2.1 Testing Prior to or When Initiating Treatment with DOVATO

Prior to or when initiating DOVATO, test patients for HBV infection [see Warnings and Precautions (5.1)].

2.2 Recommended Dosage

DOVATO is a fixed-dose combination product containing 50 mg of dolutegravir and 300 mg of lamivudine. The recommended dosage regimen of DOVATO in adults and adolescents 12 years of age and older and weighing at least 25 kg is one tablet taken orally once daily with or without food [see Clinical Pharmacology (12.3)].

2.3 Recommended Dosage with Certain Coadministered Drugs

The dolutegravir dose (50 mg) in DOVATO is insufficient when coadministered with drugs listed in Table 1 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended.

2.4 Not Recommended in Patients with Renal Impairment

Because DOVATO is a fixed-dose tablet and cannot be dose adjusted, DOVATO is not recommended in patients with creatinine clearance less than 30 mL/min [see Use in Specific Populations (8.6)].

2.5 Not Recommended in Patients with Severe Hepatic Impairment

DOVATO is not recommended in patients with severe hepatic impairment (Child-Pugh Score C) [see Use in Specific Populations (8.7)].

5.1 Patients Co-infected with HIV-1 and HBV: Emergence of Lamivudine-Resistant HBV and the Risk of Posttreatment Exacerbations of HBV

All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO.

Emergence of Lamivudine-Resistant HBV

Safety and efficacy of lamivudine have not been established for treatment of chronic HBV in subjects dually infected with HIV-1 and HBV. Emergence of HBV variants associated with resistance to lamivudine has been reported in HIV‑1–infected subjects who have received lamivudine‑containing antiretroviral regimens in the presence of concurrent infection with HBV. If a decision is made to administer DOVATO to patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen.

Severe Acute Exacerbations of HBV in Patients Co-infected with HIV-1 and HBV

Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing lamivudine, and may occur with discontinuation of DOVATO. Patients who are co-infected with HIV-1 and HBV who discontinue DOVATO should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with DOVATO. If appropriate, initiation of anti-HBV therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 Hypersensitivity Reactions

Hypersensitivity reactions have been reported with the use of dolutegravir, a component of DOVATO, and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. These events were reported in <1% of subjects receiving dolutegravir in Phase 3 clinical trials.

Discontinue DOVATO immediately if signs or symptoms of hypersensitivity reactions develop (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). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with DOVATO or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction [see Contraindications (4)].

5.3 Hepatotoxicity

Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen [see Adverse Reactions (6.1)]. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of DOVATO [see Adverse Reactions (6.1)]. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or HBV reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure, have also 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 leading to liver transplant has been reported with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended.

5.4 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 analogues, including lamivudine (a component of DOVATO). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Monitor closely when administering DOVATO to any patient with known risk factors for liver disease. Treatment with DOVATO should be suspended 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.

5.5 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The coadministration of DOVATO and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4), Drug Interactions (7.4)]:

•

Loss of therapeutic effect of DOVATO and possible development of resistance.

•

Possible clinically significant adverse reactions from greater exposures of coadministered drugs.

See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with DOVATO, review coadministered drugs during therapy with DOVATO, and monitor for the adverse reactions associated with the coadministered drugs.

5.6 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including DOVATO. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré 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 treatment.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trials in Adults with No Antiretroviral Treatment History

The safety assessment of DOVATO in HIV-1–infected adults with no antiretroviral treatment history and with a plasma viral load ≤500,000 HIV-1 RNA copies/mL at the screening visit, is based on the pooled Week 144 analyses of data from 2 identical, multicenter, double-blind, controlled trials, GEMINI-1 and GEMINI-2. A total of 1,433 HIV-1–infected adults with no antiretroviral treatment history received either dolutegravir (TIVICAY) 50 mg plus lamivudine (EPIVIR) 300 mg, as a complete regimen once daily, or TIVICAY 50 mg plus fixed-dose combination tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (TRUVADA), administered once daily.

The rates of adverse events leading to discontinuation in the pooled analysis were 4% of subjects who received TIVICAY plus EPIVIR and 5% in subjects who received TIVICAY plus TRUVADA. The most common adverse events leading to discontinuation were psychiatric disorders: 2% of subjects who received TIVICAY plus EPIVIR and 1% in subjects who received TIVICAY plus TRUVADA.

