cations (e.g., magnesium, aluminum, laxatives, buffered medications, cation-containing products) with dolutegravir in the fasted state may decrease absorption of dolutegravir resulting in decreased plasma concentrations of the drug.[1]

Administer dolutegravir/lamivudine at least 2 hours before or 6 hours after drugs or preparations containing polyvalent cations.[1]

Cardiac Drugs

Bosentan

Pharmacokinetic interactions are possible if dolutegravir is used concomitantly with bosentan (decreased dolutegravir concentrations); some experts state that dosage adjustments are not needed if bosentan and dolutegravir are used concomitantly.[200]

Dalfampridine

Concomitant use of dalfampridine and dolutegravir/lamivudine may result in increased dalfampridine concentrations and may increase the risk of seizures.[1] Weigh the potential benefits of concomitant use of dalfampridine and dolutegravir/lamivudine against the risk of seizures.[1]

Dofetilide

Concomitant use of dofetilide and dolutegravir/lamivudine may increase dofetilide plasma concentrations and increase the risk of serious and/or life-threatening adverse effects.[1]

Concomitant use of dofetilide and dolutegravir/lamivudine is contraindicated.[1]

GI Drugs

Antacids

Antacids containing aluminum, calcium, or magnesium decrease plasma concentrations and AUC of dolutegravir.[1]

Administer dolutegravir/lamivudine at least 2 hours before or 6 hours after antacids containing aluminum, calcium, or magnesium.[1]

Sucralfate

Sucralfate may decrease plasma concentrations of dolutegravir.[1]

Administer dolutegravir/lamivudine at least 2 hours before or 6 hours after sucralfate.[1]

Interferon Alfa

Concomitant use of interferon alfa and lamivudine does not have any clinically important effects on the pharmacokinetics of lamivudine.[1]

Metformin

Concomitant use of metformin hydrochloride (500 mg twice daily) and dolutegravir (50 mg once or twice daily) increases peak plasma concentrations and AUC of metformin.[1] If concomitant use of metformin and dolutegravir/lamivudine is being considered, assess the benefits and risks.[3]

Some experts recommend that if metformin is initiated in a patient receiving dolutegravir, the lowest metformin dosage should be used and dosage should be titrated based on glycemic control while monitoring for metformin-associated adverse effects.[200] When initiating or discontinuing dolutegravir in patients receiving metformin, dosage of metformin may need to be adjusted to maintain optimal glycemic control and/or minimize metformin-associated adverse effects.[200]

Methadone

Dolutegravir does not have a clinically important effect on the pharmacokinetics of methadone;[1] dosage adjustments are not needed if methadone and dolutegravir are used concomitantly.[200]

Sorbitol

Concomitant use of lamivudine and sorbitol decreases plasma concentrations and AUC of lamivudine.[1]

Avoid concomitant use of dolutegravir/lamivudine and sorbitol-containing drugs.[1]

St. John's Wort

Concomitant use of St. John's wort (Hypericum perforatum) and dolutegravir may decrease dolutegravir plasma concentrations.[1]

Avoid concomitant use of St. John's wort and dolutegravir/lamivudine; data are insufficient to make dosage recommendations.[1]

Description

Dolutegravir sodium and lamivudine (dolutegravir/lamivudine) is a fixed combination containing 2 human immunodeficiency virus (HIV) antiretrovirals.[1] Dolutegravir is an HIV integrase strand transfer inhibitor (INSTI) and lamivudine is an HIV nucleoside reverse transcriptase inhibitor (NRTI).[1] There is no in vitro evidence of antagonistic anti-HIV effects between dolutegravir and lamivudine.[1]

Dolutegravir binds to the active site of HIV integrase and blocks the strand transfer step of retroviral DNA integration, which is essential for HIV replication.[1] Dolutegravir is active against HIV type 1 (HIV-1)[1] and also has in vitro activity against HIV type 2 (HIV-2).[200]

Lamivudine is a prodrug that is phosphorylated intracellularly to the active 5'-triphosphate metabolite (lamivudine triphosphate).[1][219] After conversion to the pharmacologically active metabolite, the drug acts as a reverse transcriptase inhibitor via DNA chain termination after incorporation of the nucleotide analogue.[1][219] Lamivudine is active against HIV-1[1][219] and also is active against hepatitis B virus (HBV).[200]

Strains of HIV-1 resistant to dolutegravir have been produced in vitro and have emerged in HIV-infected patients receiving the drug; amino acid substitution G118R confers a tenfold decrease in in vitro susceptibility to dolutegravir.[1] Strains of HIV-1 resistant to lamivudine have been produced in vitro and have emerged in HIV-infected patients receiving lamivudine-containing regimens; HIV-1 resistance to lamivudine often involves amino acid substitutions M184V or M184I.[1][219] In a phase 3 clinical study evaluating a 2-drug regimen of dolutegravir and lamivudine in antiretroviral-naive adults, treatment-emergent INSTI- or NRTI-resistance substitutions were not reported in any patients at 48, 96, or 144 weeks.[1][2][3] In preliminary studies evaluating a 2-drug regimen of dolutegravir and lamivudine for switch therapy in previously treated HIV-1-infected adults, emergence of dolutegravir resistance-associated mutations was not reported[4][6][7][11] and presence of the M184V lamivudine resistance-associated mutation was not a predictor of virologic failure.[6][7] In a phase 3 clinical study evaluating a 2-drug regimen of dolutegravir and lamivudine in virologically suppressed patients, no patients met the protocol-defined confirmed virologic withdrawal criteria through week 144.[1] No emergent INSTI- or NRTI-resistance was detected by genotypic or phenotypic analyses of the last on-treatment isolate from 1 patient who received dolutegravir/lamivudine with HIV-1 RNA >=400 copies/mL at withdrawal.[1] Cross-resistance occurs among HIV INSTIs (e.g., dolutegravir, elvitegravir, raltegravir).[1] Cross-resistance also occurs among HIV NRTIs (e.g., abacavir, emtricitabine, lamivudine, zidovudine).[1]

