ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed in other sections of the labeling:oSerious and sometimes fatal hypersensitivity reaction [see Boxed Warning, Warnings and Precautions (5.1)].oExacerbations of hepatitis [see Boxed Warning, Warnings and Precautions (5.3)].oHepatotoxicity [see Warnings and Precautions (5.4)].oLactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.5)].oImmune reconstitution syndrome [see Warnings and Precautions (5.8)].oMyocardial infarction [see Warnings and Precautions (5.9)].. oSerious and sometimes fatal hypersensitivity reaction [see Boxed Warning, Warnings and Precautions (5.1)].. oExacerbations of hepatitis [see Boxed Warning, Warnings and Precautions (5.3)].. oHepatotoxicity [see Warnings and Precautions (5.4)].. oLactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions (5.5)].. oImmune reconstitution syndrome [see Warnings and Precautions (5.8)].. oMyocardial 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 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 AdultsSerious and Fatal Abacavir-Associated Hypersensitivity Reactions: In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, component of TRIUMEQ [see Boxed Warning, Warnings and Precautions (5.1)]. These reactions have been characterized by 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 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, 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 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 2.Table 2. Treatment-Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 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 ReactionTIVICAY EPZICOMOnce Daily(n 414)ATRIPLAOnce Daily(n 419)Psychiatric Insomnia3%3% Depression 1%2% Abnormal dreams<1%2%Nervous System Dizziness <1%5% Headache2%2%Gastrointestinal Nausea<1%3% Diarrhea<1%2%General Disorders Fatigue2%2%Skin and Subcutaneous Tissue Rasha <1%6%Ear and Labyrinth Vertigo02% 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 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 less than 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 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 to 4) with 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 to 4) in Treatment-Naive Subjects in SINGLE (Week 144 Analysis)ULN Upper limit of normal.Laboratory AbnormalityTIVICAY EPZICOM Once Daily(n 414)ATRIPLAOnce Daily(n 419)ALT Grade (>2.5-5.0 ULN)3%5% Grade to (>5.0 ULN)1%<1%AST Grade (>2.5-5.0 ULN)3%4% Grade to (>5.0 ULN)1%3%Creatine kinase Grade (6.0-9.9 ULN)5%3% Grade to (>=10.0 ULN)7%8%Hyperglycemia Grade (126-250 mg/dL)9%6% Grade (>250 mg/dL)2%<1%Lipase Grade (>1.5-3.0 ULN)11%11% Grade to (>3.0 ULN)5%4%Total neutrophils Grade (0.75-0.99 109)4%5% Grade to (<0.75 109)3%3%Table 4. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naive Subjects in SINGLE (Week 144 Analysisa)a Subjects on lipid-lowering agents at baseline were excluded from these analyses (TIVICAY EPZICOM: = 30 and ATRIPLA: = 27). Seventy-two subjects initiated 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: = 36 and ATRIPLA: = 36).LipidTIVICAY EPZICOM Once Daily(n 414)ATRIPLAOnce Daily(n 419)Cholesterol (mg/dL)24.026.7HDL cholesterol (mg/dL)5.47.2LDL cholesterol (mg/dL)16.014.6Triglycerides (mg/dL)13.631.9 Treatment-Experienced Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naive trials.Hepatitis Virus Co-infection: In SINGLE, the pivotal Phase trial, subjects with hepatitis virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed times the upper limit of normal; subjects with hepatitis co-infection were excluded. Overall, the safety profile in subjects with hepatitis virus co-infection was similar to that observed in subjects without hepatitis co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis virus co-infection for both treatment groups. Grades to ALT abnormalities in hepatitis 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 weeks of treatment and remained stable through 144 weeks. In SINGLE, 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 SubjectsAbacavir 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 and Grade adverse events. One event of Grade hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade or 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 48-week multicenter, open-label, non-comparative trial of approximately 160 HIV-1-infected pediatric subjects aged weeks to less than 18 years, of which, 23 treatment-experienced, INSTI-naive 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 ADRs reported by more than one subject were decreased neutrophil count (n 2). No Grade or ADRs were reported. No ADRs led to discontinuation. The Grade laboratory abnormalities reported in subject each were elevated total bilirubin, elevated lipase, and decreased white blood cell count. There was one Grade 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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Blood and Lymphatic SystemsAplastic anemia, anemia (including pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly.DigestiveStomatitis.GastrointestinalPancreatitis.GeneralWeakness.Hepatobiliary DisordersAcute liver failure, liver transplant.HypersensitivitySensitization reactions (including anaphylaxis), urticaria [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].InvestigationsWeight increased.Metabolism and Nutrition DisordersHyperlactemia.MusculoskeletalCPK elevation, muscle weakness, myalgia, rhabdomyolysis.NervousParesthesia, peripheral neuropathy, seizures.PsychiatricAnxiety.RespiratoryAbnormal breath sounds/wheezing. SkinAlopecia, 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)].

BOXED WARNING SECTION.

WARNING: HYPERSENSITIVITY REACTIONS, AND EXACERBATIONS OF HEPATITIS B. Hypersensitivity ReactionsSerious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, component of TRIUMEQ (abacavir, dolutegravir, and lamivudine). Patients who carry the HLA-B5701 allele are at higher risk of hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA-B5701 allele [see Warnings and Precautions (5.1)]. TRIUMEQ is contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients [see Contraindications (4), Warnings and Precautions (5.1)]. All patients should be screened for the HLA-B5701 allele prior to initiating therapy with TRIUMEQ or reinitiation of therapy with TRIUMEQ, unless patients have previously documented HLA-B5701 allele assessment. Discontinue TRIUMEQ immediately if hypersensitivity reaction is suspected, regardless of HLA-B5701 status and even when other diagnoses are possible [see Contraindications (4), Warnings and Precautions (5.1)]. Following 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 BSevere acute exacerbations of hepatitis have been reported in patients who are co-infected with hepatitis virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, 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 therapy may be warranted [see Warnings and Precautions (5.2)]. WARNING: HYPERSENSITIVITY REACTIONS, AND EXACERBATIONS OF HEPATITIS BSee full prescribing information for complete boxed warning.Hypersensitivity ReactionsoSerious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products. (5.1)oHypersensitivity to abacavir is multi-organ clinical syndrome. (5.1)oPatients who carry the HLA-B5701 allele are at higher risk of experiencing hypersensitivity reaction to abacavir. (5.1)oTRIUMEQ is contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients. (4)oDiscontinue TRIUMEQ as soon as hypersensitivity reaction is suspected. Regardless of HLA-B5701 status, permanently discontinue TRIUMEQ if hypersensitivity cannot be ruled out, even when other diagnoses are possible. (5.1)oFollowing hypersensitivity reaction to TRIUMEQ, NEVER restart TRIUMEQ or any other abacavir-containing product. (5.1)Exacerbations of Hepatitis BoSevere acute exacerbations of hepatitis have been reported in patients who are co-infected with hepatitis virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, component of TRIUMEQ. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis treatment. (5.2). oSerious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing products. (5.1). oHypersensitivity to abacavir is multi-organ clinical syndrome. (5.1). oPatients who carry the HLA-B5701 allele are at higher risk of experiencing hypersensitivity reaction to abacavir. (5.1). oTRIUMEQ is contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients. (4). oDiscontinue TRIUMEQ as soon as hypersensitivity reaction is suspected. Regardless of HLA-B5701 status, permanently discontinue TRIUMEQ if hypersensitivity cannot be ruled out, even when other diagnoses are possible. (5.1). oFollowing hypersensitivity reaction to TRIUMEQ, NEVER restart TRIUMEQ or any other abacavir-containing product. (5.1). oSevere acute exacerbations of hepatitis have been reported in patients who are co-infected with hepatitis virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, component of TRIUMEQ. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis treatment. (5.2).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityDolutegravir: Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 26-fold higher than those in humans at the recommended dose of 50 mg once daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 17-fold and 30-fold higher in males and females, respectively, than those in humans at the recommended dose of 50 mg once daily.Abacavir: Abacavir was administered orally at dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of to 28 times the human exposure at the recommended dose of 600 mg.Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the recommended dose of 300 mg.MutagenicityDolutegravir: Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.Abacavir: Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assay, in an in vitro cell transformation assay, in rat micronucleus test, in rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.Impairment of FertilityDolutegravir, abacavir, or lamivudine did not affect male or female fertility in rats at doses associated with exposures approximately 44, 9, or 112 times (respectively) higher than the exposures in humans at the doses of 50 mg, 600 mg, and 300 mg (respectively).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. TRIUMEQ is fixed-dose combination of the HIV-1 antiretroviral agents abacavir, dolutegravir, and lamivudine [see Microbiology (12.4)]. 12.2 Pharmacodynamics. Effects on ElectrocardiogramA thorough QT trial has been conducted for dolutegravir. Neither the effects of abacavir nor lamivudine as single entities or the combination of abacavir, dolutegravir, and lamivudine on the QT interval have been evaluated.In randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3-fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose.Effects on Renal FunctionThe effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n 37) who received dolutegravir 50 mg once daily (n 12), dolutegravir 50 mg twice daily (n 13), or placebo once daily (n 12) for 14 days. decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.. 12.3 Pharmacokinetics. Pharmacokinetics in AdultsOne TRIUMEQ tablet was bioequivalent to one dolutegravir (TIVICAY) tablet (50 mg) plus one abacavir and lamivudine fixed-dose combination tablet (EPZICOM) under fasted conditions in healthy subjects (n 62).Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 +- 1.19 mcg per mL (mean +- SD) and AUC was 11.95 +- 2.51 mcgohour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5-carboxylic acid and glucuronyl transferase to form the 5-glucuronide. In single-dose trials, the observed elimination half-life (t 1/2 was 1.54 +- 0.63 hours. After intravenous administration, total clearance was 0.80 +- 0.24 per hour per kg (mean +- SD).Dolutegravir: Following oral administration of dolutegravir, peak plasma concentrations were observed to hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately days with average accumulation ratios for AUC, Cmax, and C24 ranging from 1.2 to 1.5. Dolutegravir is P-gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established. Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 based on population pharmacokinetic analysis. Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After single oral dose of [14C] dolutegravir, 53% of the total oral dose is excreted unchanged in the feces. Thirty-one percent of the total oral dose is excreted in the urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was less than 1% of the dose. Dolutegravir has terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 per hour based on population pharmacokinetic analyses.The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV-1-infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV-1-infected subjects. Table 6. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1- Infected AdultsParameter50 mg Once DailyGeometric Mean (%CV)AUC(0-24) (mcgoh/mL)53.6 (27)Cmax (mcg/mL)3.67 (20)Cmin (mcg/mL)1.11 (46) Cerebrospinal Fluid (CSF): In 11 treatment-naive subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 18 ng per mL (range: ng per mL to 23.2 ng per mL) to hours postdose after weeks of treatment. The clinical relevance of this finding has not been established. Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2.04 +- 0.54 mcg per mL (mean +- SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 +- 1.83 mcgohour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). In most single-dose trials with plasma sampling up to 48 or 72 hours after dosing, the observed mean elimination half-life (t 1/2 ranged from 13 to 19 hours. In HIV-1-infected subjects, total clearance was 398.5 +- 69.1 mL per min (mean +- SD).Effect of Food on Oral AbsorptionTRIUMEQ may be taken with or without food. Overall, when compared with fasted conditions, administration of TRIUMEQ to healthy adult subjects with high-fat meal (53% fat, 869 calories) resulted in decreased Cmax for abacavir and increased Cmax and AUC for dolutegravir. Lamivudine exposures were not affected by food. With high-fat meal, the Cmax of abacavir decreased 23% and the Cmax and AUC of dolutegravir increased 37% and 48%, respectively.Specific PopulationsPatients with Renal Impairment: The pharmacokinetics for the individual components of TRIUMEQ have been evaluated in patients with renal impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components).Patients with Hepatic Impairment: The pharmacokinetics for the individual components of TRIUMEQ have been evaluated in patients with varying degrees of hepatic impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components).Pediatric Patients: The pharmacokinetics for the individual components of TRIUMEQ (abacavir, dolutegravir, and lamivudine) have been evaluated in pediatric subjects. Dolutegravir: The pharmacokinetics of dolutegravir in HIV-1-infected children (n 14) weighing at least 40 kg were similar to those observed in HIV-1-infected adults who received dolutegravir 50 mg once daily (Table 7) [see Clinical Studies (14.2)].Table 7. Dolutegravir Steady-State Pharmacokinetic Parameters in Pediatric SubjectsWeight (n)Dose of TIVICAYDolutegravir Pharmacokinetic Parameter EstimatesGeometric Mean (%CV)Cmax (mcg/mL)AUC(0-24) (mcg.h/mL)C24 (mcg/mL)>=40 kg (n 14)50 mgonce daily3.89 (43)50.1 (53)0.99 (66) Abacavir and Lamivudine: The pharmacokinetic data for abacavir and lamivudine once daily following administration of EPZICOM in pediatric subjects weighing at least 40 kg are limited. The dosing recommendations in this population are based on the safety and efficacy established in controlled trial conducted using either the combination of EPIVIR and ZIAGEN or EPZICOM. Refer to the prescribing information for EPIVIR and ZIAGEN for pharmacokinetic information on the individual products in pediatric patients [see Dosage and Administration (2.2), Clinical Studies (14.2)]. Geriatric Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. The pharmacokinetics of abacavir or lamivudine have not been studied in subjects older than 65 years.Male and Female Patients: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components.Racial Groups: There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components.Drug Interaction StudiesThe drug interaction trials described were conducted with dolutegravir, abacavir, and/or lamivudine as single entities; no drug interaction trials have been conducted using the combination of abacavir, dolutegravir, and lamivudine. No clinically significant drug interactions are expected between dolutegravir, abacavir, and lamivudine. Dosing recommendations as result of established and other potentially significant drug-drug interactions with the individual components of TRIUMEQ are provided in Section 7.3 [see Drug Interactions (7)].Table 8. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugsa The number of subjects represents the maximum number of subjects that were evaluated.Coadministered Drug(s) and Dose(s)Dose of DolutegravirnGeometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without DolutegravirNo Effect 1.00Cmax AUCC or C24 Daclatasvir 60 mg once daily50 mgonce daily121.03(0.84 to 1.25)0.98(0.83 to 1.15)1.06(0.88 to 1.29)Ethinyl estradiol 0.035 mg50 mg twice daily150.99(0.91 to 1.08)1.03(0.96 to 1.11)1.02(0.93 to 1.11)Metformin 500 mg twice daily50 mgonce daily15a 1.66(1.53 to 1.81)1.79(1.65 to 1.93)--Metformin 500 mg twice daily50 mg twice daily15a 2.11(1.91 to 2.33)2.45(2.25 to 2.66)--Methadone 16 to 150 mg50 mg twice daily111.00(0.94 to 1.06)0.98(0.91 to 1.06)0.99(0.91 to 1.07)Midazolam mg25 mgonce daily10--0.95(0.79 to 1.15)--Norelgestromin 0.25 mg50 mg twice daily150.89(0.82 to 0.97)0.98(0.91 to 1.04)0.93(0.85 to 1.03)Rilpivirine 25 mg once daily50 mgonce daily161.10(0.99 to 1.22)1.06(0.98 to 1.16)1.21(1.07 to 1.38)Tenofovir disoproxil fumarate 300 mg once daily50 mgonce daily151.09(0.97 to 1.23)1.12(1.01 to 1.24)1.19(1.04 to 1.35)Table 9. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily. The number of subjects represents the maximum number of subjects that were evaluated.Coadministered Drug(s)and Dose(s)Dose of DolutegravirnGeometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered DrugsNo Effect 1.00Cmax AUCC or C24 Atazanavir 400 mg once daily30 mg once daily121.50(1.40 to 1.59)1.91(1.80 to 2.03)2.80(2.52 to 3.11)Atazanavir/ritonavir 300/100 mg once daily30 mg once daily121.34(1.25 to 1.42)1.62(1.50 to 1.74)2.21(1.97 to 2.47)Darunavir/ritonavir 600/100 mg twice daily30 mg once daily150.89(0.83 to 0.97)0.78(0.72 to 0.85)0.62(0.56 to 0.69)Efavirenz 600 mg once daily50 mgonce daily120.61(0.51 to 0.73)0.43(0.35 to 0.54)0.25(0.18 to 0.34)Etravirine 200 mg twice daily50 mgonce daily160.48(0.43 to 0.54)0.29(0.26 to 0.34)0.12(0.09 to 0.16)Etravirine darunavir/ritonavir 200 mg 600/100 mg twice daily50 mgonce daily90.88(0.78 to 1.00)0.75(0.69 to 0.81)0.63(0.52 to 0.76)Etravirine lopinavir/ritonavir 200 mg 400/100 mg twice daily50 mg once daily81.07(1.02 to 1.13)1.11(1.02 to 1.20)1.28(1.13 to 1.45)Fosamprenavir/ritonavir 700 mg /100 mg twice daily50 mg once daily120.76(0.63 to 0.92)0.65(0.54 to 0.78)0.51(0.41 to 0.63)Lopinavir/ritonavir 400/100 mg twice daily30 mg once daily151.00(0.94 to 1.07)0.97(0.91 to 1.04)0.94(0.85 to 1.05)Rilpivirine 25 mg once daily50 mg once daily161.13 (1.06 to 1.21)1.12 (1.05 to 1.19)1.22 (1.15 to 1.30)Tenofovir 300 mg once daily50 mg once daily150.97(0.87 to 1.08)1.01(0.91 to 1.11)0.92(0.82 to 1.04)Tipranavir/ritonavir 500/200 mg twice daily50 mg once daily140.54(0.50 to 0.57)0.41(0.38 to 0.44)0.24(0.21 to 0.27)Antacid (MAALOX) simultaneous administration50 mg single dose160.28(0.23 to 0.33)0.26(0.22 to 0.32)0.26(0.21 to 0.31)Antacid (MAALOX) h after dolutegravir50 mg single dose160.82(0.69 to 0.98)0.74(0.62 to 0.90)0.70(0.58 to 0.85)Boceprevir 800 mg every h50 mg once daily131.05(0.96 to 1.15)1.07(0.95 to 1.20)1.08(0.91 to 1.28)Calcium carbonate 1,200 mg simultaneous administration (fasted)50 mg single dose120.63(0.50 to 0.81)0.61(0.47 to 0.80)0.61(0.47 to 0.80)Calcium carbonate 1,200 mg simultaneous administration (fed)50 mg single dose111.07(0.83 to 1.38)1.09(0.84 to 1.43)1.08(0.81 to 1.42)Calcium carbonate 1,200 mg h after dolutegravir50 mg single dose111.00(0.78 to 1.29)0.94(0.72 to 1.23)0.90(0.68 to 1.19)Carbamazepine 300 mg twice daily50 mg once daily16c 0.67(0.61 to 0.73)0.51(0.48 to 0.55)0.27(0.24 to 0.31)Daclatasvir 60 mg once daily50 mgonce daily121.29(1.07 to 1.57)1.33(1.11 to 1.59)1.45(1.25 to 1.68)Ferrous fumarate 324 mg simultaneous administration (fasted)50 mg single dose110.43(0.35 to 0.52)0.46(0.38 to 0.56)0.44(0.36 to 0.54)Ferrous fumarate 324 mg simultaneous administration (fed)50 mg single dose111.03(0.84 to 1.26)0.98(0.81 to 1.20)1.00(0.81 to 1.23)Ferrous fumarate 324 mg h after dolutegravir50 mg single dose100.99(0.81 to 1.21)0.95(0.77 to 1.15)0.92(0.74 to 1.13)Multivitamin (One-A-Day) simultaneous administration50 mgsingle dose160.65(0.54 to 0.77)0.67(0.55 to 0.81)0.68(0.56 to 0.82)Omeprazole 40 mg once daily50 mg single dose120.92(0.75 to 1.11)0.97(0.78 to 1.20)0.95(0.75 to 1.21)Prednisone 60 mg once daily with taper50 mg once daily121.06(0.99 to 1.14)1.11(1.03 to 1.20)1.17(1.06 to 1.28)Rifampina 600 mg once daily50 mg twice daily110.57(0.49 to 0.65)0.46(0.38 to 0.55)0.28(0.23 to 0.34)Rifampinb 600 mg once daily50 mg twice daily111.18(1.03 to 1.37)1.33(1.15 to 1.53)1.22(1.01 to 1.48)Rifabutin 300 mg once daily50 mg once daily91.16(0.98 to 1.37)0.95(0.82 to 1.10)0.70(0.57 to 0.87)Abacavir or Lamivudine: The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities. Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents: In vitro studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on in vitro study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: OATP1B1/3, BCRP or P-gp, OCT1, OCT2, OCT3 (lamivudine only), or MATE1 and MATE2-K.Abacavir, Dolutegravir, and Lamivudine: Coadministration of single dose of riociguat (0.5 mg) to HIV-1-infected subjects receiving TRIUMEQ is reported to increase riociguat AUC() compared with riociguat AUC() reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see Drug Interactions (7.3)]. Effect of Other Agents on the Pharmacokinetics of Abacavir or Lamivudine: In vitro, abacavir is not substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, MRP2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in clinically relevant impact on abacavir concentrations.Lamivudine is substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.Lamivudine is substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine. Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure. Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in trial of 19 healthy male subjects. Methadone: In trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see Drug Interactions (7.3)]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n 18), stavudine (n 10), or zidovudine (n 6) were coadministered as part of multi-drug regimen to HIV-1/HCV co-infected subjects. Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received single 300-mg dose of lamivudine oral solution alone or coadministered with single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.Abacavir, Lamivudine, Zidovudine: Fifteen HIV-1-infected subjects were enrolled in crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.Lamivudine and Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 10.Table 10. Effect of Coadministered Drugs on Abacavir or Lamivudine Increase; <-> No significant change; AUC Area under the concentration versus time curve; CI Confidence interval. The drug-drug interaction was only evaluated in males.Coadministered Drug and DoseDrug and DosenConcentrations of Abacavir or LamivudineConcentration of Coadministered DrugAUCVariabilityEthanol 0.7 g/kg AbacavirSingle 600 mg 2441%90% CI:35% to 48%<->a Nelfinavir 750 mg every h 7 to 10 daysLamivudineSingle 150 mg 1110%95% CI:1% to 20%<->Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily 5 daysLamivudineSingle 300 mg 1443%90% CI:32% to 55%<->. 12.4 Microbiology. Mechanism of ActionDolutegravir: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified recombinant HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.Abacavir: Abacavir is carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.Lamivudine: Lamivudine is synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.Antiviral Activity in Cell CultureDolutegravir: Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentration of drug necessary to effect viral replication by 50 percent (EC50) values of 0.5 nM (0.21 ng per mL) to 2.1 nM (0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade isolates with median EC50 value of 0.54 nM (range: 0.41 to 0.60 nM) in viral susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against panel of HIV-1 clinical isolates with median EC50 values of 0.18 nM (n 3, range: 0.09 to 0.5 nM), 0.08 nM (n 5, range: 0.05 to 2.14 nM) 0.12 nM (n 4, range: 0.05 to 0.51 nM), 0.17 nM (n 3, range: 0.16 to 0.35 nM), 0.24 nM (n 3, range: 0.09 to 0.32 nM), 0.17 nM (n 4, range: 0.07 to 0.44 nM), 0.2 nM (n 3, range: 0.02 to 0.87 nM), and 0.42 nM (n 3, range: 0.41 to 1.79 nM) for clades A, B, C, D, E, F, and G, and group viruses, respectively. Dolutegravir EC50 values against three HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM.Abacavir: The antiviral activity of abacavir against HIV-1 was assessed in number of cell lines including in primary monocytes/macrophages and PBMCs. EC50 values ranged from 3.7 to 5.8 microM (1 microM 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 +- 0.18 microM against clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B), respectively. The EC50 values against HIV-2 isolates (n 4), ranged from 24 to 490 nM.Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: to 40 nM), 30 nM (range: to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B) respectively. The EC50 values against HIV-2 isolates (n 4) from to 120 nM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.Antiviral Activity in Combination with Other Antiviral AgentsNeither dolutegravir, abacavir, nor lamivudine were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir), TIVICAY (dolutegravir), and EPIVIR (lamivudine).Resistance in Cell CultureDolutegravir: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold. Abacavir and Lamivudine: HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions K65R, L74V, Y115F, and M184V/I in HIV-1 RT. M184V or substitutions resulted in high-level resistance to lamivudine and approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74V, or Y115F with M184V or conferred 7- to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.Resistance in Clinical SubjectsNo subjects in the treatment arm receiving dolutegravir EPZICOM in SINGLE (treatment-naive trial) had detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n 11 with HIV-1 RNA greater than 400 copies per mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and subject with 275 copies per mL HIV-1 RNA had treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to abacavir and lamivudine, components of TRIUMEQ, was observed in the arm receiving dolutegravir EPZICOM in the SINGLE trial through Week 144.Cross-ResistanceDolutegravir: Cross-resistance has been observed among INSTIs. The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8.5-fold and 17-fold decreases in dolutegravir susceptibility, respectively.Abacavir and Lamivudine: Cross-resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation (TAM) substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with progressive reduction in abacavir susceptibility.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Adult Subjects. The efficacy of TRIUMEQ is supported by data from randomized, controlled trial (double-blind through 96 weeks and open-label phase from 96 to 144 weeks) in antiretroviral treatment-naive subjects, SINGLE (ING114467, NCT01263015) and other trials in treatment-naive subjects. See full prescribing information for TIVICAY. The efficacy of dolutegravir, in combination with at least two active background regimens in treatment-experienced, INSTI-naive subjects is supported by data from SAILING (ING111762, NCT01231516) (refer to the prescribing information for TIVICAY).Treatment-Naive SubjectsIn SINGLE, 833 subjects were randomized and received at least dose of either TIVICAY 50 mg once daily with fixed-dose abacavir and lamivudine (EPZICOM) or fixed-dose efavirenz/emtricitabine/tenofovir disoproxil fumarate (ATRIPLA). At baseline, the median age of subjects was 35 years, 16% female, 32% non-white, 7% had hepatitis co-infection (hepatitis virus co-infection was excluded), 4% were CDC Class (AIDS), 32% had HIV-1 RNA greater than 100,000 copies per mL, and 53% had CD4+ cell count less than 350 cells per mm3; these characteristics were similar between treatment groups.Week 144 (open-label-phase analysis which followed the Week 96 double-blind phase) outcomes for SINGLE are provided in Table 11.Table 11. Virologic Outcomes of Randomized Treatment in SINGLE at 144 Weeks (Snapshot Algorithm)a Adjusted for pre-specified stratification factors.b Includes subjects who discontinued due to an adverse event or death at any time point if this resulted in no virologic data on treatment during the analysis window. Other includes reasons such as withdrew consent, loss to follow-up, moved, and protocol deviation.d The primary endpoint was assessed at Week 48 and the virologic success rate was 88% in the group receiving TIVICAY and 81% in the ATRIPLA group, with treatment difference of 7.4% and 95% CI of (2.5%, 12.3%).TIVICAY EPZICOM Once Daily(n 414)ATRIPLAOnce Daily(n 419)HIV-1 RNA <50 copies/mL 71%63% Treatment differencea 8.3% (95% CI: 2.0%, 14.6%)d Virologic nonresponse10%7% Data in window not <50 copies/mL4%<1% Discontinued for lack of efficacy3%3% Discontinued for other reasons while not suppressed3%4%No virologic data 18%30%Reasons Discontinued study/study drug due to adverse event or deathb 4%14% Discontinued study/study drug for other reasonsc 12%13% Missing data during window but on study2%3%Proportion (%) of Subjects with HIV-1 RNA <50 copies/mL by Baseline Category Plasma viral load (copies/mL) <=100,00073%64% >100,00069%61%Gender Male 72%66% Female 69%48%Race White 72%71% African-American/African Heritage/Other71%47%Treatment differences were maintained across baseline characteristics including baseline viral load, CD4+ cell count, age, gender, and race. The adjusted mean changes in CD4+ cell counts from baseline were 378 cells per mm3 in the group receiving TIVICAY EPZICOM and 332 cells per mm3 for the ATRIPLA group at 144 weeks. The adjusted difference between treatment arms and 95% CI was 46.9 cells per mm3 (15.6 cells per mm3, 78.2 cells per mm3) (adjusted for pre-specified stratification factors: baseline HIV-1 RNA, and baseline CD4+ cell count).Treatment-ExperiencedIn SAILING, there were 715 subjects included in the efficacy and safety analyses (see full prescribing information for TIVICAY). At Week 48, 71% of subjects randomized to TIVICAY plus background regimen versus 64% of subjects randomized to raltegravir plus background regimen had HIV-1 RNA less than 50 copies per mL (treatment difference and 95% CI: 7.4% [0.7%, 14.2%]).. 14.2 Pediatric Subjects The efficacy of the individual components of TRIUMEQ for the treatment of HIV-1 infection was evaluated in pediatric patients enrolled in the IMPAACT P1093 trial (NCT01302847) or the ARROW trial (NCT02028676), as summarized below. oAbacavir and lamivudine once daily, in combination with third antiretroviral drug, were evaluated in randomized, multicenter trial (ARROW) in HIV-1-infected, treatment-naive subjects. Subjects randomized to once-daily dosing (n 336) and who weighed at least 25 kg received abacavir 600 mg and lamivudine 300 mg, as either the single entities or as EPZICOM. At Week 96, 67% of subjects receiving abacavir and lamivudine once-daily in combination with third antiretroviral drug, had HIV-1 RNA less than 80 copies per mL. oDolutegravir, in combination with other antiretroviral drugs was evaluated in treatment-experienced, INSTI-naive, HIV-1-infected subjects aged to less than 18 years in 48-week open-label, multicenter, dose-finding clinical trial, IMPAACT P1093. Subjects aged 12 to less than 18 years were enrolled in Cohort and subjects aged to less than 12 years were enrolled in Cohort IIA. At 48 weeks, 61% (14/23) of subjects aged 12 to less than 18 years treated with TIVICAY once daily plus optimized background therapy achieved virologic response defined as HIV-1 RNA less than 50 copies per mL. Across both cohorts, virologic suppression at Week 48 was achieved in 67% (16/24) of subjects weighing at least 40 kg.. oAbacavir and lamivudine once daily, in combination with third antiretroviral drug, were evaluated in randomized, multicenter trial (ARROW) in HIV-1-infected, treatment-naive subjects. Subjects randomized to once-daily dosing (n 336) and who weighed at least 25 kg received abacavir 600 mg and lamivudine 300 mg, as either the single entities or as EPZICOM. At Week 96, 67% of subjects receiving abacavir and lamivudine once-daily in combination with third antiretroviral drug, had HIV-1 RNA less than 80 copies per mL. oDolutegravir, in combination with other antiretroviral drugs was evaluated in treatment-experienced, INSTI-naive, HIV-1-infected subjects aged to less than 18 years in 48-week open-label, multicenter, dose-finding clinical trial, IMPAACT P1093. Subjects aged 12 to less than 18 years were enrolled in Cohort and subjects aged to less than 12 years were enrolled in Cohort IIA. At 48 weeks, 61% (14/23) of subjects aged 12 to less than 18 years treated with TIVICAY once daily plus optimized background therapy achieved virologic response defined as HIV-1 RNA less than 50 copies per mL. Across both cohorts, virologic suppression at Week 48 was achieved in 67% (16/24) of subjects weighing at least 40 kg.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. TRIUMEQ is contraindicated in patients:owho have the HLA-B5701 allele [see Warnings and Precautions (5.1)].owith prior hypersensitivity reaction to abacavir, dolutegravir [see Warnings and Precautions (5.1)], or lamivudine.oreceiving 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)].owith moderate or severe hepatic impairment [see Use in Specific Populations (8.7)].. owho have the HLA-B5701 allele [see Warnings and Precautions (5.1)].. owith prior hypersensitivity reaction to abacavir, dolutegravir [see Warnings and Precautions (5.1)], or lamivudine.. oreceiving 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)].. owith moderate or severe hepatic impairment [see Use in Specific Populations (8.7)].. oPresence of HLA-B5701 allele. (4)oPrior hypersensitivity reaction to abacavir, dolutegravir, or lamivudine. (4)oCoadministration with dofetilide. (4)oModerate or severe hepatic impairment. (4, 8.7). oPresence of HLA-B5701 allele. (4). oPrior hypersensitivity reaction to abacavir, dolutegravir, or lamivudine. (4). oCoadministration with dofetilide. (4). oModerate or severe hepatic impairment. (4, 8.7).

DESCRIPTION SECTION.