Adverse reactions (all grades) observed in at least 2% of subjects in either treatment arm of the Week 144 pooled analysis from GEMINI-1 and GEMINI-2 trials are provided in Table 2.

The adverse reactions observed for TIVICAY plus EPIVIR in the Week 144 analysis of the pooled data from GEMINI-1 and GEMINI-2 were generally consistent with the adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents.

Adverse reactions of at least Grade 2 occurring in ≥1% of subjects treated with TIVICAY plus EPIVIR were headache, anxiety, suicidal ideation, and insomnia (all at 1%).

Less Common Adverse Reactions: The following adverse reactions (all grades) occurred in <2% of subjects receiving dolutegravir plus lamivudine or are from studies described in the prescribing information of the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine). Some events have been included because of their seriousness and assessment of potential causal relationship.

            Blood and Lymphatic Systems Disorders: Anemia, neutropenia, thrombocytopenia.

            Gastrointestinal Disorders: Abdominal discomfort, abdominal pain, flatulence, upper abdominal pain, vomiting.

            General: Fever.

            Hepatobiliary Disorders: Hepatitis.

            Immune System Disorders: Hypersensitivity, immune reconstitution syndrome.

            Musculoskeletal Disorders: Myositis.

            Nervous System Disorders: Somnolence.

            Psychiatric Disorders: Abnormal dreams, depression. Suicidal ideation, attempt, behavior, or completion; these events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness.

            Renal and Urinary Disorders: Renal impairment.

            Skin and Subcutaneous Tissue Disorders: Pruritus, rash.

Clinical Trials in Virologically Suppressed Adults

The safety of DOVATO in virologically suppressed adults was based on Week 144 data from 740 subjects in a randomized, parallel-group, open-label, multicenter, non-inferiority controlled trial (TANGO). Subjects who were on a stable suppressive tenofovir alafenamide-based regimen (TBR) were randomized to receive DOVATO once daily or continue with their TBR for up to 148 weeks; at Week 148, the subjects randomized to continue with their TBR were switched to DOVATO once daily. All subjects are followed up to Week 200. Overall, the safety profile of DOVATO in virologically suppressed adult subjects in the TANGO trial was similar to that of TIVICAY plus EPIVIR in subjects with no antiretroviral treatment history in the GEMINI trials [see Clinical Studies (14.3)]. Adverse reactions observed in at least 2% of subjects in the TANGO trial who were treated with DOVATO were weight increased (3%) and insomnia (2%).

Laboratory Abnormalities

Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4.

Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology (12.2)]. Increases in serum creatinine occurred within the first 4 weeks of treatment in both arms and remained stable through 144 weeks. A mean change from baseline of 0.144 mg/dL and 0.176 mg/dL was observed after 144 weeks of treatment with TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively. These changes are not considered to be clinically relevant.

Clinical Trial Experience in Adolescents

The safety of DOVATO was evaluated in HIV-1–infected treatment-naïve subjects between the ages of 12 to less than 18 years and weighing at least 25 kg (N = 32) through Week 48, in an open label clinical trial, DANCE (Trial 205861). Overall, the observed safety profile in adolescent subjects was similar to those seen in adults [see Use in Specific Populations (8.4), and Clinical Studies (14.4)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during postmarketing experience in patients receiving a dolutegravir- or lamivudine-containing regimen. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole

Redistribution/accumulation of body fat.

Endocrine and Metabolic

Hyperglycemia.

General

Weakness.

Hemic and Lymphatic

Anemia (including pure red cell aplasia and severe anemias progressing on therapy).

Hepatic and Pancreatic

Lactic acidosis and hepatic steatosis [see Warnings and Precautions (5.4)], pancreatitis, posttreatment exacerbations of HBV [see Warnings and Precautions (5.1)].

Hepatobiliary Disorders

Acute liver failure, hepatotoxicity.

Hypersensitivity

Anaphylaxis, urticaria.

Investigations

Weight increased.

Musculoskeletal

Arthralgia, creatinine phosphokinase (CPK) elevation, muscle weakness, myalgia, rhabdomyolysis.

Nervous System

Paresthesia, peripheral neuropathy.

Skin

Alopecia.

7.1 Coadministration with Other Antiretroviral Drugs

DOVATO is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral drugs for the treatment of HIV-1 infection is not recommended [see Indications and Usage (1)]. Information regarding potential drug-drug interactions with other antiretroviral drugs is not provided [see Contraindications (4), Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].

