Triumeq

WARNING: HYPERSENSITIVITY REACTIONS, AND EXACERBATIONS OF HEPATITIS B Hypersensitivity Reactions Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of TRIUMEQ and TRIUMEQ PD (abacavir, dolutegravir, and lamivudine). Patients who carry the HLA ‑ B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir, although hypersensitivity reactions have occurred in patients who do not carry the HLA ‑ B*5701 allele [see Warnings and Precautions ( 5.1 )] . TRIUMEQ and TRIUMEQ PD are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA ‑ B*5701-positive patients [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . All patients should be screened for the HLA ‑ B*5701 allele prior to initiating therapy with TRIUMEQ or TRIUMEQ PD or reinitiation of therapy with TRIUMEQ or TRIUMEQ PD, unless patients have a previously documented HLA ‑ B*5701 allele assessment. Discontinue TRIUMEQ or TRIUMEQ PD immediately if a hypersensitivity reaction is suspected, regardless of HLA ‑ B*5701 status and even when other diagnoses are possible [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )] . Following a hypersensitivity reaction to TRIUMEQ or TRIUMEQ PD, NEVER restart TRIUMEQ or TRIUMEQ PD or any other abacavir ‑ containing product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see Warnings and Precautions ( 5.1 )] . Exacerbations of Hepatitis B All patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) prior to or when initiating TRIUMEQ or TRIUMEQ PD. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If TRIUMEQ or TRIUMEQ PD is used in 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 hepatitis B have been reported in patients who are co ‑ infected with HBV and HIV-1 and have discontinued lamivudine, a component of TRIUMEQ and TRIUMEQ PD. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment [see Warnings and Precautions ( 5.2 )]. WARNING: HYPERSENSITIVITY REACTIONS, AND EXACERBATIONS OF HEPATITIS B See full prescribing information for complete boxed warning. Hypersensitivity Reactions • Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products. ( 5.1 ) • Hypersensitivity to abacavir is a multi-organ clinical syndrome. ( 5.1 ) • Patients who carry the HLA ‑ B*5701 allele are at a higher risk of experiencing a hypersensitivity reaction to abacavir. ( 5.1 ) • TRIUMEQ and TRIUMEQ PD are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. ( 4 ) • Discontinue TRIUMEQ or TRIUMEQ PD as soon as a hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue TRIUMEQ or TRIUMEQ PD if hypersensitivity cannot be ruled out, even when other diagnoses are possible. ( 5.1 ) • Following a hypersensitivity reaction to TRIUMEQ or TRIUMEQ PD, NEVER restart TRIUMEQ, TRIUMEQ PD, or any other abacavir ‑ containing product. ( 5.1 ) Exacerbations of Hepatitis B • All patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) prior to or when initiating TRIUMEQ or TRIUMEQ PD. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If TRIUMEQ or TRIUMEQ PD is used in 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 have been reported in patients who are co-infected with HBV and HIV ‑ 1 and have discontinued lamivudine, a component of TRIUMEQ and TRIUMEQ PD. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment. ( 5.2 )

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity has been reported in patients receiving a dolutegravir-containing regimen. 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 ) • TRIUMEQ tablets and TRIUMEQ PD tablets for oral suspension are not substitutable. ( 2.3 , 5.7 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions have been reported with the use of abacavir or dolutegravir, components of TRIUMEQ and TRIUMEQ PD. Abacavir Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing regimens. See full prescribing information for ZIAGEN (abacavir). Abacavir hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment [see Adverse Reactions ( 6.1 )] . Patients who carry the HLA‑B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA‑B*5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA‑B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making. Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir: • All patients should be screened for the HLA‑B*5701 allele prior to initiating therapy with TRIUMEQ or TRIUMEQ PD or reinitiation of therapy with TRIUMEQ or TRIUMEQ PD, unless patients have a previously documented HLA‑B*5701 allele assessment. • TRIUMEQ and TRIUMEQ PD are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA‑B*5701‑positive patients. • Before starting TRIUMEQ or TRIUMEQ PD, review medical history for prior exposure to any abacavir-containing product. NEVER restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA‑B*5701 status. • To reduce the risk of a life‑threatening hypersensitivity reaction, regardless of HLA‑B*5701 status, discontinue TRIUMEQ or TRIUMEQ PD immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). Clinical status, including liver chemistries, should be monitored and appropriate therapy initiated. • If a hypersensitivity reaction cannot be ruled out, do not restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours. • Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ or TRIUMEQ PD would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or TRIUMEQ PD or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ or TRIUMEQ PD due to a hypersensitivity reaction. • If a hypersensitivity reaction is ruled out, patients may restart TRIUMEQ or TRIUMEQ PD. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of TRIUMEQ or TRIUMEQ PD, or any other abacavir-containing product, is recommended only if medical care can be readily accessed. • A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill. Dolutegravir Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in <1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TRIUMEQ or TRIUMEQ PD and other suspect agents 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 TRIUMEQ or TRIUMEQ PD or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ or TRIUMEQ PD would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or TRIUMEQ PD or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ or TRIUMEQ PD due to a hypersensitivity reaction. 5.2 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 TRIUMEQ or TRIUMEQ PD. 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 TRIUMEQ or TRIUMEQ PD 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 TRIUMEQ or TRIUMEQ PD. Patients who are co-infected with HIV-1 and HBV who discontinue TRIUMEQ or TRIUMEQ PD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with TRIUMEQ or TRIUMEQ PD. 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. 5.3 Hepatotoxicity Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen [see Adverse Reactions ( 6.1 , 6.2 )] . Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ or TRIUMEQ PD [see Adverse Reactions ( 6.1 )] . In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B 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, including pediatric 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. 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 abacavir and lamivudine (components of TRIUMEQ and TRIUMEQ PD). 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. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Treatment with TRIUMEQ or TRIUMEQ PD 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 concomitant use of TRIUMEQ or TRIUMEQ PD and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications ( 4 ), Drug Interactions ( 7.3 )] : • Loss of therapeutic effect of TRIUMEQ or TRIUMEQ PD and possible development of resistance. • Possible clinically significant adverse reactions from greater exposures of concomitant drugs. See Table 6 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 TRIUMEQ or TRIUMEQ PD, review concomitant medications during therapy with TRIUMEQ or TRIUMEQ PD, and monitor for the adverse reactions associated with the concomitant drugs. 5.6 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIUMEQ or TRIUMEQ PD. 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, Guillain-Barré syndrome, autoimmune hepatitis) 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. 5.7 Different Formulations Are Not Substitutable TRIUMEQ and TRIUMEQ PD are not bioequivalent and are not substitutable on a milligram-per-milligram basis [see Clinical Pharmacology ( 12.3 )] . If a pediatric patient switches from the tablets for oral suspension to the tablets, the dosage must be adjusted [see Dosage and Administration ( 2.3 , 2.5 )] . Incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure to the individual components. 5.8 Myocardial Infarction Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir‑treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir and the risk of MI is inconclusive. As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Serious and sometimes fatal hypersensitivity reaction [see Boxed Warning , Warnings and Precautions ( 5.1 )] . • Exacerbations of hepatitis B [see Boxed Warning , Warnings and Precautions ( 5.3 )] . • 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 )] . • Myocardial infarction [see Warnings and Precautions ( 5.8 )] . The most commonly reported adverse reactions of at least moderate intensity and incidence at least 2% (in those receiving TRIUMEQ) were insomnia, headache, and fatigue. ( 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 Serious and Fatal Abacavir-Associated Hypersensitivity Reactions: In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIUMEQ and TRIUMEQ PD [see Boxed Warning , Warnings and Precautions ( 5.1 )]. These reactions have been characterized by 2 or more of the following signs or symptoms: (1) fever; (2) rash; (3) gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); (4) constitutional symptoms (including generalized malaise, fatigue, or achiness); (5) respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome. Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash). There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x‑ray findings (predominantly infiltrates, which were localized). Serious Dolutegravir Hypersensitivity Reactions: In clinical trials, hypersensitivity reactions have occurred with dolutegravir, a component of TRIUMEQ and TRIUMEQ PD [see Warnings and Precautions ( 5.1 )]. These hypersensitivity reactions have been characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. Additional Treatment-Emergent Adverse Drug Reactions (ADRs) with Use of TRIUMEQ: The safety assessment of TRIUMEQ is primarily based on the analyses of data from a randomized, international, multicenter, double-blind, active-controlled trial, SINGLE (ING114467) and supported by data in treatment-experienced, INSTI-naive subjects from SAILING (ING111762) and by data from other treatment-naive trials. See full prescribing information for TIVICAY. Treatment-Naive Subjects: In SINGLE, 833 adult subjects were randomized and received at least one dose of either dolutegravir (TIVICAY) 50 mg with fixed-dose abacavir and lamivudine (EPZICOM) once daily (n = 414) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA) once daily (n = 419) (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rate of adverse events leading to discontinuation was 4% in subjects receiving TIVICAY + EPZICOM and 14% in subjects receiving ATRIPLA once daily. Treatment‑emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm of SINGLE are provided in Table 3 . Table 3. Treatment-Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-Naive Subjects in SINGLE (Week 144 Analysis) a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption. Adverse Reaction TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Psychiatric Insomnia 3% 3% Depression 1% 2% Abnormal dreams <1% 2% Nervous System Dizziness <1% 5% Headache 2% 2% Gastrointestinal Nausea <1% 3% Diarrhea <1% 2% General Disorders Fatigue 2% 2% Skin and Subcutaneous Tissue Rash a <1% 6% Ear and Labyrinth Vertigo 0 2% Treatment-Experienced Subjects: SAILING is an international, double-blind trial in INSTI-naive, antiretroviral treatment-experienced adult subjects. Subjects were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rate of adverse events leading to discontinuation was consistent with that seen in the overall treatment-naive patient population. See full prescribing information for TIVICAY. The ADRs observed in the subset of subjects who received TIVICAY + EPZICOM were generally consistent with those seen in the overall treatment-naive patient population. Less Common Adverse Reactions Observed in Clinical Trials: The following adverse reactions occurred in <2% of treatment-naive or treatment-experienced subjects in any one trial. These events have been included because of their seriousness and/or assessment of potential causal relationship. Gastrointestinal Disorders: Abdominal pain, abdominal distention, abdominal discomfort, dyspepsia, flatulence, gastroesophageal reflux disease, upper abdominal pain, vomiting. General Disorders: Fever, lethargy. Hepatobiliary Disorders: Hepatitis. Metabolism and Nutrition Disorders: Anorexia, hypertriglyceridemia. Musculoskeletal Disorders: Arthralgia, myositis. Nervous System Disorders: Somnolence. Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Nightmare and sleep disorder. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities: Treatment-Naive Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects in SINGLE are presented in Table 4 . The mean change from baseline observed for selected lipid values is presented in Table 5 . Table 4. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naive Subjects in SINGLE (Week 144 Analysis) ALT = Alanine aminotransferase, AST = Aspartate aminotransferase, ULN = upper limit of normal. Laboratory Abnormality TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) ALT Grade 2 (>2.5-5.0 x ULN) 3% 5% Grade 3 to 4 (>5.0 x ULN) 1% <1% AST Grade 2 (>2.5-5.0 x ULN) 3% 4% Grade 3 to 4 (>5.0 x ULN) 1% 3% Creatine kinase Grade 2 (6.0-9.9 x ULN) 5% 3% Grade 3 to 4 (≥10.0 x ULN) 7% 8% Hyperglycemia Grade 2 (126-250 mg/dL) 9% 6% Grade 3 (>250 mg/dL) 2% <1% Lipase Grade 2 (>1.5-3.0 x ULN) 11% 11% Grade 3 to 4 (>3.0 ULN) 5% 4% Total neutrophils Grade 2 (0.75-0.99 x 10 9 ) 4% 5% Grade 3 to 4 (<0.75 x 10 9 ) 3% 3% Table 5. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naive Subjects in SINGLE (Week 144 Analysis a ) HDL = High-density lipoprotein, LDL = Low-density lipoprotein. a Subjects on lipid-lowering agents at baseline were excluded from these analyses (TIVICAY + EPZICOM: n = 30 and ATRIPLA: n = 27). Seventy-two subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless of whether they discontinued the agent (TIVICAY + EPZICOM: n = 36 and ATRIPLA: n = 36). Lipid TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Cholesterol (mg/dL) 24.0 26.7 HDL cholesterol (mg/dL) 5.4 7.2 LDL cholesterol (mg/dL) 16.0 14.6 Triglycerides (mg/dL) 13.6 31.9 Treatment-Experienced Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naive trials. Hepatitis C Virus Co-infection: In SINGLE, the pivotal Phase 3 trial, subjects with hepatitis C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal; subjects with hepatitis B co-infection were excluded. Overall, the safety profile in subjects with hepatitis C virus co-infection was similar to that observed in subjects without hepatitis C co-infection, although the rates of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) abnormalities were higher in the subgroup with hepatitis C virus co-infection for both treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis C co-infected compared with HIV mono-infected subjects receiving TRIUMEQ were observed in 15% and 2% (vs. 24% and 4% of subjects treated with ATRIPLA) (Week 96 analysis), respectively [see Warnings and Precautions ( 5.2 )] . See also full prescribing information for TIVICAY. 