11 DESCRIPTION. TRIUMEQTRIUMEQ contains an INSTI (dolutegravir) and nucleoside analogues (abacavir and lamivudine) with inhibitory activity against HIV.Each film-coated tablet contains abacavir sulfate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg of dolutegravir, and 300 mg of lamivudine. TRIUMEQ tablets are purple, biconvex, oval, debossed with 572 Tri on one side and contain the inactive ingredients D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet film-coating (OPADRY II Purple 85F90057) contains the inactive ingredients iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium oxide.Abacavir SulfateThe chemical name of abacavir sulfate is (1S,cis)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). It has molecular formula of (C14H18N6O)2oH2SO4 and molecular weight of 670.76 per mol. It has the following structural formula:Abacavir sulfate is white to off-white solid and is soluble in water.DolutegravirThe chemical name of dolutegravir sodium is sodium (4R,12aS)-9-[(2,4-difluorophenyl)methyl]carbamoyl-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1,2:4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The empirical formula is C20H18F2N3NaO5 and the molecular weight is 441.36 per mol. It has the following structural formula:Dolutegravir sodium is white to light yellow powder and is slightly soluble in water.LamivudineThe chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2,3-dideoxy, 3-thiacytidine. It has molecular formula of C8H11N3O3S and molecular weight of 229.3 per mol. It has the following structural formula:Lamivudine is white to off-white crystalline solid and is soluble in water.. Ziagen chem structure. dolutegravir chemical structure. Epivir Chem Struc.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oBefore initiating TRIUMEQ, screen for the HLA-B5701 allele because TRIUMEQ contains abacavir. (2.1). oPregnancy Testing: Pregnancy testing is recommended before initiation of TRIUMEQ in adolescents and adults of childbearing potential. (2.2, 5.6, 8.1, 8.3)oAdults and pediatric patients weighing at least 40 kg: One tablet daily. May be taken with or without food. (2.3)oIf 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. (2.4) oBecause TRIUMEQ is fixed-dose tablet and cannot be dose adjusted, TRIUMEQ is not recommended in patients with creatinine clearance less than 30 mL per minute or patients with hepatic impairment. (2.5, 4). oBefore initiating TRIUMEQ, screen for the HLA-B5701 allele because TRIUMEQ contains abacavir. (2.1). oPregnancy Testing: Pregnancy testing is recommended before initiation of TRIUMEQ in adolescents and adults of childbearing potential. (2.2, 5.6, 8.1, 8.3). oAdults and pediatric patients weighing at least 40 kg: One tablet daily. May be taken with or without food. (2.3). oIf 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. (2.4) oBecause TRIUMEQ is fixed-dose tablet and cannot be dose adjusted, TRIUMEQ is not recommended in patients with creatinine clearance less than 30 mL per minute or patients with hepatic impairment. (2.5, 4). 2.1 Screening for HLA-B5701 Allele prior to Starting TRIUMEQ. Screen for the HLA-B5701 allele prior to initiating therapy with TRIUMEQ [see Boxed Warning, Warnings and Precautions (5.1)].. 2.2 Pregnancy Testing before Initiation of TRIUMEQ Pregnancy testing is recommended before initiation of TRIUMEQ in adolescents and adults of childbearing potential [see Warnings and Precautions 5.6), Use in Specific Populations (8.1, 8.3)].. 2.3 Recommended Dosage. TRIUMEQ is 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.. 2.4 Dosage Recommendation with Certain Concomitant Medications. The dolutegravir dose (50 mg) in TRIUMEQ is insufficient when coadministered with medications listed in Table that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended.Table 1. Dosing Recommendations for TRIUMEQ with Coadministered MedicationsCoadministered DrugDosing RecommendationEfavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampinThe recommended dolutegravir dosage regimen is 50 mg twice daily. An additional dolutegravir 50-mg tablet, separated by 12 hours from TRIUMEQ, should be taken.. 2.5 Not Recommended Due to Lack of Dosage Adjustment Because TRIUMEQ is fixed-dose tablet and cannot be dose adjusted, TRIUMEQ is not recommended in: patients with creatinine clearance less than 30 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)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. TRIUMEQ tablets are purple, biconvex, oval, and debossed with 572 Tri on one side. Each film-coated tablet contains abacavir sulfate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg of dolutegravir, and 300 mg of lamivudine [see Description (11)].. Tablets: 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. (3).

DRUG INTERACTIONS SECTION.

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, dalfampridine, and metformin) [see Contraindications (4), Drug Interactions (7.3)]. In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) (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 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 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 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 Interactionsa See Clinical Pharmacology (12.3) Table or Table for magnitude of interaction.Concomitant Drug Class:Drug NameEffect on ConcentrationClinical CommentHIV-1 Antiviral AgentsNon-nucleoside reverse transcriptase inhibitor: Etravirinea DolutegravirUse of TRIUMEQ with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended.Non-nucleoside reverse transcriptase inhibitor: Efavirenza DolutegravirAdjust 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: NevirapineDolutegravirAvoid coadministration with TRIUMEQ because there are insufficient data to make dosing recommendations.Protease inhibitor: Fosamprenavir/ritonavira Tipranavir/ritonavira DolutegravirAdjust dolutegravir dose to 50 mg twice daily. An additional dolutegravir 50-mg dose should be taken, separated by 12 hours from TRIUMEQ.Other AgentsAntiarrhythmic: DofetilideDofetilideCoadministration is contraindicated with TRIUMEQ [see Contraindications (4)].Potassium channel blocker: DalfampridineDalfampridineElevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with TRIUMEQ should be considered against the risk of seizures in these patients. Carbamazepinea DolutegravirAdjust 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. Johns wort (Hypericum perforatum)DolutegravirAvoid 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 medicationsDolutegravirAdminister TRIUMEQ hours before or hours after taking medications containing polyvalent cations.Oral calcium and iron supplements, including multivitamins containing calcium or ironaDolutegravirWhen taken with food, TRIUMEQ and supplements or multivitamins containing calcium or iron can be taken at the same time. Under fasting conditions, TRIUMEQ should be taken hours before or hours after taking supplements containing calcium or iron. Metformina MetforminRefer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of TRIUMEQ and metformin. Rifampina DolutegravirAdjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from TRIUMEQ. MethadoneAbacavir: In 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 methadone dose modification in the majority of patients; however, an increased methadone dose may be required in small number of patients.SorbitolLamivudine: Coadministration of single doses of lamivudine and sorbitol resulted in sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines [see Clinical Pharmacology (12.3)].RiociguatAbacavir: Coadministration with TRIUMEQ resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions [see Clinical Pharmacology (12.3)]. The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. TRIUMEQ tablets, 600 mg of abacavir as abacavir sulfate, 50 mg of dolutegravir as dolutegravir sodium, and 300 mg lamivudine, are purple, oval, film-coated, biconvex tablets debossed with 572 Tri on one side.Bottle of 30 with child-resistant closure NDC 49702-231-13.Store and dispense in the original package, protect from moisture, and keep the bottle tightly closed. Do not remove desiccant.Store at 25C (77F); excursions permitted 15 to 30C (59 to 86F). [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. TRIUMEQ is indicated for the treatment of human immunodeficiency virus type (HIV-1) infection in adults and in pediatric patients weighing at least 40 kg.Limitations of Use:oTRIUMEQ 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).. oTRIUMEQ 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, 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:oTRIUMEQ 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). oTRIUMEQ 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).Drug InteractionsTRIUMEQ may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. Johns wort [see Contraindications (4), Warnings and Precautions (5.7), Drug Interactions (7)]. Hypersensitivity ReactionInform patients:othat Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of TRIUMEQ, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about TRIUMEQ. The complete text of the Medication Guide is reprinted at the end of this document.oto carry the Warning Card with them.ohow to identify hypersensitivity reaction [see Warnings and Precautions (5.1), Medication Guide].othat if they develop symptoms consistent with hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking TRIUMEQ.othat hypersensitivity reaction can worsen and lead to hospitalization or death if TRIUMEQ is not immediately discontinued.oto not restart TRIUMEQ or any other abacavir-containing product following hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.othat if they have hypersensitivity reaction, they should dispose of any unused TRIUMEQ to avoid restarting abacavir.othat hypersensitivity reaction is usually reversible if it is detected promptly and TRIUMEQ is stopped right away.othat if they have interrupted TRIUMEQ for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.oto not restart TRIUMEQ or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.oto not restart TRIUMEQ or any other dolutegravir-containing product following hypersensitivity reaction to TRIUMEQ.HepatotoxicityInform patients that hepatotoxicity has been reported with dolutegravir, component of TRIUMEQ [see Warnings and Precautions (5.4), Adverse Reactions (6.1)]. Inform patients that monitoring for hepatotoxicity during therapy with TRIUMEQ is recommended.Posttreatment Exacerbations of Hepatitis in Patients with Hepatitis Co-infectionAdvise patients co-infected with HIV-1 and HBV that worsening of liver disease has occurred in some cases when treatment with lamivudine was discontinued. Advise patients to discuss any changes in regimen with their physician [see Warnings and Precautions (5.2)]. Lactic Acidosis/HepatomegalyInform patients that some HIV medicines, including TRIUMEQ, can cause rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly) [see Boxed Warning, Warnings and Precautions (5.5)]. Embryo-Fetal ToxicityAdvise adolescents and adults of childbearing potential, including those actively trying to become pregnant, to discuss the risks and benefits of TRIUMEQ with their healthcare provider to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy. If pregnancy is confirmed in the first trimester, advise patients to contact their healthcare provider [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)]. Adolescents and adults of childbearing potential taking TRIUMEQ should be counseled on the consistent use of effective contraception [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)].Immune Reconstitution SyndromeAdvise patients to inform their healthcare provider immediately of any signs and symptoms of infection as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when TRIUMEQ is started [see Warnings and Precautions (5.8)]. Pregnancy