7.2 Potential for DOVATO to Affect Other Drugs

Dolutegravir, a component of DOVATO, inhibits the renal organic cation transporters (OCT)2 and multidrug and toxin extrusion transporter (MATE)1; thus, it may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide, dalfampridine, and metformin [see Contraindications (4), Drug Interactions (7.4), Clinical Pharmacology (12.3)].

7.3 Potential for Other Drugs to Affect the Components of DOVATO

Dolutegravir is metabolized by uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 with some contribution from cytochrome P450 (CYP)3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of DOVATO [see Drug Interactions (7.4), Clinical Pharmacology (12.3)]. Coadministration of DOVATO and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations.

Coadministration of dolutegravir with polyvalent cation-containing products may lead to decreased absorption of dolutegravir [see Drug Interactions (7.4), Clinical Pharmacology (12.3)].

7.4 Established and Other Potentially Significant Drug Interactions

No drug interaction studies were conducted with DOVATO. The drug interactions described are based on studies conducted with dolutegravir or lamivudine when administered alone [see Clinical Pharmacology (12.3)]. Information regarding potential drug interactions with DOVATO are provided in Table 5. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy [see Contraindications (4), Clinical Pharmacology (12.3)].

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to DOVATO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1‑800‑258‑4263.

Risk Summary

Data from two, ongoing birth outcome surveillance studies in Botswana and Eswatini which together include over 14,000 individuals evaluated during pregnancy show similar prevalence of neural tube defects among infants born to individuals taking dolutegravir at the time of conception compared to those born to individuals taking non-dolutegravir-containing regimens at conception or infants born to HIV-negative individuals (see Data).

There are insufficient human data on the use of DOVATO during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. However, available human data from the APR with the individual components of DOVATO do not indicate an increased risk of birth defects (see Data). The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In animal reproduction studies, no evidence of adverse developmental outcomes (including neural tube defects) was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and 50 times (rats) the exposure in humans at the recommended human dose (RHD) (see Data). Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at systemic exposure (AUC) similar to the RHD; however, no adverse developmental effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the RHD (see Data).

Data

Human Data:

            Dolutegravir:

                  Observational studies: The first interim analysis from an ongoing birth outcome surveillance study in Botswana identified an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. A subsequent analysis was conducted based on a larger cohort from the birth outcome surveillance study in Botswana and included over 9,460 individuals exposed to dolutegravir at conception, 23,664 individuals exposed to non-dolutegravir-containing regimens, and 170,723 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.11% (95% CI: 0.05-0.19%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.11%, 95% CI: 0.07-0.16%), or to HIV-negative individuals (0.06%, 95% CI: 0.05-0.08%).

The Eswatini birth outcome surveillance study includes 9,743 individuals exposed to dolutegravir at conception, 1,838 individuals exposed to non-dolutegravir-containing regimens, and 32,259 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.08% (95% CI: 0.04-0.16%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.22%, 95% CI: 0.06-0.56%) or to HIV-negative individuals (0.08%, 95% CI: 0.06-0.12%). The observed prevalence of neural tube defects in infants delivered to individuals taking non-dolutegravir-containing regimens had a wide confidence interval due to low sample size.

Limitations of these birth outcome surveillance studies include insufficient data to determine if baseline characteristics were balanced between the study groups or to assess other factors such as the use of folic acid during the preconception or first trimester periods.

                  Antiretroviral Pregnancy Registry:

Based on prospective reports to the APR, of 1,377 exposures to dolutegravir during pregnancy resulting in live births (including 874 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 2.2% to 4.7%) following first-trimester exposure to dolutegravir-containing regimens and 5.0% (95% CI: 3.2% to 7.3%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%.

Dolutegravir has been shown to cross the placenta. In a clinical trial in Uganda and South Africa in women during the last trimester of pregnancy receiving dolutegravir 50 mg once daily, 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) (n = 15).

            Lamivudine: Based on prospective reports to the APR of exposures to lamivudine during pregnancy resulting in live births (including over 5,600 exposed in the first trimester and over 7,500 exposed in the second/third 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 U.S. reference population of the MACDP. The prevalence of defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5% to 3.3%) following second/third trimester exposure to lamivudine-containing regimens.

Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using lamivudine 150 mg twice daily with zidovudine, 10 women at 38 weeks’ gestation using lamivudine 150 mg twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9-fold (1.2- to 12.8-fold) greater compared with paired maternal serum concentration (n = 8).

