DOVATO is a fixed-dose combination tablet containing dolutegravir (as dolutegravir sodium), an integrase strand transfer inhibitor (INSTI), and lamivudine (also known as 3TC), a nucleoside analogue reverse transcriptase inhibitor (NRTI). DOVATO tablets are for oral administration. Each film-coated tablet contains the active ingredients 50 mg of dolutegravir (equivalent to 52.6 mg dolutegravir sodium) and 300 mg of lamivudine and the inactive ingredients magnesium stearate, mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, sodium stearyl fumarate. The tablet film-coating contains the inactive ingredients hypromellose, polyethylene glycol, titanium dioxide. Dolutegravir The chemical name of dolutegravir sodium is sodium (4 R ,12a S )-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2 H -pyrido[1',2':4,5]pyrazino[2,1- b ][1,3]oxazin-7-olate. The empirical formula is C 20 H 18 F 2 N 3 NaO 5 , and the molecular weight is 441.36 g/mol. It has the following structural formula: Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water. Lamivudine The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (‑)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (‑)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C 8 H 11 N 3 O 3 S and a molecular weight of 229.3 g/mol. It has the following structural formula: Lamivudine is a white to off‑white crystalline solid and is soluble in water. Dolutegravir sodium chemical structure Lamivudine chemical structure

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.

DOVATO tablets are oval, biconvex, white, film-coated tablets, debossed with “SV 137” on one face. Each tablet contains 50 mg of dolutegravir and 300 mg of lamivudine. Tablets: 50 mg of dolutegravir and 300 mg of lamivudine.

• Prior to or when initiating DOVATO, test patients for hepatitis B virus (HBV) infection. • One tablet taken orally once daily with or without food. • 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

Testing Prior to or When Initiating Treatment with DOVATO Prior to or when initiating DOVATO, test patients for HBV infection

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

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

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

Not Recommended in Patients with Severe Hepatic Impairment DOVATO is not recommended in patients with severe hepatic impairment (Child-Pugh Score C) .

• 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. • 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. • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. • Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. 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

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

Hepatotoxicity Hepatic adverse events have 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 use of DOVATO . 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

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

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 : • 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

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.

• 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. • 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 . Information regarding potential drug-drug interactions with other antiretroviral drugs is not provided

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

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 . 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

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 . 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 . 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 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 . Anticonvulsant: Carbamazepine a ↓Dolutegravir An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from DOVATO . 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 . Herbal product: St. John’s wort ( Hypericum perforatum ) ↓Dolutegravir Avoid coadministration with DOVATO because there are insufficient data to make dosing recommendations. Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids a or laxatives Sucralfate Buffered medications ↓Dolutegravir Administer DOVATO 2 hours before or 6 hours after taking medications containing polyvalent cations. Oral calcium and iron supplements , including multivitamins containing calcium or iron a ↓Dolutegravir When taken with food, DOVATO and supplements or multivitamins containing calcium or iron can be taken at the same time. Under fasting conditions, DOVATO should be taken 2 hours before or 6 hours after taking supplements containing calcium or iron. Potassium channel blocker: Dalfampridine ↑Dalfampridine Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with DOVATO should be considered against the risk of seizures in these patients. Sorbitol a ↓Lamivudine When possible, avoid use of sorbitol-containing medicines with DOVATO.