RegistryInform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to TRIUMEQ during pregnancy [see Use in Specific Populations (8.1)].LactationInstruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].Missed DoseInstruct patients that if they miss dose of TRIUMEQ, to take it as soon as they remember. Advise patients not to double their next dose or take more than the prescribed dose [see Dosage and Administration (2)].Availability of Medication GuideInstruct patients to read the Medication Guide before starting TRIUMEQ and to re-read it each time the prescription is renewed. Instruct patients to inform their physician or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.StorageInstruct patients to store TRIUMEQ in the original package, protect from moisture, and keep the bottle tightly closed. Do not remove desiccant.EPIVIR, EPZICOM, TIVICAY, TRIUMEQ, and ZIAGEN are trademarks owned by or licensed to the ViiV Healthcare group of companies.EPIVIR-HBV is trademark owned by or licensed to the GSK group of companies.The other brands listed are trademarks owned by or licensed to their respective owners and are not owned by or licensed to the ViiV Healthcare group of companies. The makers of these brands are not affiliated with and do not endorse the ViiV Healthcare group of companies or its products.Manufactured for:ViiV HealthcareResearch Triangle Park, NC 27709by:GlaxoSmithKlineResearch Triangle Park, NC 27709(C)2021 ViiV Healthcare group of companies or its licensor. TRM:13PI. othat Medication Guide and Warning Card summarizing the symptoms of the abacavir hypersensitivity reaction and other product information will be dispensed by the pharmacist with each new prescription and refill of TRIUMEQ, and instruct the patient to read the Medication Guide and Warning Card every time to obtain any new information that may be present about TRIUMEQ. The complete text of the Medication Guide is reprinted at the end of this document.. oto carry the Warning Card with them.. ohow to identify hypersensitivity reaction [see Warnings and Precautions (5.1), Medication Guide].. othat if they develop symptoms consistent with hypersensitivity reaction they should call their healthcare provider right away to determine if they should stop taking TRIUMEQ.. othat hypersensitivity reaction can worsen and lead to hospitalization or death if TRIUMEQ is not immediately discontinued.. oto not restart TRIUMEQ or any other abacavir-containing product following hypersensitivity reaction because more severe symptoms can occur within hours and may include life-threatening hypotension and death.. othat if they have hypersensitivity reaction, they should dispose of any unused TRIUMEQ to avoid restarting abacavir.. othat hypersensitivity reaction is usually reversible if it is detected promptly and TRIUMEQ is stopped right away.. othat if they have interrupted TRIUMEQ for reasons other than symptoms of hypersensitivity (for example, those who have an interruption in drug supply), serious or fatal hypersensitivity reaction may occur with reintroduction of abacavir.. oto not restart TRIUMEQ or any other abacavir-containing product without medical consultation and only if medical care can be readily accessed by the patient or others.. oto not restart TRIUMEQ or any other dolutegravir-containing product following hypersensitivity reaction to TRIUMEQ.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. TRIUMEQ is fixed-dose combination of the HIV-1 antiretroviral agents abacavir, dolutegravir, and lamivudine [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionDolutegravir: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified recombinant HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.Abacavir: Abacavir is carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.Lamivudine: Lamivudine is synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.Antiviral Activity in Cell CultureDolutegravir: Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean concentration of drug necessary to effect viral replication by 50 percent (EC50) values of 0.5 nM (0.21 ng per mL) to 2.1 nM (0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade isolates with median EC50 value of 0.54 nM (range: 0.41 to 0.60 nM) in viral susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against panel of HIV-1 clinical isolates with median EC50 values of 0.18 nM (n 3, range: 0.09 to 0.5 nM), 0.08 nM (n 5, range: 0.05 to 2.14 nM) 0.12 nM (n 4, range: 0.05 to 0.51 nM), 0.17 nM (n 3, range: 0.16 to 0.35 nM), 0.24 nM (n 3, range: 0.09 to 0.32 nM), 0.17 nM (n 4, range: 0.07 to 0.44 nM), 0.2 nM (n 3, range: 0.02 to 0.87 nM), and 0.42 nM (n 3, range: 0.41 to 1.79 nM) for clades A, B, C, D, E, F, and G, and group viruses, respectively. Dolutegravir EC50 values against three HIV-2 clinical isolates in PBMC assays ranged from 0.09 nM to 0.61 nM.Abacavir: The antiviral activity of abacavir against HIV-1 was assessed in number of cell lines including in primary monocytes/macrophages and PBMCs. EC50 values ranged from 3.7 to 5.8 microM (1 microM 0.28 mcg per mL) and 0.07 to 1.0 microM against HIV-1IIIB and HIV-1BaL, respectively, and the mean EC50 value was 0.26 +- 0.18 microM against clinical isolates. The median EC50 values of abacavir were 344 nM (range: 14.8 to 676 nM), 16.9 nM (range: 5.9 to 27.9 nM), 8.1 nM (range: 1.5 to 16.7 nM), 356 nM (range: 35.7 to 396 nM), 105 nM (range: 28.1 to 168 nM), 47.6 nM (range: 5.2 to 200 nM), 51.4 nM (range: 7.1 to 177 nM), and 282 nM (range: 22.4 to 598 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B), respectively. The EC50 values against HIV-2 isolates (n 4), ranged from 24 to 490 nM.Lamivudine: The antiviral activity of lamivudine against HIV-1 was assessed in number of cell lines including monocytes and PBMCs using standard susceptibility assays. EC50 values were in the range of 0.003 to 15 microM (1 microM 0.23 mcg per mL). The median EC50 values of lamivudine were 60 nM (range: 20 to 70 nM), 35 nM (range: 30 to 40 nM), 30 nM (range: 20 to 90 nM), 20 nM (range: to 40 nM), 30 nM (range: to 60 nM), 30 nM (range: 20 to 70 nM), 30 nM (range: to 70 nM), and 30 nM (range: 20 to 90 nM) against HIV-1 clades A-G and group viruses (n 3 except = for clade B) respectively. The EC50 values against HIV-2 isolates (n 4) from to 120 nM in PBMCs. Ribavirin (50 microM) used in the treatment of chronic HCV infection decreased the anti-HIV-1 activity of lamivudine by 3.5-fold in MT-4 cells.Antiviral Activity in Combination with Other Antiviral AgentsNeither dolutegravir, abacavir, nor lamivudine were antagonistic to all tested anti-HIV agents. See full prescribing information for ZIAGEN (abacavir), TIVICAY (dolutegravir), and EPIVIR (lamivudine).Resistance in Cell CultureDolutegravir: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold. Abacavir and Lamivudine: HIV-1 isolates with reduced susceptibility to the combination of abacavir and lamivudine have been selected in cell culture with amino acid substitutions K65R, L74V, Y115F, and M184V/I in HIV-1 RT. M184V or substitutions resulted in high-level resistance to lamivudine and approximately 2-fold decrease in susceptibility to abacavir. Substitutions K65R, L74V, or Y115F with M184V or conferred 7- to 8-fold reduction in abacavir susceptibility, and combinations of three substitutions were required to confer more than an 8-fold reduction in susceptibility.Resistance in Clinical SubjectsNo subjects in the treatment arm receiving dolutegravir EPZICOM in SINGLE (treatment-naive trial) had detectable decrease in susceptibility to dolutegravir or background NRTIs in the resistance analysis subset (n 11 with HIV-1 RNA greater than 400 copies per mL at failure or last visit and having resistance data). Two virologic failure subjects in SINGLE had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and subject with 275 copies per mL HIV-1 RNA had treatment-emergent Q157Q/P integrase substitution detected at Week 24. None of these subjects had corresponding decrease in dolutegravir susceptibility. No treatment-emergent genotypic resistance to abacavir and lamivudine, components of TRIUMEQ, was observed in the arm receiving dolutegravir EPZICOM in the SINGLE trial through Week 144.Cross-ResistanceDolutegravir: Cross-resistance has been observed among INSTIs. The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M, E92Q/N155H, G140C/Q148R, G140S/Q148H, or K, Q148R/N155H, T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference). In HIV-2 mutants, combinations of substitutions A153G/N155H/S163G and E92Q/T97A/N155H/S163D conferred 4-fold decreases in dolutegravir susceptibility, and E92Q/N155H and G140S/Q148R showed 8.5-fold and 17-fold decreases in dolutegravir susceptibility, respectively.Abacavir and Lamivudine: Cross-resistance has been observed among NRTIs. The combination of abacavir/lamivudine has demonstrated decreased susceptibility to viruses with K65R substitution with or without an M184V/I substitution, viruses with L74V plus the M184V/I substitution, and viruses with thymidine analog mutation (TAM) substitutions (M41L, D67N, K70R, L210W, T215Y/F, K219 E/R/H/Q/N) plus M184V. An increasing number of TAMs is associated with progressive reduction in abacavir susceptibility.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenicityDolutegravir: Two-year carcinogenicity studies in mice and rats were conducted with dolutegravir. Mice were administered doses of up to 500 mg per kg, and rats were administered doses of up to 50 mg per kg. In mice, no significant increases in the incidence of drug-related neoplasms were observed at the highest doses tested, resulting in dolutegravir AUC exposures approximately 26-fold higher than those in humans at the recommended dose of 50 mg once daily. In rats, no increases in the incidence of drug-related neoplasms were observed at the highest dose tested, resulting in dolutegravir AUC exposures 17-fold and 30-fold higher in males and females, respectively, than those in humans at the recommended dose of 50 mg once daily.Abacavir: Abacavir was administered orally at dosage levels to separate groups of mice and rats in 2-year carcinogenicity studies. Results showed an increase in the incidence of malignant and non-malignant tumors. Malignant tumors occurred in the preputial gland of males and the clitoral gland of females of both species, and in the liver of female rats. In addition, non-malignant tumors also occurred in the liver and thyroid gland of female rats. These observations were made at systemic exposures in the range of to 28 times the human exposure at the recommended dose of 600 mg.Lamivudine: Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 12 times (mice) and 57 times (rats) the human exposures at the recommended dose of 300 mg.MutagenicityDolutegravir: Dolutegravir was not genotoxic in the bacterial reverse mutation assay, mouse lymphoma assay, or in the in vivo rodent micronucleus assay.Abacavir: Abacavir induced chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes. Abacavir was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay. Abacavir was not mutagenic in bacterial mutagenicity assays in the presence and absence of metabolic activation.Lamivudine: Lamivudine was mutagenic in an L5178Y mouse lymphoma assay and clastogenic in cytogenetic assay using cultured human lymphocytes. Lamivudine was not mutagenic in microbial mutagenicity assay, in an in vitro cell transformation assay, in rat micronucleus test, in rat bone marrow cytogenetic assay, and in an assay for unscheduled DNA synthesis in rat liver.Impairment of FertilityDolutegravir, abacavir, or lamivudine did not affect male or female fertility in rats at doses associated with exposures approximately 44, 9, or 112 times (respectively) higher than the exposures in humans at the doses of 50 mg, 600 mg, and 300 mg (respectively).. 