Animal Data:

            Dolutegravir: Dolutegravir was administered orally to pregnant rats and rabbits (up to 1,000 mg/kg/day) on Gestation Days 6 to 17 and 6 to 18, respectively, and also to rats on Gestation Day 6 to Lactation/Postpartum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed up to the highest dose tested. During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the RHD and in rats were approximately 50 times the exposure in humans at the RHD. In the rat pre/postnatal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 50 times human exposure at the RHD).

            Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg/kg/day) and rabbits (at 90, 300 and 1,000 mg/kg/day and at 15, 40, and 90 mg/kg/day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the RHD. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the RHD. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre- and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg/kg/day (from prior to mating through Postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, was not affected by the maternal administration of lamivudine.

8.2 Lactation

Risk Summary

Dolutegravir and lamivudine are present in human milk. There is no information on the effects of DOVATO or the components of DOVATO on the breastfed infant or the effects of the drugs on milk production.

Potential risks of breastfeeding include: (1) HIV‑1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1–positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults.

8.4 Pediatric Use

The safety and efficacy of DOVATO for the treatment of HIV-1 infection have been established in adolescents 12 years of age and older and weighing at least 25 kg. Use of DOVATO for this indication is supported by DANCE trial in treatment-naïve adolescents and evidence from adequate and well-controlled trials in adults, GEMINI-1, GEMINI-2 (treatment-naïve adults) and TANGO (virologically-suppressed adults) [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14)]. Overall, the safety and efficacy data in adolescent subjects from the DANCE trial were comparable to those observed in adults, and there was no clinically significant difference in exposure for the components of DOVATO [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.4)].

The safety and efficacy of DOVATO have not been established in pediatric patients less than 12 years of age or weighing less than 25 kg.

8.5 Geriatric Use

Clinical trials of DOVATO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of DOVATO in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment

DOVATO is not recommended for patients with creatinine clearance <30 mL/min because DOVATO is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of DOVATO, is required for patients with creatinine clearance <30 mL/min, then the individual components should be used.

Patients with a creatinine clearance between 30 and 49 mL/min receiving DOVATO may experience a 1.6- to 3.3-fold higher lamivudine exposure (AUC) than patients with a creatinine clearance ≥50 mL/min. There are no safety data from randomized, controlled trials comparing DOVATO to the individual components in patients with a creatinine clearance between 30 and 49 mL/min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of hematologic toxicities (neutropenia and anemia), although discontinuations due to neutropenia or anemia each occurred in <1% of subjects. Patients with a sustained creatinine clearance between 30 and 49 mL/min who receive DOVATO should be monitored for hematologic toxicities. If new or worsening neutropenia or anemia develop, dose adjustment of lamivudine, per lamivudine prescribing information, is recommended. If lamivudine dose adjustment is indicated, DOVATO should be discontinued and the individual components should be used to construct the treatment regimen.

8.7 Hepatic Impairment

No dosage adjustment of DOVATO is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Score A or B). Dolutegravir has not been studied in patients with severe hepatic impairment (Child-Pugh Score C); therefore, DOVATO is not recommended for patients with severe hepatic impairment.

12.1 Mechanism of Action

DOVATO is a fixed-dose combination of the HIV‑1 antiretroviral agents, dolutegravir and lamivudine [see Microbiology (12.4)].

12.2 Pharmacodynamics

Cardiac Electrophysiology

The effect of combination therapy as DOVATO or lamivudine given alone on the QT interval has not been studied. At a 250-mg suspension dose (exposures approximately 3-fold that of the 50-mg once-daily dose at steady state), dolutegravir given alone did not prolong the QTc interval to any clinically relevant extent.

Effects of Dolutegravir on Renal Function

No clinically significant dolutegravir exposure-response relationship on the glomerular filtration rate or effective renal plasma flow was observed. The effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n = 37) who received dolutegravir 50 mg once daily (n = 12), dolutegravir 50 mg twice daily (n = 13), or placebo once daily (n = 12) for 14 days.

12.3 Pharmacokinetics

The Cmax, Ctrough, and AUCtau parameters of the components of DOVATO are provided in Table 6.

The absorption, distribution, and elimination pharmacokinetic parameters of the components of DOVATO are provided in Table 7.