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 and remained stable through 144 weeks. In SINGLE, a mean change from baseline of 0.14 mg/dL (range: -0.25 mg/dL to 0.81 mg/dL) was observed after 144 weeks of treatment. Creatinine increases were similar in treatment-experienced subjects. Abacavir and Lamivudine: Laboratory abnormalities observed in clinical trials of ZIAGEN (in combination with other antiretroviral treatment) were anemia, neutropenia, liver function test abnormalities, and elevations of creatine phosphokinase (CPK), blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR (in combination with other antiretroviral treatment) were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase. Clinical Trials Experience in Pediatric Subjects Abacavir, Dolutegravir and Lamivudine: The safety of TRIUMEQ PD and TRIUMEQ in pediatric subjects with HIV-1 infection weighing at least 6 kg was evaluated in the IMPAACT 2019 trial. This was a multicenter, open-label, non-comparative trial of pediatric subjects with HIV-1 infection, younger than 12 years of age. Fifty-seven subjects weighing at least 6 kg to less than 40 kg were enrolled in this trial [ see Use in Specific Populations ( 8.4 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 )] . Overall, the safety data in this pediatric study was similar to that seen in adults. The safety analysis through Week 48 included 57 subjects weighing at least 6 kg at enrollment who received the recommended dose (determined by weight) and formulation. This analysis showed that 26% of subjects experienced clinical adverse reactions. The most common adverse reactions were classified as laboratory abnormalities and included decreased glomerular filtration rate (n = 13, 23%), increased blood creatinine (n = 10, 18%), and increased ALT (n = 3, 5%). All other adverse reactions occurred at a rate of <2% of participants. Two subjects reported Grade 3 or 4 adverse reactions. One subject, an 8-year-old female who weighed 22 kg at baseline, experienced Grade 3 increased blood creatinine and Grade 3 decreased glomerular filtration rate. By Week 48, the glomerular filtration rate was improving, and the events did not lead to drug discontinuation. Another subject, a 7-year-old male who weighed 20 kg at baseline, experienced drug-induced liver injury with Grade 4 increased ALT and AST following 36 weeks of treatment with TRIUMEQ PD. Clinical signs or symptoms of hepatitis were not reported, and ALT and AST values normalized after TRIUMEQ PD was discontinued. Abacavir and Lamivudine: The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as EPZICOM, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events. One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. No additional safety issues were identified in pediatric subjects compared with historical data in adults. Dolutegravir: The safety of dolutegravir in pediatric subjects with HIV-1 infection weighing at least 6 kg was evaluated in the IMPAACT P1093 trial [see Use in Specific Populations ( 8.4 ), Clinical Pharmacology ( 12.3 )] . Overall, the safety data in this pediatric study was similar to that seen in adults. IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of pediatric subjects with HIV-1 infection, aged <18 years. One hundred and forty-two subjects weighing at least 6 kg were enrolled in this trial [see Use in Specific Populations ( 8.4 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.2 )] . The safety analysis through Week 24 included 60 subjects weighing at least 6 kg at enrollment who received the recommended dose (determined by weight and age) and formulation. This analysis showed that 13% of subjects experienced adverse reactions. Grade 1 to 2 adverse reactions reported by more than one subject was immune reconstitution inflammatory syndrome (n = 2). There were no Grade 3 or 4 adverse reactions reported. No adverse reactions led to discontinuation. The Grade 3 or 4 laboratory abnormalities reported in more than one subject weighing at least 6 kg at enrollment were decreased neutrophil count (n = 5), decreased blood bicarbonate (n = 3), increased lipase (n = 2), and increased blood potassium (n = 2). These laboratory events were not considered to be drug related. Changes in median serum creatinine were similar to those observed in adults. 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use with one or more of the components of TRIUMEQ and TRIUMEQ PD. Because these 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. Blood and Lymphatic Systems Aplastic anemia, anemia (including pure red cell aplasia, sideroblastic anemia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly. Digestive Stomatitis. Gastrointestinal Pancreatitis. General Weakness. Hepatobiliary Disorders Acute liver failure, liver transplant [see Warnings and Precautions ( 5.3 )] . Hypersensitivity Sensitization reactions (including anaphylaxis), urticaria [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 )] . Investigations Weight increased. Metabolism and Nutrition Disorders Hyperlactemia. Musculoskeletal CPK elevation, muscle weakness, myalgia, rhabdomyolysis. Nervous Paresthesia, peripheral neuropathy, seizures. Psychiatric Anxiety. Respiratory Abnormal breath sounds/wheezing. Skin Alopecia, erythema multiforme. Suspected Stevens‑Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively. Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases [see Adverse Reactions ( 6.1 )] .