13.2 Animal Toxicology and/or Pharmacology. Myocardial degeneration was found in mice and rats following administration of abacavir for years. The systemic exposures were equivalent to to 21 times the expected systemic exposure in humans at dose of 600 mg. The clinical relevance of this finding has not been determined.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no known specific treatment for overdose with TRIUMEQ. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.DolutegravirAs dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.AbacavirIt is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.LamivudineBecause negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in lamivudine overdose event.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINICPAL DISPLAY PANELNDC 49702-231-13Triumeq(abacavir, dolutegravir, and lamivudine)600 mg/50 mg/300 mgTABLETSNotice ot Authorized Dispenser:Each time TRIUMEQ is dispensed, give the patient Medication Guide and Warning Card.Rx only30 TabletsEach film-coated tablet contains abacavir sulfate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg of dolutegravir, and 300 mg of lamivudine.This package is child-resistant. Keep out of reach of children. Store in original package at controlled room temperature of 25C (77F); excursions permitted to 15 to 30C (59 to 86F) (See USP). Keep bottle tightly closed; protect from moisture. Do not remove desiccant.See prescribing information for dosage information.Manufactured for:ViiV HealthcareRTP, NC 27709by:GlaxoSmithKlineResearch Triangle Park, NC 27709www.triumeq.com(C)2018 ViiV Healthcare group of companies or its licensor. 62000000034392Rev. 10/19. 62000000034392Rev. 10/19. Triumeq 30 count label.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Effects on ElectrocardiogramA thorough QT trial has been conducted for dolutegravir. Neither the effects of abacavir nor lamivudine as single entities or the combination of abacavir, dolutegravir, and lamivudine on the QT interval have been evaluated.In randomized, placebo-controlled, cross-over trial, 42 healthy subjects received single-dose oral administrations of placebo, dolutegravir 250-mg suspension (exposures approximately 3-fold of the 50-mg once-daily dose at steady state), and moxifloxacin 400 mg (active control) in random sequence. After baseline and placebo adjustment, the maximum mean QTc change based on Fridericia correction method (QTcF) for dolutegravir was 2.4 msec (1-sided 95% upper CI: 4.9 msec). Dolutegravir did not prolong the QTc interval over 24 hours postdose.Effects on Renal FunctionThe effect of dolutegravir on renal function was evaluated in an open-label, randomized, 3-arm, parallel, placebo-controlled trial in healthy subjects (n 37) who received dolutegravir 50 mg once daily (n 12), dolutegravir 50 mg twice daily (n 13), or placebo once daily (n 12) for 14 days. decrease in creatinine clearance, as determined by 24-hour urine collection, was observed with both doses of dolutegravir after 14 days of treatment in subjects who received 50 mg once daily (9% decrease) and 50 mg twice daily (13% decrease). Neither dose of dolutegravir had significant effect on the actual glomerular filtration rate (determined by the clearance of probe drug, iohexol) or effective renal plasma flow (determined by the clearance of probe drug, para-amino hippurate) compared with the placebo.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Pharmacokinetics in AdultsOne TRIUMEQ tablet was bioequivalent to one dolutegravir (TIVICAY) tablet (50 mg) plus one abacavir and lamivudine fixed-dose combination tablet (EPZICOM) under fasted conditions in healthy subjects (n 62).Abacavir: Following oral administration, abacavir is rapidly absorbed and extensively distributed. After oral administration of single dose of 600 mg of abacavir in 20 subjects, Cmax was 4.26 +- 1.19 mcg per mL (mean +- SD) and AUC was 11.95 +- 2.51 mcgohour per mL. Binding of abacavir to human plasma proteins is approximately 50% and was independent of concentration. Total blood and plasma drug-related radioactivity concentrations are identical, demonstrating that abacavir readily distributes into erythrocytes. The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5-carboxylic acid and glucuronyl transferase to form the 5-glucuronide. In single-dose trials, the observed elimination half-life (t 1/2 was 1.54 +- 0.63 hours. After intravenous administration, total clearance was 0.80 +- 0.24 per hour per kg (mean +- SD).Dolutegravir: Following oral administration of dolutegravir, peak plasma concentrations were observed to hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately days with average accumulation ratios for AUC, Cmax, and C24 ranging from 1.2 to 1.5. Dolutegravir is P-gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established. Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 based on population pharmacokinetic analysis. Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. After single oral dose of [14C] dolutegravir, 53% of the total oral dose is excreted unchanged in the feces. Thirty-one percent of the total oral dose is excreted in the urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was less than 1% of the dose. Dolutegravir has terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 per hour based on population pharmacokinetic analyses.The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV-1-infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV-1-infected subjects. Table 6. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1- Infected AdultsParameter50 mg Once DailyGeometric Mean (%CV)AUC(0-24) (mcgoh/mL)53.6 (27)Cmax (mcg/mL)3.67 (20)Cmin (mcg/mL)1.11 (46) Cerebrospinal Fluid (CSF): In 11 treatment-naive subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 18 ng per mL (range: ng per mL to 23.2 ng per mL) to hours postdose after weeks of treatment. The clinical relevance of this finding has not been established. Lamivudine: Following oral administration, lamivudine is rapidly absorbed and extensively distributed. After multiple-dose oral administration of lamivudine 300 mg once daily for days to 60 healthy subjects, steady-state Cmax (Cmax,ss) was 2.04 +- 0.54 mcg per mL (mean +- SD) and the 24-hour steady-state AUC (AUC24,ss) was 8.87 +- 1.83 mcgohour per mL. Binding to plasma protein is low. Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours). In most single-dose trials with plasma sampling up to 48 or 72 hours after dosing, the observed mean elimination half-life (t 1/2 ranged from 13 to 19 hours. In HIV-1-infected subjects, total clearance was 398.5 +- 69.1 mL per min (mean +- SD).Effect of Food on Oral AbsorptionTRIUMEQ may be taken with or without food. Overall, when compared with fasted conditions, administration of TRIUMEQ to healthy adult subjects with high-fat meal (53% fat, 869 calories) resulted in decreased Cmax for abacavir and increased Cmax and AUC for dolutegravir. Lamivudine exposures were not affected by food. With high-fat meal, the Cmax of abacavir decreased 23% and the Cmax and AUC of dolutegravir increased 37% and 48%, respectively.Specific PopulationsPatients with Renal Impairment: The pharmacokinetics for the individual components of TRIUMEQ have been evaluated in patients with renal impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components).Patients with Hepatic Impairment: The pharmacokinetics for the individual components of TRIUMEQ have been evaluated in patients with varying degrees of hepatic impairment (see the U.S. prescribing information for the individual abacavir, dolutegravir, and lamivudine components).Pediatric Patients: The pharmacokinetics for the individual components of TRIUMEQ (abacavir, dolutegravir, and lamivudine) have been evaluated in pediatric subjects. Dolutegravir: The pharmacokinetics of dolutegravir in HIV-1-infected children (n 14) weighing at least 40 kg were similar to those observed in HIV-1-infected adults who received dolutegravir 50 mg once daily (Table 7) [see Clinical Studies (14.2)].Table 7. Dolutegravir Steady-State Pharmacokinetic Parameters in Pediatric SubjectsWeight (n)Dose of TIVICAYDolutegravir Pharmacokinetic Parameter EstimatesGeometric Mean (%CV)Cmax (mcg/mL)AUC(0-24) (mcg.h/mL)C24 (mcg/mL)>=40 kg (n 14)50 mgonce daily3.89 (43)50.1 (53)0.99 (66) Abacavir and Lamivudine: The pharmacokinetic data for abacavir and lamivudine once daily following administration of EPZICOM in pediatric subjects weighing at least 40 kg are limited. The dosing recommendations in this population are based on the safety and efficacy established in controlled trial conducted using either the combination of EPIVIR and ZIAGEN or EPZICOM. Refer to the prescribing information for EPIVIR and ZIAGEN for pharmacokinetic information on the individual products in pediatric patients [see Dosage and Administration (2.2), Clinical Studies (14.2)]. Geriatric Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. The pharmacokinetics of abacavir or lamivudine have not been studied in subjects older than 65 years.Male and Female Patients: There are no significant or clinically relevant gender differences in the pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components.Racial Groups: There are no significant or clinically relevant racial differences in pharmacokinetics of the individual components (dolutegravir, abacavir, or lamivudine) based on the available information that was analyzed for each of the individual components.Drug Interaction StudiesThe drug interaction trials described were conducted with dolutegravir, abacavir, and/or lamivudine as single entities; no drug interaction trials have been conducted using the combination of abacavir, dolutegravir, and lamivudine. No clinically significant drug interactions are expected between dolutegravir, abacavir, and lamivudine. Dosing recommendations as result of established and other potentially significant drug-drug interactions with the individual components of TRIUMEQ are provided in Section 7.3 [see Drug Interactions (7)].Table 8. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugsa The number of subjects represents the maximum number of subjects that were evaluated.Coadministered Drug(s) and Dose(s)Dose of DolutegravirnGeometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without DolutegravirNo Effect 1.00Cmax AUCC or C24 Daclatasvir 60 mg once daily50 mgonce daily121.03(0.84 to 1.25)0.98(0.83 to 1.15)1.06(0.88 to 1.29)Ethinyl estradiol 0.035 mg50 mg twice daily150.99(0.91 to 1.08)1.03(0.96 to 1.11)1.02(0.93 to 1.11)Metformin 500 mg twice daily50 mgonce daily15a 1.66(1.53 to 1.81)1.79(1.65 to 1.93)--Metformin 500 mg twice daily50 mg twice daily15a 2.11(1.91 to 2.33)2.45(2.25 to 2.66)--Methadone 16 to 150 mg50 mg twice daily111.00(0.94 to 1.06)0.98(0.91 to 1.06)0.99(0.91 to 1.07)Midazolam mg25 mgonce daily10--0.95(0.79 to 1.15)--Norelgestromin 0.25 mg50 mg twice daily150.89(0.82 to 0.97)0.98(0.91 to 1.04)0.93(0.85 to 1.03)Rilpivirine 25 mg once daily50 mgonce daily161.10(0.99 to 1.22)1.06(0.98 to 1.16)1.21(1.07 to 1.38)Tenofovir disoproxil fumarate 300 mg once daily50 mgonce daily151.09(0.97 to 1.23)1.12(1.01 to 1.24)1.19(1.04 to 1.35)Table 9. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily. The number of subjects represents the maximum number of subjects that were evaluated.Coadministered Drug(s)and Dose(s)Dose of DolutegravirnGeometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered DrugsNo Effect 1.00Cmax AUCC or C24 Atazanavir 400 mg once daily30 mg once daily121.50(1.40 to 1.59)1.91(1.80 to 2.03)2.80(2.52 to 3.11)Atazanavir/ritonavir 300/100 mg once daily30 mg once daily121.34(1.25 to 1.42)1.62(1.50 to 1.74)2.21(1.97 to 2.47)Darunavir/ritonavir 600/100 mg twice daily30 mg once daily150.89(0.83 to 0.97)0.78(0.72 to 0.85)0.62(0.56 to 0.69)Efavirenz 600 mg once daily50 mgonce daily120.61(0.51 to 0.73)0.43(0.35 to 0.54)0.25(0.18 to 0.34)Etravirine 200 mg twice daily50 mgonce daily160.48(0.43 to 0.54)0.29(0.26 to 0.34)0.12(0.09 to 0.16)Etravirine darunavir/ritonavir 200 mg 600/100 mg twice daily50 mgonce daily90.88(0.78 to 1.00)0.75(0.69 to 0.81)0.63(0.52 to 0.76)Etravirine lopinavir/ritonavir 200 mg 400/100 mg twice daily50 mg once daily81.07(1.02 to 1.13)1.11(1.02 to 1.20)1.28(1.13 to 1.45)Fosamprenavir/ritonavir 700 mg /100 mg twice daily50 mg once daily120.76(0.63 to 0.92)0.65(0.54 to 0.78)0.51(0.41 to 0.63)Lopinavir/ritonavir 400/100 mg twice daily30 mg once daily151.00(0.94 to 1.07)0.97(0.91 to 1.04)0.94(0.85 to 1.05)Rilpivirine 25 mg once daily50 mg once daily161.13 (1.06 to 1.21)1.12 (1.05 to 1.19)1.22 (1.15 to 1.30)Tenofovir 300 mg once daily50 mg once daily150.97(0.87 to 1.08)1.01(0.91 to 1.11)0.92(0.82 to 1.04)Tipranavir/ritonavir 500/200 mg twice daily50 mg once daily140.54(0.50 to 0.57)0.41(0.38 to 0.44)0.24(0.21 to 0.27)Antacid (MAALOX) simultaneous administration50 mg single dose160.28(0.23 to 0.33)0.26(0.22 to 0.32)0.26(0.21 to 0.31)Antacid (MAALOX) h after dolutegravir50 mg single dose160.82(0.69 to 0.98)0.74(0.62 to 0.90)0.70(0.58 to 0.85)Boceprevir 800 mg every h50 mg once daily131.05(0.96 to 1.15)1.07(0.95 to 1.20)1.08(0.91 to 1.28)Calcium carbonate 1,200 mg simultaneous administration (fasted)50 mg single dose120.63(0.50 to 0.81)0.61(0.47 to 0.80)0.61(0.47 to 0.80)Calcium carbonate 1,200 mg simultaneous administration (fed)50 mg single dose111.07(0.83 to 1.38)1.09(0.84 to 1.43)1.08(0.81 to 1.42)Calcium carbonate 1,200 mg h after dolutegravir50 mg single dose111.00(0.78 to 1.29)0.94(0.72 to 1.23)0.90(0.68 to 1.19)Carbamazepine 300 mg twice daily50 mg once daily16c 0.67(0.61 to 0.73)0.51(0.48 to 0.55)0.27(0.24 to 0.31)Daclatasvir 60 mg once daily50 mgonce daily121.29(1.07 to 1.57)1.33(1.11 to 1.59)1.45(1.25 to 1.68)Ferrous fumarate 324 mg simultaneous administration (fasted)50 mg single dose110.43(0.35 to 0.52)0.46(0.38 to 0.56)0.44(0.36 to 0.54)Ferrous fumarate 324 mg simultaneous administration (fed)50 mg single dose111.03(0.84 to 1.26)0.98(0.81 to 1.20)1.00(0.81 to 1.23)Ferrous fumarate 324 mg h after dolutegravir50 mg single dose100.99(0.81 to 1.21)0.95(0.77 to 1.15)0.92(0.74 to 1.13)Multivitamin (One-A-Day) simultaneous administration50 mgsingle dose160.65(0.54 to 0.77)0.67(0.55 to 0.81)0.68(0.56 to 0.82)Omeprazole 40 mg once daily50 mg single dose120.92(0.75 to 1.11)0.97(0.78 to 1.20)0.95(0.75 to 1.21)Prednisone 60 mg once daily with taper50 mg once daily121.06(0.99 to 1.14)1.11(1.03 to 1.20)1.17(1.06 to 1.28)Rifampina 600 mg once daily50 mg twice daily110.57(0.49 to 0.65)0.46(0.38 to 0.55)0.28(0.23 to 0.34)Rifampinb 600 mg once daily50 mg twice daily111.18(1.03 to 1.37)1.33(1.15 to 1.53)1.22(1.01 to 1.48)Rifabutin 300 mg once daily50 mg once daily91.16(0.98 to 1.37)0.95(0.82 to 1.10)0.70(0.57 to 0.87)Abacavir or Lamivudine: The drug interactions described are based on trials conducted with abacavir or lamivudine as single entities. Effect of Abacavir and Lamivudine on the Pharmacokinetics of Other Agents: In vitro studies have shown that abacavir has potential to inhibit CYP1A1 and limited potential to inhibit metabolism mediated by CYP3A4. Lamivudine does not inhibit or induce CYP3A4. Abacavir and lamivudine do not inhibit or induce other CYP enzymes (such as CYP2C9 or CYP2D6). Based on in vitro study results, abacavir and lamivudine at therapeutic drug exposures are not expected to affect the pharmacokinetics of drugs that are substrates of the following transporters: OATP1B1/3, BCRP or P-gp, OCT1, OCT2, OCT3 (lamivudine only), or MATE1 and MATE2-K.Abacavir, Dolutegravir, and Lamivudine: Coadministration of single dose of riociguat (0.5 mg) to HIV-1-infected subjects receiving TRIUMEQ is reported to increase riociguat AUC() compared with riociguat AUC() reported in healthy subjects due to CYP1A1 inhibition by abacavir. The exact magnitude of increase in riociguat exposure has not been fully characterized based on findings from two studies [see Drug Interactions (7.3)]. Effect of Other Agents on the Pharmacokinetics of Abacavir or Lamivudine: In vitro, abacavir is not substrate of OATP1B1, OATP1B3, OCT1, OCT2, OAT1, MATE1, MATE2-K, MRP2 or MRP4; therefore, drugs that modulate these transporters are not expected to affect abacavir plasma concentrations. Abacavir is substrate of BCRP and P-gp in vitro; however, considering its absolute bioavailability (83%), modulators of these transporters are unlikely to result in clinically relevant impact on abacavir concentrations.Lamivudine is substrate of MATE1, MATE2-K, and OCT2 in vitro. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations. This interaction is not considered clinically significant as no dose adjustment of lamivudine is needed.Lamivudine is substrate of P-gp and BCRP; however, considering its absolute bioavailability (87%), it is unlikely that these transporters play significant role in the absorption of lamivudine. Therefore, coadministration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine. Ethanol: Abacavir has no effect on the pharmacokinetic properties of ethanol. Ethanol decreases the elimination of abacavir causing an increase in overall exposure. Interferon Alfa: There was no significant pharmacokinetic interaction between lamivudine and interferon alfa in trial of 19 healthy male subjects. Methadone: In trial of 11 HIV-1-infected subjects receiving methadone-maintenance therapy (40 mg and 90 mg daily), with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased 22% (90% CI: 6% to 42%) [see Drug Interactions (7.3)]. The addition of methadone has no clinically significant effect on the pharmacokinetic properties of abacavir. Ribavirin: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n 18), stavudine (n 10), or zidovudine (n 6) were coadministered as part of multi-drug regimen to HIV-1/HCV co-infected subjects. Sorbitol (Excipient): Lamivudine and sorbitol solutions were coadministered to 16 healthy adult subjects in an open-label, randomized-sequence, 4-period, crossover trial. Each subject received single 300-mg dose of lamivudine oral solution alone or coadministered with single dose of 3.2 grams, 10.2 grams, or 13.4 grams of sorbitol in solution. Coadministration of lamivudine with sorbitol resulted in dose-dependent decreases of 20%, 39%, and 44% in the AUC(0-24); 14%, 32%, and 36% in the AUC(); and 28%, 52%, and 55% in the Cmax; of lamivudine, respectively.Abacavir, Lamivudine, Zidovudine: Fifteen HIV-1-infected subjects were enrolled in crossover-designed drug interaction trial evaluating single doses of abacavir (600 mg), lamivudine (150 mg), and zidovudine (300 mg) alone or in combination. Analysis showed no clinically relevant changes in the pharmacokinetics of abacavir with the addition of lamivudine or zidovudine or the combination of lamivudine and zidovudine. Lamivudine exposure (AUC decreased 15%) and zidovudine exposure (AUC increased 10%) did not show clinically relevant changes with concurrent abacavir.Lamivudine and Zidovudine: No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult patients given single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg every 12 hours).The effects of other coadministered drugs on abacavir or lamivudine are provided in Table 10.Table 10. Effect of Coadministered Drugs on Abacavir or Lamivudine Increase; <-> No significant change; AUC Area under the concentration versus time curve; CI Confidence interval. The drug-drug interaction was only evaluated in males.Coadministered Drug and DoseDrug and DosenConcentrations of Abacavir or LamivudineConcentration of Coadministered DrugAUCVariabilityEthanol 0.7 g/kg AbacavirSingle 600 mg 2441%90% CI:35% to 48%<->a Nelfinavir 750 mg every h 7 to 10 daysLamivudineSingle 150 mg 1110%95% CI:1% to 20%<->Trimethoprim 160 mg/ Sulfamethoxazole 800 mg daily 5 daysLamivudineSingle 300 mg 1443%90% CI:32% to 55%<->.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TRIUMEQ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk SummaryData from an ongoing birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir, component of TRIUMEQ, is administered at the time of conception. As defects related to closure of the neural tube occur from conception through the first weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first weeks of gestation are at potential risk. Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with use of TRIUMEQ. Assess the risks and benefits of TRIUMEQ and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester. benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero dolutegravir exposure during critical periods of fetal development [see Warnings and Precautions (5.6)].There are insufficient human data on the use of TRIUMEQ during pregnancy to definitively assess drug-associated risk for birth defects and miscarriage. The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 50 times (rats) the exposure in humans at the recommended human dose (RHD) (see Data). 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 times the human exposure (AUC) at the RHD. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at 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). DataHuman Data: Dolutegravir: In birth outcome surveillance study in Botswana, there were cases of neural tube defects reported out of 3,591 deliveries (0.19%) to women who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.11% (21/19,361 deliveries) in the non-dolutegravir arm and 0.07% (87/119,630 deliveries) in the HIV-uninfected arm. Seven cases reported with dolutegravir included cases of myelomeningocele, cases of encephalocele, and one case each of anencephaly and iniencephaly. In the same study, no increased risk of neural tube defects was identified in women who started dolutegravir during pregnancy. Two infants out of 4,448 (0.04%) deliveries to women who started dolutegravir during pregnancy had neural tube defect, compared with infants out of 6,748 (0.07%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana. It is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate.Data analyzed to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to definitively address the risk of neural tube defects with dolutegravir.Data from the birth outcome surveillance study described above and postmarketing sources with more than 1,000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.Based on prospective reports to the APR of 842 exposures to dolutegravir during pregnancy resulting in live births (including 512 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 1.9% to 5.3%) following first-trimester exposure to dolutegravir-containing regimens and 4.8% (95% CI: 2.8% to 7.8%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%. Abacavir: Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third 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 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) 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 exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third 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: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudine-containing regimens.Lamivudine pharmacokinetics were studied in pregnant women during 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 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 to 17 and to 18, respectively, and to rats on Gestation Day 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 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 through 17 and 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 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 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 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 through 16 [rat] and 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.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Pregnancy Testing before Initiation of TRIUMEQ (2.2)03/2021Dosage and Administration, Not Recommended Due to Lack of Dosage Adjustment (2.5)03/2021Warnings and Precautions, Embryo-Fetal Toxicity (5.6)03/2021.

SPL MEDGUIDE SECTION.