Specific Populations

No clinically significant differences in the pharmacokinetics of the components of DOVATO were observed based on age, sex, or race. Pharmacokinetic data for dolutegravir and lamivudine in subjects aged 65 years and older are limited.

Patients with Renal Impairment: The pharmacokinetics for the individual components of DOVATO have been evaluated in patients with renal impairment. See the U.S. prescribing information for the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine).

Patients with Hepatic Impairment: The pharmacokinetics for the individual components of DOVATO have been evaluated in patients with varying degrees of hepatic impairment. See the U.S. prescribing information for the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine).

Pediatric Subjects: In adolescents receiving DOVATO, dolutegravir and lamivudine exposures were higher as 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 DOVATO (Table 8).

Pregnant women: Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples.

Drug Interaction Studies

Clinical Studies: No drug interaction studies were conducted with DOVATO. The drug interaction studies described below were conducted with dolutegravir or lamivudine when used alone. Table 9 summarizes the effects of dolutegravir on the pharmacokinetics of coadministered drugs. Table 10 summarizes the effect of other drugs on the pharmacokinetics of dolutegravir when used alone and Table 11 summarizes the effect of sorbitol on the pharmacokinetics of lamivudine when used alone.

No clinically significant differences in the pharmacokinetics of tenofovir (organic anion transporter [OAT]1 and OAT3 substrates) or para-amino hippurate (OAT1 and OAT3 substrates) were observed when coadministered with dolutegravir.

No clinically significant differences in the pharmacokinetics of trimethoprim/sulfamethoxazole were observed when coadministered with lamivudine.

No clinically significant differences in the pharmacokinetics of lamivudine were observed when coadministered with trimethoprim (MATE1, MATE2-K, and OCT2 inhibitor)/sulfamethoxazole, interferon alfa, or ribavirin.

In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically: Dolutegravir: Dolutegravir does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. Dolutegravir does not induce CYP1A2, CYP2B6, or CYP3A4.

Dolutegravir is a substrate of UGT1A3 and UGT1A9. Dolutegravir does not inhibit UGT1A1 or UGT2B7.

Dolutegravir is a substrate of BCRP and P-gp. Dolutegravir does not inhibit P‑gp, BCRP, bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. Dolutegravir is not a substrate of OATP1B1 or OATP1B3.

            Lamivudine: Lamivudine is a substrate of P-gp and BCRP. Lamivudine does not inhibit OATP1B1/3, BCRP, P-gp, MATE1, MATE2-K, OCT1, OCT2, or OCT3.

12.4 Microbiology

Mechanism of Action

Dolutegravir: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified recombinant HIV‑1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.

Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC‑TP). The principal mode of action of 3TC‑TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue.

Antiviral Activity in Cell Culture

Dolutegravir: Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV‑1 with mean concentrations of drug necessary to affect viral replication by 50 percent (EC50) values of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells.

Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a mean EC50 value of 0.52 nM in a viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates (3 in each group of M [clades A-G], and 3 in group O) with EC50 values ranging from 0.02 nM to 2.14 nM for HIV-1. Dolutegravir EC50 values against three HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM.

Lamivudine: The antiviral activity of lamivudine against HIV‑1 was assessed in a number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 3 to 15,000 nM (1 nM = 0.23 ng/mL). The EC50 values of lamivudine against different HIV-1 clades (A-G) and group O viruses ranged from 1 to 120 nM, and against HIV-2 isolates from 3 to 120 nM in PBMCs.

Antiviral Activity in Combination with Other Antiviral Agents

Neither dolutegravir nor lamivudine were antagonistic to all tested anti-HIV agents.

Resistance

Cell Culture: Dolutegravir: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV‑1 strains and clades. Amino acid substitutions emerged in different passages; the substitution G118R emergence conferred decreased susceptibility to dolutegravir of 10-fold, while substitutions E92Q, S153F or Y, G193E, or R263K conferred decreased susceptibility to dolutegravir of up to 4-fold.

            Lamivudine: HIV-1 resistance to lamivudine involves the development of a M184V or M184I amino acid change close to the active site of the viral RT. This variant arises both in cell culture and in HIV-1–infected patients treated with lamivudine-containing antiretroviral therapy. Substitutions M184V or I confer high-level resistance to lamivudine.

