Dolutegravirside effects

The following adverse reactions are discussed in other sections of the labeling:

Patients co-infected with HIV-1 and HBV

Hypersensitivity reactions

Hepatotoxicity

Lactic acidosis and severe hepatomegaly with steatosis

Immune reconstitution syndrome The most common adverse reactions (all grades) observed in ≥2% (in those receiving DOVATO) were headache, nausea, diarrhea, insomnia, fatigue, and anxiety. 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: 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. 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. Table 3. Selected Laboratory Abnormalities (Grades 2 to 4; Week 144 Pooled Analyses) in GEMINI-1 and GEMINI-2 Trials ULN = Upper limit of normal. Laboratory Parameter Abnormality TIVICAY plus EPIVIR (n = 716) TIVICAY plus TRUVADA (n = 717) Alanine aminotransferase (ALT) Grade 2 (2.5 to <5.0 x ULN) 4% 4% Grade 3 to 4 (≥5.0 x ULN) 4% 3% Aspartate aminotransferase (AST) Grade 2 (2.5 to <5.0 x ULN) 5% 5% Grade 3 to 4 (≥5.0 x ULN) 3% 4% Total bilirubin Grade 2 (1.6 to <2.6 x ULN) 3% 4% Grade 3 to 4 (≥2.6 x ULN) 1% 1% Creatine kinase Grade 2 (6.0 to <10 x ULN) 5% 5% Grade 3 to 4 (≥10.0 x ULN) 8% 9% Hyperglycemia (glucose) Grade 2 (126 to 250 mg/dL) 11% 8% Grade 3 to 4 (>250 mg/dL) 1% 1% Hypophosphatemia (phosphate) Grade 2 (1.4 to <2.0 mg/dL) 11% 12% Grade 3 to 4 (<1.4 mg/dL) 1% 2% Lipase Grade 2 (1.5 to <3.0 x ULN) 7% 8% Grade 3 to 4 (≥3.0 x ULN) 3% 5% Table 4. Mean Change from Baseline in Fasted Lipid Values (Week 144 Pooled Analyses a ) in GEMINI 1 and GEMINI 2 Trials HDL = High density lipoprotein; LDL = Low density lipoprotein. a Subjects on lipid-lowering agents at baseline are excluded (TIVICAY plus EPIVIR, n = 30; TIVICAY plus TRUVADA, n = 23). The last available fasted, on-treatment lipid value prior to initiation of a lipid-lowering agent was carried forward in place of observed values after initiation of a lipid-lowering agent. A total of 51 and 28 subjects receiving TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively, initiated lipid-lowering agents post-baseline. Laboratory Parameter Preferred Term TIVICAY plus EPIVIR (n = 716) TIVICAY plus TRUVADA (n = 717) Cholesterol (mg/dL) 15 -2 HDL cholesterol (mg/dL) 7 4 LDL cholesterol (mg/dL) 7 -4 Triglycerides (mg/dL) 10 -9 Total cholesterol/HDL cholesterol ratio -0.2 -0.4 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. 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 12 to less than 18 years of age 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.

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, sideroblastic anemia, and severe anemias progressing on therapy). Hepatic and Pancreatic Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbations of HBV. 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.