<table ID="_RefTable_3" width="100%"><caption>Table 3. Treatment-Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-Naive Subjects in SINGLE (Week 144 Analysis)</caption><col width="45%"/><col width="28%"/><col width="27%"/><tfoot><tr><td align="left" colspan="3" valign="top">^a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">TIVICAY + EPZICOM</content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 414)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">ATRIPLA</content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 419)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Psychiatric </content></paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Depression </paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Abnormal dreams</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Dizziness </paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal </content></paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">General Disorders </content></paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Fatigue</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Skin and Subcutaneous Tissue </content></paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Rash^a</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Ear and Labyrinth </content></paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Vertigo</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>2%</paragraph></td></tr></tbody></table>

<table ID="_RefTable_4" width="100%"><caption>Table 4. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naive Subjects in SINGLE (Week 144 Analysis)</caption><col width="47%"/><col width="26%"/><col width="27%"/><tfoot><tr><td align="left" colspan="3" valign="top">ALT = Alanine aminotransferase, AST = Aspartate aminotransferase, ULN = upper limit of normal.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Laboratory Abnormality</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">TIVICAY + EPZICOM Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 414)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">ATRIPLA</content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 419)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>ALT</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (&gt;2.5-5.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 3 to 4 (&gt;5.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>AST</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (&gt;2.5-5.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 3 to 4 (&gt;5.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Creatine kinase</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (6.0-9.9 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 3 to 4 (&#x2265;10.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Hyperglycemia</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (126-250 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 3 (&gt;250 mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>&lt;1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Lipase</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (&gt;1.5-3.0 x ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Grade 3 to 4 (&gt;3.0 ULN)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Total neutrophils</paragraph></td><td styleCode="Rrule Lrule " valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Grade 2 (0.75-0.99 x 10⁹)</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Grade 3 to 4 (&lt;0.75 x 10⁹)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3%</paragraph></td></tr></tbody></table>

<table ID="_RefTable_5" width="100%"><caption>Table 5. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naive Subjects in SINGLE (Week 144 Analysis^a)</caption><col width="46%"/><col width="26%"/><col width="28%"/><tfoot><tr><td align="left" colspan="3" valign="top">HDL = High-density lipoprotein, LDL = Low-density lipoprotein.</td></tr><tr><td align="left" colspan="3" valign="top">^aSubjects on lipid-lowering agents at baseline were excluded from these analyses (TIVICAY + EPZICOM: n = 30 and ATRIPLA: n = 27). Seventy-two subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless of whether they discontinued the agent (TIVICAY + EPZICOM: n = 36 and ATRIPLA: n = 36).</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Lipid</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">TIVICAY + EPZICOM Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 414)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">ATRIPLA</content></paragraph><paragraph><content styleCode="bold">Once Daily</content></paragraph><paragraph><content styleCode="bold">(n = 419)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cholesterol (mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>24.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>26.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>HDL cholesterol (mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>5.4</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>7.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>LDL cholesterol (mg/dL)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>16.0</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>14.6</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Triglycerides (mg/dL)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>13.6</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>31.9</paragraph></td></tr></tbody></table>