Clinical Subjects: At Week 144, none of the 12 subjects in the dolutegravir plus lamivudine group or the 9 subjects in the dolutegravir plus TDF/FTC group who met the protocol-defined confirmed virologic withdrawal criteria across the pooled GEMINI-1 and GEMINI-2 trials had emergent INSTI- or NRTI-resistance substitutions.

No subject who received DOVATO in the TANGO trial met the protocol-defined confirmed virologic withdrawal criteria through Week 144. No emergent INSTI- or NRTI-resistance was detected by genotypic or phenotypic analyses of the last on-treatment isolate from one subject who received DOVATO with HIV-1 RNA ≥400 copies/mL at withdrawal. No emergent resistance was detected by genotypic or phenotypic analyses of HIV-1 integrase, protease, or reverse transcriptase at the time of virologic failure in 3 subjects in the TBR arm who met the confirmed virologic withdrawal criteria.

Cross-Resistance

Dolutegravir: The susceptibility of dolutegravir was tested against 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions). The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a >2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M; E92Q/N155H; G140C/Q148R; G140S/Q148H, R or K; Q148R/N155H; T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a >2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference).

Lamivudine: Cross-resistance conferred by the M184V or I RT has been observed within the NRTI class of antiretroviral agents. The M184V or I substitution confers resistance to emtricitabine and to abacavir, which selects M184V or I plus additional RT substitutions K65R, L74V, and Y115F. Zidovudine maintains its antiretroviral activities against lamivudine-resistant HIV-1. Abacavir and tenofovir maintain antiretroviral activity against lamivudine-resistant HIV-1 harboring only the M184V or I substitution.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

Dolutegravir: Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg/kg, and rats were administered doses of up to 50 mg/kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 26 times higher than those in humans at the recommended dose. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 17 times higher than those in humans at the recommended dose.

Lamivudine: Long‑term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the recommended dose.

Mutagenicity

Dolutegravir: Dolutegravir was not genotoxic in the bacterial reverse mutation assay, in a mouse lymphoma assay, or in the in vivo rodent micronucleus assay.

Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in a cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in a microbial mutagenicity assay, in an in vitro cell transformation assay, in a rat micronucleus test, in a rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.

Impairment of Fertility

Dolutegravir or lamivudine did not affect male or female fertility in rats at doses associated with exposures approximately 44 or 112 times, respectively, higher than the exposures in humans at the recommended dose.

14.1 Description of Clinical Trials

The efficacy and safety of DOVATO were evaluated in the studies summarized in Table 12.

14.2 Clinical Trial Results in HIV-1–Infected Adult Subjects with No Antiretroviral Treatment History

GEMINI-1 and GEMINI-2 are identical 148-week, Phase 3, randomized, multicenter, parallel-group, non-inferiority trials. A total of 1,433 HIV-1–infected adults with no antiretroviral treatment history received treatment in the trials. Subjects were enrolled with a screening plasma HIV-1 RNA of 1,000 to ≤500,000 copies/mL and without evidence of major resistance-associated mutations or evidence of HBV infection. Subjects were randomized to receive a 2-drug regimen of TIVICAY 50 mg plus EPIVIR 300 mg administered once daily or TIVICAY 50 mg plus fixed-dose TRUVADA administered once daily. The primary efficacy endpoint for each GEMINI trial was the proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48 (Snapshot algorithm) who were randomized and treated.

At baseline, in the pooled analysis, the median age of subjects was 33 years, 15% female, 69% white, 9% were CDC Stage 3 (AIDS), the median plasma HIV-1 RNA was 4.4 log10 copies/mL, 20% had HIV-1 RNA >100,000 copies/mL, the median CD4+ cell count was 432 cells/mm3, and 8% had CD4+ cell count ≤200 cells/mm3; these characteristics were similar between trials and treatment arms within each trial.

Week 144 outcomes (including outcomes by key baseline covariates) for the pooled GEMINI-1 and GEMINI-2 trials are shown in Table 13. The results of the pooled analysis are consistent with the results from the individual trials, for which the secondary endpoint is the difference in proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 144 based on the Snapshot algorithm for TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA. The proportions of subjects with plasma HIV-1 RNA <50 copies/mL in the group receiving TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA were 79% and 83%, respectively, in GEMINI‑1 and 84% in both treatment arms of GEMINI-2. The adjusted difference was -3.6% (95% CI: -9.4%, 2.1) for GEMINI-1 and 0.0% (95% CI: -5.3%, 5.3%) for GEMINI-2. At Week 144, no subjects who met the protocol-defined confirmed virologic withdrawal criteria had any treatment-emergent substitutions associated with resistance to dolutegravir or NRTIs.

