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 [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.
Treatment-Emergent Adverse Drug Reactions (ADRs)
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.
In SINGLE, 833 adult subjects were randomized and received at least one dose of either dolutegravir (TIVICAY) 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM®) once daily (n = 414) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA®) once daily (n = 419). Through 96 weeks, the rate of adverse events leading to discontinuation was 3% in subjects receiving TIVICAY + EPZICOM and 12% 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 96 Analysis)
|Adverse Reaction||TIVICAY + EPZICOM Once Daily
(N = 414)
|ATRIPLA Once Daily
(N = 419)
|Abnormal dreams||< 1%||2%|
|Skin and Subcutaneous Tissue|
|Ear and Labyrinth Vertigo||0||2%|
|aIncludes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption.|
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.
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.
Psychiatric: Nightmare and sleep disorder.
Renal and Urinary Disorders: Renal impairment.
Skin and Subcutaneous Tissue Disorders: Pruritus.
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 96 Analysis)
|Laboratory Abnormality||TIVICAY + EPZICOM Once Daily
(N = 414)
|ATRIPLA Once Daily
(N = 419)
|Grade 2 ( > 2.5-5.0 x ULN)||2%||5%|
|Grade 3 to 4 ( > 5.0 x ULN)||< 1%||< 1%|
|Grade 2 ( > 2.5-5.0 x ULN)||3%||3%|
|Grade 3 to 4 ( > 5.0 x ULN)||< 1%||3%|
|Grade 2 (6.0-9.9 x ULN)||4%||1%|
|Grade 3 to 4 ( ≥ 10.0 x ULN)||5%||7%|
|Grade 2 (126-250 mg/dL)||7%||5%|
|Grade 3 ( > 250 mg/dL)||2%||< 1%|
|Grade 2 ( > 15-3.0 x ULN)||9%||9%|
|Grade 3 to 4 ( > 3.0 ULN)||4%||3%|
|Grade 2 (0.75-0.99 x 109)||3%||5%|
|Grade 3 to 4 ( < 0.75 x 109)||2%||3%|
|ULN = Upper limit of normal.|
Table 4: Mean Change from Baseline in Fasted Lipid Values in Treatment-naïve Subjects in SINGLE (Week 96 Analysisa)
|Lipid||TIVICAY + EPZICOM Once Daily
(N = 414)
|ATRIPLA Once Daily
(N = 419)
|HDL cholesterol (mg/dL)||5.2||7.4|
|LDL cholesterol (mg/dL)||14.5||18.0|
|aSubjects on lipid-lowering agents at baseline were excluded from these analyses (TIVICAY n = 30 and ATRIPLA n = 27). Fifty-five 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 (SINGLE: TIVICAY n = 25 and ATRIPLA: n = 30).|
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), 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 24 to 96 weeks. In SINGLE, a mean change from baseline of 0.14 mg per dL (range: -0.32 mg per dL to 0.59 mg per dL) was observed after 96 weeks of treatment. Creatinine increases were similar in treatment-experienced subjects.
Abacavir Sulfate 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.
In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. 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.
Abacavir and/or Lamivudine
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.
Metabolism and Nutrition Disorders: Hyperlactemia.
Musculoskeletal: Muscle weakness, CPK elevation, 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.