5 WARNINGS AND PRECAUTIONS

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 Embryo-Fetal Toxicity

An ongoing observational study showed 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. As there is limited understanding of the association of reported types of neural tube defects with dolutegravir use, inform individuals of childbearing potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with DOVATO. Assess the risks and benefits of DOVATO 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 [see Use in Specific Populations (8.1, 8.3)].

Pregnancy testing is recommended before initiation of DOVATO in individuals of childbearing potential [see Dosage and Administration (2.1)].

Individuals of childbearing potential should be counseled on the consistent use of effective contraception [see Use in Specific Populations (8.1, 8.3)].

DOVATO may be considered during the second and third trimesters of pregnancy if the expected benefit justifies the potential risk to the pregnant woman and the fetus.

5.5 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.

5.6 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)]:

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

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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.

5.7 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.

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)

Embryo-fetal toxicity may occur when used at the time of conception and in early pregnancy. Assess the risks and benefits of DOVATO 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 due to the risk of neural tube defects. Individuals of childbearing potential should be counseled on the consistent use of effective contraception. (2.1, 5.4, 8.1, 8.3)

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. (5.5)

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. (5.7)

2 DOSAGE AND ADMINISTRATION

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)].

Pregnancy testing is recommended before initiation of DOVATO in individuals of childbearing potential [see Warnings and Precautions (5.4), Use in Specific Populations (8.1, 8.3)].

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)].

Prior to or when initiating DOVATO, test patients for hepatitis B virus (HBV) infection. (2.1)

Pregnancy testing: Pregnancy testing is recommended before initiation of DOVATO in individuals of childbearing potential. (2.1, 5.4, 8.1, 8.3)

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)