The primary endpoint was assessed at Week 48 and the virologic success rate was 91% in the group receiving TIVICAY plus EPIVIR and 93% in the group receiving TIVICAY plus TRUVADA, with a treatment difference of -1.7% (95% CI: -4.4%, 1.1%) in the pooled data. The results of the pooled analysis are similar to the individual trials, for which the primary endpoint (proportion of subjects with plasma HIV-1 RNA <50 copies/mL at Week 48 based on the Snapshot algorithm for TIVICAY plus EPIVIR versus TIVICAY plus TRUVADA) was met. The adjusted difference was -2.6% (95% CI: ‑6.7%, 1.5%) for GEMINI-1 and -0.7% (95% CI: ‑4.3%, 2.9%) for GEMINI-2.

The adjusted mean change from baseline in CD4+ cell count based on the pooled analysis at Week 144 was 302 cells/mm3 for the group receiving TIVICAY plus EPIVIR and 300 cells/mm3 for the group receiving TIVICAY plus TRUVADA.

14.3 Clinical Trial Results in HIV-1–Infected Virologically Suppressed Adult Subjects Who Switched to DOVATO

The efficacy of DOVATO in HIV-1–infected, antiretroviral treatment-experienced, virologically suppressed subjects is supported by data from a 200-week, Phase 3, randomized, open-label, multicenter, parallel-group, non-inferiority controlled trial (TANGO). A total of 741 adult HIV-1–infected subjects who were on a stable suppressive TBR received treatment in the trial. Subjects were randomized in a 1:1 ratio to receive DOVATO once daily or continue with their TBR for up to 148 weeks; at Week 148, the subjects randomized to continue with their TBR were switched to DOVATO once daily. All subjects are followed up to Week 200. Randomization was stratified by baseline third-agent class (protease inhibitor [PI], INSTI, or non-nucleoside reverse transcriptase inhibitor [NNRTI]). The primary efficacy endpoint was the proportion of subjects with plasma HIV-1 RNA ≥50 copies/mL (virologic non-response) at Week 48 (Snapshot algorithm adjusting for randomization stratification factor).

At baseline, the median age of subjects was 39 years, 8% were female, 21% non-white, 5% were CDC Class C (AIDS), and 98% of subjects had baseline CD4+ cell count ≥200 cells/mm3; these characteristics were similar between treatment arms. Subjects receiving DOVATO and a TBR had been on an antiretroviral regimen for a median of 2.8 and 2.9 years, respectively, prior to Day 1. Most subjects were on an integrase inhibitor-based TBR (78% and 80% of subjects who received DOVATO and a TBR, respectively).

In the primary 48 week analysis, <1% of subjects in both arms experienced virologic failure (HIV-1 RNA ≥50 copies/mL) at Week 48 based on the Snapshot algorithm. Based on a 4% non-inferiority margin, DOVATO was non-inferior to TBR in the primary analysis (proportion of subjects with plasma HIV-1 RNA ≥50 copies/mL), as the upper bound of the 95% CI for the adjusted treatment difference (-1.2%, 0.7%) was less than 4%.

At Week 144, the proportion of subjects with HIV-1 RNA ≥50 copies/mL (Snapshot) was 0.3% and 1.3% in the DOVATO and TBR treatment arms, respectively (Table 14).

In TANGO, treatment outcomes between treatment arms were similar across the stratification factor, baseline third-agent class (PI, INSTI, or NNRTI), and across subgroups by age, sex, race, baseline CD4+ cell count, CDC HIV disease stage, and countries. The median change from baseline in CD4+ T-cell count at Week 144 was 36.0 cells/mm3 in the DOVATO arm and 35.0 cells/mm3 in the TBR arm.

14.4 Clinical Trial Results in Adolescent Subjects

The 48 week efficacy of DOVATO was evaluated in an open-label multicenter trial (DANCE) in 30 evaluable treatment-naïve HIV-1–infected adolescents aged 12 to less than18 years and weighing at least 25 kg. Eighty-seven percent (26/30) of subjects achieved HIV-1 RNA <50 copies/mL at Week 48, and the mean increase from baseline in CD4+ cell count was 234 cells/mm3 at Week 48 [see Adverse Reactions (6.1), Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].