Abacavir, Dolutegravir, and Lamivudine Film-coated Tablets

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

• Serious and sometimes fatal hypersensitivity reaction [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
• Lactic acidosis and severe hepatomegaly with steatosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
• Effects on serum liver biochemistries in patients with hepatitis B or C co-infection [see WARNINGS AND PRECAUTIONS].
• Exacerbations of hepatitis B [see BOXED WARNING, WARNINGS AND PRECAUTIONS].
• Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see WARNINGS AND PRECAUTIONS].
• Immune reconstitution syndrome [see WARNINGS AND PRECAUTIONS].
• Fat redistribution [see WARNINGS AND PRECAUTIONS].
• Myocardial infarction [see WARNINGS AND PRECAUTIONS].

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.

Serious And Fatal Abacavir-Associated Hypersensitivity Reactions

In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIUMEQ [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. 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 [see WARNINGS AND PRECAUTIONS]. 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-naïve subjects from SAILING (ING111762) and by data from other treatment-naïve trials. See full prescribing information for TIVICAY.

Treatment-Naïve 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 2.

Table 2: Treatment-Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-Naïve Subjects in SINGLE (Week 144 Analysis)

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
Rasha	< 1%	6%
Ear and Labyrinth
Vertigo	0	2%
a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption.

Treatment-Experienced Subjects: SAILING is an international, double-blind trial in INSTI-naïve, 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-naïve 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-naïve patient population.

Less Common Adverse Reactions Observed In Clinical Trials

The following adverse reactions occurred in less than 2% of treatment-naïve 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: Somnolence.

Psychiatric: 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-Naïve 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 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) in Treatment-Naïve Subjects in SINGLE (Week 144 Analysis)

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 ( > 15-3.0 x ULN)	11%	11%
Grade 3 to 4 ( > 3.0 ULN)	5%	4%
Total neutrophils
Grade 2 (0.75-0.99 x 109)	4%	5%
Grade 3 to 4 ( < 0.75 x 109)	3%	3%
ULN = Upper limit of normal.

Table 4: Mean Change from Baseline in Fasted Lipid Values in Treatment-Naïve Subjects in SINGLE (Week 144 Analysisa)

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
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 if they discontinued the agent (TIVICAY + EPZICOM n = 36 and ATRIPLA: n = 36).

Treatment-Experienced Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve 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 AST and 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]. 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]. 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 per dL (range: -0.25 mg per dL to 0.81 mg per 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 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.

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. 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.

Digestive

Stomatitis.

Gastrointestinal

Pancreatitis.

General

Weakness.

Blood and Lymphatic Systems

Aplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.

Hypersensitivity

Sensitization reactions (including anaphylaxis), urticaria [see WARNINGS AND PRECAUTIONS, Clinical Trials Experience].

Metabolism and Nutrition Disorders

Hyperlactemia.

Musculoskeletal

CPK elevation, muscle weakness, myalgia, rhabdomyolysis.

Nervous

Paresthesia, peripheral neuropathy, seizures.

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 Clinical Trials Experience].

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