Data from FDA - Curated by EPG Health - Last updated 01 June 2018

Indication(s)

1 INDICATIONS AND USAGE TRIUMEQ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and in pediatric patients weighing at least 40 kg. Limitations of Use: •TRIUMEQ alone is not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in TRIUMEQ is insufficient in these subpopulations. See full prescribing information for TIVICAY (dolutegravir). TRIUMEQ, a combination of dolutegravir (integrase strand transfer inhibitor [INSTI]), abacavir, and lamivudine (both nucleoside analogue reverse transcriptase inhibitors) is indicated for the treatment of HIV-1 infection in adults and in pediatric patients weighing at least 40 kg. (1) Limitations of Use: •TRIUMEQ alone is not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in TRIUMEQ is insufficient in these subpopulations. See the dolutegravir prescribing information. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS TRIUMEQ is contraindicated in patients: •who have the HLA-B*5701 allele [see Warnings and Precautions (5.1)]. •with prior hypersensitivity reaction to abacavir, dolutegravir [see Warnings and Precautions (5.1)], or lamivudine. •receiving dofetilide, due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events with concomitant use of dolutegravir [see Drug Interactions (7)]. •with moderate or severe hepatic impairment [see Use in Specific Populations (8.7)]. •Presence of HLA-B*5701 allele. (4) •Prior hypersensitivity reaction to abacavir, dolutegravir, or lamivudine. (4) •Coadministration with dofetilide. (4) •Moderate or severe hepatic impairment. (4, 8.7)
Adverse reactions
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 ( 5.2 )]. •Hepatotoxicity [see Warnings and Precautions (5.4)]. •Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.5)]. •Hepatic decompensation in patients co-infected with HIV-1 and Hepatitis C [see Warnings and Precautions (5.7)]. •Immune reconstitution syndrome [see Warnings and Precautions (5.8)]. •Myocardial infarction [see Warnings and Precautions (5.9)]. 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 [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 [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-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 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-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 (>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 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 (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 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. Clinical Trials Experience in Pediatric Subjects 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: IMPAACT P1093 is a 48-week multicenter, open-label, non-comparative trial of approximately 160 HIV‑1‑infected pediatric subjects aged 4 weeks to less than 18 years, of which, 23 treatment-experienced, INSTI-naïve subjects aged 12 to less than 18 years were enrolled [see Use in Specific Populations (8.4), Clinical Studies (14.2)]. The ADR profile was similar to that for adults. Grade 2 ADRs reported by more than one subject were decreased neutrophil count (n = 2). No Grade 3 or 4 ADRs were reported. No ADRs led to discontinuation. The Grade 3 laboratory abnormalities reported in 1 subject each were elevated total bilirubin, elevated lipase, and decreased white blood cell count. There was one Grade 4 decreased neutrophil count. The changes in mean 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. 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. Hepatobiliary Disorders Acute liver failure, liver transplant. Hypersensitivity Sensitization reactions (including anaphylaxis), urticaria [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. 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)].