Following oral administration of dolutegravir in the fasted state, peak plasma concentrations of the drug are attained 2.5 hours after a dose;[1] absolute oral bioavailability has not been established.[236] Dolutegravir is metabolized primarily by uridine diphosphate-glucuronosyltransferase (UGT) 1A1; cytochrome P-450 (CYP) isoenzyme 3A plays only a minor role in metabolism of the drug.[1] Following an oral dose of dolutegravir, 64% of the dose is eliminated in feces (53% as unchanged drug) and 31% is eliminated in urine (<1% as unchanged drug).[1] Dolutegravir has a plasma elimination half-life of approximately 14 hours.[1] In vitro studies indicate that dolutegravir is approximately 99% bound to plasma proteins.[1]

Following oral administration of lamivudine in the fasted state, peak plasma concentrations of the drug are attained 1 hour after a dose[1] and absolute oral bioavailability is 86%.[219] Lamivudine is principally eliminated in urine by active cationic secretion; approximately 71% of a dose is eliminated in urine.[1][219] Lamivudine is not significantly metabolized and is not metabolized by CYP isoenzymes to any clinically important extent.[1][219] Lamivudine has a plasma elimination half-life of 13-19 hours.[1] Lamivudine is 36% bound to plasma proteins.[1]

Administration of dolutegravir/lamivudine with a high-fat meal does not have a clinically important effect on the pharmacokinetics of either component.[1] No clinically significant differences in the pharmacokinetics of dolutegravir or lamivudine have been observed based on age, sex, or race.[1] Lamivudine pharmacokinetics in pregnant women are similar to those observed in non-pregnant and postpartum women.[1]

Advice To Patients

Inform patients about the critical nature of compliance with human immunodeficiency virus (HIV) therapy and importance of remaining under the care of a clinician.[200] Inform patients to take the antiretroviral regimen as prescribed and to not alter or discontinue the antiretroviral regimen without consulting a clinician.[1][200]Advise patients to take dolutegravir/lamivudine once every day at a regularly scheduled time with or without food.[1] Inform patients that dolutegravir/lamivudine is used alone as a complete regimen for the treatment of HIV-1 infection.[1]If a dose of dolutegravir/lamivudine is missed, instruct patients to take the dose as soon as it is remembered.[1] Advise patients not to double their next dose and not to take more than the prescribed dose.[1]Inform patients that testing for hepatitis B virus (HBV) infection is recommended before antiretroviral therapy is initiated.[1] Advise patients that emergence of HBV resistant to lamivudine has been reported in HIV-infected patients coinfected with HBV who have received lamivudine-containing antiretroviral regimens.[1] Also advise patients that severe acute exacerbations of HBV infection have been reported following discontinuance of lamivudine in HIV-infected patients coinfected with HBV and may occur with dolutegravir/lamivudine.[1] Inform patients with HIV and HBV coinfection that it is important to discuss with their clinician whether additional treatment for chronic HBV is warranted.[1]Advise patients to immediately discontinue dolutegravir/lamivudine and seek medical attention if rash occurs and is associated with fever, generally ill feeling, extreme tiredness, muscle or joint aches, breathing difficulty, blisters or peeling skin, oral blisters or lesions, eye inflammation, swelling of the face, eyes, lips, or mouth, and/or signs and symptoms of liver problems (e.g., yellowing of skin or whites of the eyes, dark or tea-colored urine, pale stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching, or sensitivity on right side below ribs).[1] Advise patients that close monitoring and appropriate laboratory testing and treatment may be required if a hypersensitivity reaction occurs.[1]Inform patients that hepatotoxicity has been reported in patients receiving the components of dolutegravir/lamivudine and that monitoring for hepatotoxicity is recommended.[1]Inform patients that some HIV drugs, including dolutegravir/lamivudine, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).[1]Advise patients that signs and symptoms of inflammation from other previous infections may occur soon after initiation of antiretroviral therapy in some HIV-infected individuals.[1] Advise patients to immediately inform their clinician if any signs or symptoms of infection occur.[1]Advise women to inform their clinician if they plan to become pregnant, or if pregnancy is confirmed in the first trimester, during treatment with dolutegravir/lamivudine.[1] Advise individuals of reproductive potential, including those actively trying to become pregnant, to discuss the risks and benefits of dolutegravir with their clinician to determine if an alternative treatment should be considered at the time of conception through the first trimester.[1] Advise individuals of reproductive potential taking dolutegravir/lamivudine to consistently use effective contraception during treatment.[1]Advise women to inform their clinician if they plan to breast-feed.[1] Advise HIV-infected women not to breast-feed.[1]Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John's wort), as well as any concomitant illnesses.[1]Advise patients of other important precautionary information.[1]

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Dolutegravir Sodium and Lamivudine
RoutesDosage FormsStrengthsBrand NamesManufacturer
OralTablets, film-coated50 mg (of dolutegravir) and Lamivudine 300 mgDovato®ViiV

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