Dovato

1 INDICATIONS AND USAGE DOVATO is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 25 kg with no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DOVATO. DOVATO, a two-drug combination of dolutegravir (integrase strand transfer inhibitor [INSTI]) and lamivudine (nucleoside analogue reverse transcriptase inhibitor [NRTI]) is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 25 kg with no antiretroviral treatment history or to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and no known substitutions associated with resistance to the individual components of DOVATO. ( 1 )

2 DOSAGE AND ADMINISTRATION • Prior to or when initiating DOVATO, test patients for hepatitis B virus (HBV) infection. ( 2.1 ) • One tablet taken orally once daily with or without food. ( 2.2 ) • The dolutegravir dose (50 mg) in DOVATO is insufficient when coadministered with carbamazepine or rifampin. If DOVATO is coadministered with carbamazepine or rifampin, take one tablet of DOVATO once daily, followed by an additional dolutegravir 50-mg tablet, approximately 12 hours from the dose of DOVATO. ( 2.3 ) 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. Table 1. Dosing Recommendations for DOVATO with Coadministered Drugs Coadministered Drug Dosing Recommendation Carbamazepine, rifampin An additional dolutegravir 50-mg tablet, separated by 12 hours from DOVATO, should be taken. 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 WARNINGS AND PRECAUTIONS • Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported with dolutegravir. Discontinue DOVATO immediately if signs or symptoms of hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. ( 5.2 ) • Hepatotoxicity has been reported in patients receiving a dolutegravir-containing regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with DOVATO. Monitoring for hepatotoxicity is recommended. ( 5.3 ) • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. ( 5.4 ) • Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. ( 5.6 ) 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…

4 CONTRAINDICATIONS DOVATO is contraindicated in patients: • with prior hypersensitivity reaction to dolutegravir or lamivudine [see Warnings and Precautions ( 5.2 )] . • receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events [see Drug Interactions ( 7.2 )] . • Prior hypersensitivity reaction to dolutegravir or lamivudine. ( 4 ) • Coadministration with dofetilide. ( 4 )

7 DRUG INTERACTIONS • 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. ( 7.1 ) • Refer to the full prescribing information for important drug interactions with DOVATO. ( 4 , 5.5 , 7 ) 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 )]. Table 5. Established and Other Potentially Significant Drug Interactions for DOVATO: Alterations in Dose May Be Recommended Based on Drug Interaction Trials or Predicted Interactions ↑ = Increase, ↓ = Decrease. a See Clinical Pharmacology ( 12.3 ) Table 8 or Table 9 for magnitude of interaction. Coadministered Drug Class: Drug Name Effect on Concentration Clinical Comment Antiarrhythmic: Dofetilide ↑Dofetilide Coadministration is contraindicated with DOVATO [see Contraindications ( 4 )] . Anticonvulsant: Carbamazepine a ↓Dolutegravir An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from DOVATO [see Dosage and Administration ( 2.3 )] . Anticonvulsants: Oxcarbazepine Phenytoin Phenobarbital ↓Dolutegravir Avoid coadministration with DOVATO because there are insufficient data to make dosing recommendations. Antidiabetic: Metformin a ↑Metformin Refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of DOVATO and metformin. Antimycobacterial: Rifampin a ↓Dolutegravir An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from DOVATO [see Dosage and Administration ( 2.3 )] . Herbal product: St. John’s wort ( Hypericum perforatum ) ↓Dolutegravir Avoid coadministration with DOVATO because there a…

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 (C max ) 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. Anti…

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Patients co-infected with HIV-1 and HBV [see Warnings and Precautions ( 5.1 )] • Hypersensitivity reactions [see Warnings and Precautions ( 5.2 )] • Hepatotoxicity [see Warnings and Precautions ( 5.3 )] • Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions ( 5.4 )] • Immune reconstitution syndrome [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (all grades) observed in ≥2% (in those receiving DOVATO) were headache, nausea, diarrhea, insomnia, fatigue, and anxiety. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Table 2. Adverse Reactions (All Grades) Reported in ≥2% of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in GEMINI-1 and GEMINI-2 (Week 144 Pooled Analysis) a Fatigue: includes fatigue, asthenia, and malaise. Adverse Reaction TIVICAY plus EPIVIR (n = 716) TIVICAY plus TRUVADA (n = 717) Headache 3% 4% Nausea 2% 6% Diarrhea 2% 3% Insomnia 2% 3% Fatigue a 2% 2% Anxiety 2% 1% Dizziness 1% 2% 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: Somnole…