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION •Before initiating TRIUMEQ, screen for the HLA‑B*5701 allele because TRIUMEQ contains abacavir. (2.1). •Adults and pediatric patients weighing at least 40 kg: One tablet daily. May be taken with or without food. (2.2) •If dosing with certain UGT1A or CYP3A inducers, then the recommended dolutegravir dosage regimen is 50 mg twice daily. An additional 50-mg dose of dolutegravir, separated by 12 hours from TRIUMEQ, should be taken. (2.3) •Because TRIUMEQ is a fixed-dose tablet and cannot be dose adjusted, TRIUMEQ is not recommended in patients requiring dosage adjustment or patients with hepatic impairment. (2.4, 4) 2.1 Screening for HLA-B*5701 Allele prior to Starting TRIUMEQ Screen for the HLA‑B*5701 allele prior to initiating therapy with TRIUMEQ [see Boxed Warning, Warnings and Precautions (5.1)]. 2.2 Recommended Dosage TRIUMEQ is a fixed-dose combination product containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. The recommended dosage regimen of TRIUMEQ in adults and in pediatric patients weighing at least 40 kg is one tablet once daily orally with or without food. 2.3 Dosage Recommendation with Certain Concomitant Medications The dolutegravir dose (50 mg) in TRIUMEQ is insufficient when coadministered with medications listed in Table 1 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended. Table 1. Dosing Recommendations for TRIUMEQ with Coadministered Medications Coadministered Drug Dosing Recommendation Efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin The recommended dolutegravir dosage regimen is 50 mg twice daily. An additional dolutegravir 50-mg tablet, separated by 12 hours from TRIUMEQ, should be taken. 2.4 Not Recommended Due to Lack of Dosage Adjustment Because TRIUMEQ is a fixed-dose tablet and cannot be dose adjusted, TRIUMEQ is not recommended in: •patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations (8.6)]. •patients with mild hepatic impairment. TRIUMEQ is contraindicated in patients with moderate or severe hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Lactation: Breastfeeding is not recommended due to the potential for HIV transmission. (8.2) •Pediatrics: Not recommended for patients weighing less than 40 kg. (8.4) •TRIUMEQ is not recommended in patients with creatinine clearance less than 50 mL per min. (8.6) •If a dose reduction of abacavir, a component of TRIUMEQ, is required for patients with mild hepatic impairment, then the individual components should be used. (8.7) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TRIUMEQ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1‑800‑258‑4263. Risk Summary There are insufficient human data on the use of TRIUMEQ during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Given the limited number of pregnancies exposed to dolutegravir-based regimens reported to the APR, no definitive conclusions can be drawn on the safety of TRIUMEQ in pregnancy, and continued monitoring is ongoing through the APR. Available data from the APR show no difference in the overall risk of birth defects for abacavir or lamivudine compared with the background rate for birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data). The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir (see Data). During organogenesis in the rat and rabbit and a rat pre/postnatal developmental study, systemic exposures (AUC) to dolutegravir were less than (rabbits) and approximately 50 times (rats) the exposure in humans at the recommended human dose (RHD). Oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the RHD. No adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis at exposures approximately 9 times the human exposure (AUC) at the RHD. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at a human exposure (AUC) similar to the RHD; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times the RHD (see Data). Data Human Data: Abacavir: Based on prospective reports to the APR of over 2,000 exposures to abacavir during pregnancy resulting in live births (including over 1,000 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 2.9% (95% CI: 2.0% to 4.1%) following first trimester exposure to abacavir-containing regimens and 2.7% (95% CI: 1.9% to 3.7%) following second/third trimester exposure to abacavir-containing regimens. Abacavir has been shown to cross the placenta and concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery [see Clinical Pharmacology (12.3)]. Lamivudine: Based on prospective reports to the APR of over 11,000 exposures to lamivudine during pregnancy resulting in live births (including over 4,500 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.8% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudine-containing regimens. Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans. Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9 (1.2 to 12.8)–fold greater compared with paired maternal serum concentration (n = 8). Animal Data: Dolutegravir: Dolutegravir was administered orally to pregnant rats and rabbits (up to 1,000 mg per kg per day) on gestation Days 6 to 17 and 6 to 18, respectively, and to rats on gestation Day 6 to lactation/post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed up to the highest dose tested. During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the RHD and in rats were approximately 50 times the exposure in humans at the RHD. In the rat pre/post-natal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 50 times human exposure at the RHD). Abacavir: Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg per kg per day) and rabbits (at 125, 350, or 700 mg per kg per day) during organogenesis (on gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown‑rump length) were observed in rats at doses up to 1,000 mg per kg per day, resulting in exposures approximately 35 times the human exposure (AUC) at the RHD. No developmental effects were observed in rats at 100 mg per kg per day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose. In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg per kg per day), embryonic and fetal toxicities (increased resorptions, decreased fetal body weights) or toxicities to the offspring (increased incidence of stillbirth and lower body weights) occurred at doses up to 500 mg per kg per day. No developmental effects were observed in rats at 60 mg per kg per day, resulting in exposures (AUC) approximately 4 times the human exposure at the RHD. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the RHD. Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg per kg per day) and rabbits (at 90, 300 and 1,000 mg per kg per day and at 15, 40, and 90 mg per kg per day) during organogenesis (on gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]). No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (Cmax) approximately 35 times higher than human exposure at the recommended daily dose. Evidence of early embryolethality was seen in the rabbit at systemic exposures (AUC) similar to those observed in humans, but there was no indication of this effect in the rat at plasma concentrations (Cmax) 35 times higher than human exposure at the recommended daily dose. Studies in pregnant rats showed that lamivudine is transferred to the fetus through the placenta. In the fertility/pre- and postnatal development study in rats, lamivudine was administered orally at doses of 180, 900, and 4,000 mg per kg per day (from prior to mating through postnatal Day 20). In the study, development of the offspring, including fertility and reproductive performance, were not affected by the maternal administration of lamivudine. 8.2 Lactation The Centers for Disease Control and Prevention recommends that HIV‑1‑infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV‑1 infection. Abacavir and lamivudine are present in human milk. When administered to lactating rats, dolutegravir was present in milk (see Data). There is no information on the effects of TRIUMEQ or its components on the breastfed infant or the effects of the drug on milk production. Because of the potential for (1) HIV‑1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving TRIUMEQ. Data Animal Data: Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 50 mg per kg on lactation Day 10, with milk concentrations of up to approximately 1.3 times that of maternal plasma concentrations observed 8 hours’ post-dose. 8.4 Pediatric Use The clinical data supporting use of TRIUMEQ in HIV-1 infected pediatric patients weighing at least 40 kg is derived from the following previously conducted pediatric trials using the individual components of TRIUMEQ: •The safety and efficacy of once-daily abacavir and lamivudine were established with a randomized, multicenter trial (ARROW [COL105677]) in HIV-1–infected, treatment-naïve subjects aged 3 months to 17 years with a first-line regimen containing abacavir and lamivudine, using either the combination of EPIVIR and ZIAGEN or EPZICOM [see Adverse Reactions (6.2), Clinical Studies (14.2)]. •The safety and antiviral activity (efficacy) of dolutegravir was established through a 48-week, open-label, multicenter, dose-finding clinical trial (IMPAACT P1093), in which treatment-experienced, INSTI-naïve, HIV-1–infected subjects aged 6 to less than 18 years were treated with dolutegravir (TIVICAY) plus optimized background therapy [see Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.2)]. TRIUMEQ is a fixed-dose combination tablet which cannot be adjusted for patients weighing less than 40 kg [see Clinical Pharmacology (12.3)]. 8.5 Geriatric Use Clinical trials of abacavir, dolutegravir, or lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TRIUMEQ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)]. 8.6 Patients with Impaired Renal Function TRIUMEQ is not recommended for patients with creatinine clearance less than 50 mL per min because TRIUMEQ is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of TRIUMEQ, is required for patients with creatinine clearance less than 50 mL per min, then the individual components should be used [see Clinical Pharmacology (12.3)]. 8.7 Patients with Impaired Hepatic Function TRIUMEQ is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of abacavir, a component of TRIUMEQ, is required for patients with mild hepatic impairment (Child-Pugh Score A), then the individual components should be used [see Clinical Pharmacology (12.3)]. The safety, efficacy, and pharmacokinetic properties of abacavir have not been established in patients with moderate (Child-Pugh Score B) or severe (Child-Pugh Score C) hepatic impairment; therefore, TRIUMEQ is contraindicated in these patients [see Contraindications (4)].

Interactions

7 DRUG INTERACTIONS Coadministration of TRIUMEQ with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of TRIUMEQ. The potential drug-drug interactions must be considered prior to and during therapy. (4, 7, 12.3) 7.1 Effect of Dolutegravir on the Pharmacokinetics of Other Agents In vitro, dolutegravir inhibited the renal organic cation transporters (OCT)2 (IC50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE)1 (IC50 = 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin) [see Contraindications (4), Drug Interactions (7.3)]. In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC50 = 2.12 microM) and OAT3 (IC50 = 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3. In vitro, dolutegravir did not inhibit (IC50 greater than 50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1, UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, or multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters. In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: daclatasvir, tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, and boceprevir. 7.2 Effect of Other Agents on the Pharmacokinetics of Dolutegravir Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir (Table 5) [see Drug Interactions (7.3), Clinical Pharmacology (12.3)]. In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, daclatasvir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir. 7.3 Established and Other Potentially Significant Drug Interactions There were no drug-drug interaction trials conducted with the abacavir, dolutegravir, and lamivudine fixed-dose combination tablets. Information regarding potential drug interactions with the individual components of TRIUMEQ are provided below. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. [See Contraindications (4), Clinical Pharmacology (12.3).] Table 5. Established and Other Potentially Significant Drug Interactions for Dolutegravir: Alterations in Dose May Be Recommended Based on Drug Interaction Trials or Predicted Interactions Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment HIV-1 Antiviral Agents Antiarrhythmic: Dofetilide ↑Dofetilide Coadministration is contraindicated with TRIUMEQ [see Contraindications (4)]. Non-nucleoside reverse transcriptase inhibitor: Etravirinea ↓Dolutegravir Use of TRIUMEQ with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended. Non-nucleoside reverse transcriptase inhibitor: Efavirenza ↓Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from TRIUMEQ. Non-nucleoside reverse transcriptase inhibitor: Nevirapine ↓Dolutegravir Avoid coadministration with TRIUMEQ because there are insufficient data to make dosing recommendations. Protease inhibitor: Fosamprenavir/ritonavira Tipranavir/ritonavira ↓Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from TRIUMEQ. Other Agents Carbamazepinea ↓Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from TRIUMEQ. Oxcarbazepine Phenytoin Phenobarbital St. John’s wort (Hypericum perforatum) ↓Dolutegravir Avoid coadministration with TRIUMEQ because there are insufficient data to make dosing recommendations. Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacidsa or laxatives Sucralfate Buffered medications ↓Dolutegravir Administer TRIUMEQ 2 hours before or 6 hours after taking medications containing polyvalent cations. Oral calcium and iron supplements, including multivitamins containing calcium or iron a ↓Dolutegravir Administer TRIUMEQ 2 hours before or 6 hours after taking supplements containing calcium or iron. Alternatively, TRIUMEQ and supplements containing calcium or iron can be taken together with food. Metformina ↑Metformin With concomitant use, limit the total daily dose of metformin to 1,000 mg either when starting metformin or TRIUMEQ. When stopping TRIUMEQ, the metformin dose may require an adjustment. Monitoring of blood glucose when initiating concomitant use and after withdrawal of TRIUMEQ is recommended. Rifampina ↓Dolutegravir Adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from TRIUMEQ. a See Clinical Pharmacology (12.3) Table 8 or Table 9 for magnitude of interaction. Methadone Abacavir: In a trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased [see Clinical Pharmacology (12.3)]. This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. Sorbitol Lamivudine: Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see Clinical Pharmacology (12.3)].

More information

Category Value
Authorisation number NDA205551
Agency product number J220T4J9Q2
Orphan designation No
Product NDC 49702-231
Date Last Revised 11-05-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1546888
Marketing authorisation holder ViiV Healthcare Company
Warnings 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 (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 is 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 reinitiation of therapy with TRIUMEQ, unless patients have a previously documented HLA‑B*5701 allele assessment. Discontinue TRIUMEQ 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, NEVER restart TRIUMEQ 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 Severe acute exacerbations of hepatitis B have been reported in patients who are co‑infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of TRIUMEQ. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue TRIUMEQ and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti‑hepatitis B therapy may be warranted [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 is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. (4) • Discontinue TRIUMEQ as soon as a hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue TRIUMEQ if hypersensitivity cannot be ruled out, even when other diagnoses are possible. (5.1) • Following a hypersensitivity reaction to TRIUMEQ, NEVER restart TRIUMEQ or any other abacavir-containing product. (5.1) Exacerbations of Hepatitis B • Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of TRIUMEQ. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment. (5.2)