MEDICATION GUIDETRIUMEQ (TRI-u-meck)(abacavir, dolutegravir, and lamivudine tablets)What is the most important information should know about TRIUMEQTRIUMEQ can cause serious side effects, including:oSerious allergic reactions (hypersensitivity reaction) that can cause death have happened with TRIUMEQ and other abacavir-containing products. Your risk of this allergic reaction to abacavir is much higher if you have gene variation called HLA-B5701. Your healthcare provider can determine with blood test if you have this gene variation. If you get symptom from or more of the following groups while taking TRIUMEQ, call your healthcare provider right away to find out if you should stop taking TRIUMEQ.Symptom(s)Group 1FeverGroup 2RashGroup 3Nausea, vomiting, diarrhea, abdominal (stomach area) painGroup 4Generally ill feeling, extreme tiredness, or achinessGroup 5Shortness of breath, cough, sore throatA list of these symptoms is on the Warning Card your pharmacist gives you. Carry this Warning Card with you at all times. If you stop TRIUMEQ because of an allergic reaction, never take TRIUMEQ (abacavir, dolutegravir and lamivudine) or any other medicine that contains abacavir or dolutegravir (EPZICOM, TIVICAY, TRIZIVIR, or ZIAGEN) again. oIf you have an allergic reaction, dispose of any unused TRIUMEQ. Ask your pharmacist how to properly dispose of medicines.oIf you take TRIUMEQ or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very low blood pressure or death. oIf you stop TRIUMEQ for any other reason, even for few days, and you are not allergic to TRIUMEQ, talk with your healthcare provider before taking it again. Taking TRIUMEQ again can cause serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.If your healthcare provider tells you that you can take TRIUMEQ again, start taking it when you are around medical help or people who can call healthcare provider if you need one.oWorsening of Hepatitis virus (HBV) infection. If you have HBV infection and take TRIUMEQ, your HBV may get worse (flare-up) if you stop taking TRIUMEQ. flare-up is when your HBV infection suddenly returns in worse way than before. oDo not run out of TRIUMEQ. Refill your prescription or talk to your healthcare provider before your TRIUMEQ is all gone.oDo not stop TRIUMEQ without first talking to your healthcare provider.oIf you stop taking TRIUMEQ, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you medicine to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TRIUMEQ. oResistant HBV. If you have human immunodeficiency virus (HIV-1) and HBV, the HBV can change (mutate) during your treatment with TRIUMEQ and become harder to treat (resistant). oFor more information about side effects, see What are the possible side effects of TRIUMEQWhat is TRIUMEQTRIUMEQ is prescription medicine used to treat HIV-1 infection in adults and children who weigh at least 88 pounds (40 kg). HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS). TRIUMEQ contains the prescription medicines, abacavir, dolutegravir, and lamivudine.oTRIUMEQ is not for use by itself in people who have or have had resistance to abacavir, dolutegravir, or lamivudine.It is not known if TRIUMEQ is safe and effective in children who weigh less than 88 pounds (40 kg).Do not take TRIUMEQ if you:ohave certain type of gene variation called the HLA-B5701 allele. Your healthcare provider will test you for this before prescribing treatment with TRIUMEQ.oare allergic to abacavir, dolutegravir, lamivudine, or any of the ingredients in TRIUMEQ. See the end of this Medication Guide for complete list of ingredients in TRIUMEQ.otake dofetilide. Taking TRIUMEQ and dofetilide can cause side effects that may be serious or life-threatening.ohave certain liver problems.Before you take TRIUMEQ, tell your healthcare provider about all of your medical conditions, including if you:ohave been tested and know whether or not you have particular gene variation called HLA-B5701.ohave or have had liver problems, including hepatitis or virus infection.ohave kidney problems.ohave heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.odrink alcohol or take medicines that contain alcohol.oare pregnant or plan to become pregnant. One of the medicines in TRIUMEQ called dolutegravir may harm your unborn baby.oYour healthcare provider may prescribe different medicine than TRIUMEQ if you are planning to become pregnant or if pregnancy is confirmed during the first 12 weeks of pregnancy.oIf you can become pregnant, your healthcare provider may perform pregnancy test before you start treatment with TRIUMEQ.oIf you can become pregnant, you and your healthcare provider should talk about the use of effective birth control (contraception) during treatment with TRIUMEQ.oTell your healthcare provider right away if you are planning to become pregnant, you become pregnant, or think you may be pregnant during treatment with TRIUMEQ.Pregnancy Registry. There is pregnancy registry for individuals who take TRIUMEQ, during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.oare breastfeeding or plan to breastfeed. Do not breastfeed if you take TRIUMEQ.oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.oTwo of the medicines in TRIUMEQ (abacavir and lamivudine) pass into your breastmilk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with TRIUMEQ. Keep list of your medicines to show your healthcare provider and pharmacist when you get new medicine.oYou can ask your healthcare provider or pharmacist for list of medicines that interact with TRIUMEQ. oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TRIUMEQ with other medicines.How should take TRIUMEQoTake TRIUMEQ exactly as your healthcare provider tells you to take it.oDo not change your dose or stop taking TRIUMEQ without talking with your healthcare provider.oTRIUMEQ may be taken with or without food.oIf you take antacids, laxatives, or other medicines that contain aluminum, magnesium, or buffered medicines, TRIUMEQ should be taken at least hours before or hours after you take these medicines.oIf you need to take iron or calcium supplements by mouth during treatment with TRIUMEQ:oIf you take TRIUMEQ with food, you may take these supplements at the same time that you take TRIUMEQ.oIf you do not take TRIUMEQ with food, take TRIUMEQ at least hours before or hours after you take these supplements.oIf you miss dose of TRIUMEQ, take it as soon as you remember. Do not take doses at the same time or take more than your healthcare provider tells you to take. oStay under the care of healthcare provider during treatment with TRIUMEQ.oDo not run out of TRIUMEQ. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.oIf you take too much TRIUMEQ, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of TRIUMEQTRIUMEQ can cause serious side effects including:oSee What is the most important information should know about TRIUMEQoLiver problems. People with history of hepatitis or virus may have an increased risk of developing new or worsening changes in certain liver function tests during treatment with TRIUMEQ. Liver problems including liver failure have also happened with TRIUMEQ in people without history of liver disease or other risk factors. Liver failure resulting in liver transplant has also been reported with TRIUMEQ. Your healthcare provider may do blood tests to check your liver. Call your healthcare provider right away if you develop any of the signs or symptoms of liver problems listed below. oyour skin or the white part of your eyes turns yellow (jaundice)odark or tea-colored urineolight colored stools (bowel movements)oloss of appetiteonausea or vomitingopain, aching, or tenderness on the right side of your stomach areaoToo much lactic acid in your blood (lactic acidosis). Too much lactic acid is serious medical emergency that can lead to death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis: ofeel very weak or tiredounusual (not normal) muscle painotrouble breathingostomach pain with nausea and vomitingofeel cold, especially in your arms and legsofeel dizzy or lightheadedohave fast or irregular heartbeatoLactic acidosis can also lead to severe liver problems, which can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the signs or symptoms of liver problems which are listed above under Liver problems. oYou may be more likely to get lactic acidosis or severe liver problems if you are female or very overweight (obese).oChanges in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having new symptoms after you start taking TRIUMEQ.oHeart attack. Some HIV-1 medicines including TRIUMEQ may increase your risk of heart attack.oThe most common side effects of TRIUMEQ include:otrouble sleepingotirednessoheadacheThese are not all the possible side effects of TRIUMEQ. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TRIUMEQoStore TRIUMEQ at room temperature between 68F to 77F (20C to 25C).oStore TRIUMEQ in the original bottle.oKeep the bottle of TRIUMEQ tightly closed and protect it from moisture.oThe bottle of TRIUMEQ contains desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle.Keep TRIUMEQ and all medicines out of the reach of children.General information about the safe and effective use of TRIUMEQ.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use TRIUMEQ for condition for which it was not prescribed. Do not give TRIUMEQ to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about TRIUMEQ that is written for health professionals.What are the ingredients in TRIUMEQActive ingredients: abacavir, dolutegravir, and lamivudineInactive ingredients: D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate.Tablet film-coating contains: iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium oxide. Manufactured for: by: ViiV Healthcare GlaxoSmithKline Research Triangle Park, NC 27709 Research Triangle Park, NC 27709EPZICOM, TIVICAY, TRIUMEQ, TRIZIVIR, and ZIAGEN are trademarks owned by or licensed to the ViiV Healthcare group of companies.(C)2021 ViiV Healthcare group of companies or its licensor. TRM:13MGFor more information go to www.TRIUMEQ.com or call 1-877-844-8872.This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 03/2021. oSerious allergic reactions (hypersensitivity reaction) that can cause death have happened with TRIUMEQ and other abacavir-containing products. Your risk of this allergic reaction to abacavir is much higher if you have gene variation called HLA-B5701. Your healthcare provider can determine with blood test if you have this gene variation.. If you get symptom from or more of the following groups while taking TRIUMEQ, call your healthcare provider right away to find out if you should stop taking TRIUMEQ.. oIf you have an allergic reaction, dispose of any unused TRIUMEQ. Ask your pharmacist how to properly dispose of medicines.. oIf you take TRIUMEQ or any other abacavir-containing medicine again after you have had an allergic reaction, within hours you may get life-threatening symptoms that may include very low blood pressure or death. oIf you stop TRIUMEQ for any other reason, even for few days, and you are not allergic to TRIUMEQ, talk with your healthcare provider before taking it again. Taking TRIUMEQ again can cause serious allergic or life-threatening reaction, even if you never had an allergic reaction to it before.. oWorsening of Hepatitis virus (HBV) infection. If you have HBV infection and take TRIUMEQ, your HBV may get worse (flare-up) if you stop taking TRIUMEQ. flare-up is when your HBV infection suddenly returns in worse way than before. oDo not run out of TRIUMEQ. Refill your prescription or talk to your healthcare provider before your TRIUMEQ is all gone.oDo not stop TRIUMEQ without first talking to your healthcare provider.oIf you stop taking TRIUMEQ, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you medicine to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TRIUMEQ. oDo not run out of TRIUMEQ. Refill your prescription or talk to your healthcare provider before your TRIUMEQ is all gone.. oDo not stop TRIUMEQ without first talking to your healthcare provider.. oIf you stop taking TRIUMEQ, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver function and monitor your HBV infection. It may be necessary to give you medicine to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking TRIUMEQ.. oResistant HBV. If you have human immunodeficiency virus (HIV-1) and HBV, the HBV can change (mutate) during your treatment with TRIUMEQ and become harder to treat (resistant). oFor more information about side effects, see What are the possible side effects of TRIUMEQ. oTRIUMEQ is not for use by itself in people who have or have had resistance to abacavir, dolutegravir, or lamivudine.. ohave certain type of gene variation called the HLA-B5701 allele. Your healthcare provider will test you for this before prescribing treatment with TRIUMEQ.. oare allergic to abacavir, dolutegravir, lamivudine, or any of the ingredients in TRIUMEQ. See the end of this Medication Guide for complete list of ingredients in TRIUMEQ.. otake dofetilide. Taking TRIUMEQ and dofetilide can cause side effects that may be serious or life-threatening.. ohave certain liver problems.. ohave been tested and know whether or not you have particular gene variation called HLA-B5701.. ohave or have had liver problems, including hepatitis or virus infection.. ohave kidney problems.. ohave heart problems, smoke, or have diseases that increase your risk of heart disease such as high blood pressure, high cholesterol, or diabetes.. odrink alcohol or take medicines that contain alcohol.. oare pregnant or plan to become pregnant. One of the medicines in TRIUMEQ called dolutegravir may harm your unborn baby.oYour healthcare provider may prescribe different medicine than TRIUMEQ if you are planning to become pregnant or if pregnancy is confirmed during the first 12 weeks of pregnancy.oIf you can become pregnant, your healthcare provider may perform pregnancy test before you start treatment with TRIUMEQ.oIf you can become pregnant, you and your healthcare provider should talk about the use of effective birth control (contraception) during treatment with TRIUMEQ.oTell your healthcare provider right away if you are planning to become pregnant, you become pregnant, or think you may be pregnant during treatment with TRIUMEQ.. oYour healthcare provider may prescribe different medicine than TRIUMEQ if you are planning to become pregnant or if pregnancy is confirmed during the first 12 weeks of pregnancy.. oIf you can become pregnant, your healthcare provider may perform pregnancy test before you start treatment with TRIUMEQ.. oIf you can become pregnant, you and your healthcare provider should talk about the use of effective birth control (contraception) during treatment with TRIUMEQ.. oTell your healthcare provider right away if you are planning to become pregnant, you become pregnant, or think you may be pregnant during treatment with TRIUMEQ.. oare breastfeeding or plan to breastfeed. Do not breastfeed if you take TRIUMEQ.oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.oTwo of the medicines in TRIUMEQ (abacavir and lamivudine) pass into your breastmilk.. oYou should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. oTwo of the medicines in TRIUMEQ (abacavir and lamivudine) pass into your breastmilk.. oYou can ask your healthcare provider or pharmacist for list of medicines that interact with TRIUMEQ. oDo not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TRIUMEQ with other medicines.. oTake TRIUMEQ exactly as your healthcare provider tells you to take it.. oDo not change your dose or stop taking TRIUMEQ without talking with your healthcare provider.. oTRIUMEQ may be taken with or without food.. oIf you take antacids, laxatives, or other medicines that contain aluminum, magnesium, or buffered medicines, TRIUMEQ should be taken at least hours before or hours after you take these medicines.. oIf you need to take iron or calcium supplements by mouth during treatment with TRIUMEQ:oIf you take TRIUMEQ with food, you may take these supplements at the same time that you take TRIUMEQ.oIf you do not take TRIUMEQ with food, take TRIUMEQ at least hours before or hours after you take these supplements.. oIf you take TRIUMEQ with food, you may take these supplements at the same time that you take TRIUMEQ.. oIf you do not take TRIUMEQ with food, take TRIUMEQ at least hours before or hours after you take these supplements.. oIf you miss dose of TRIUMEQ, take it as soon as you remember. Do not take doses at the same time or take more than your healthcare provider tells you to take. oStay under the care of healthcare provider during treatment with TRIUMEQ.. oDo not run out of TRIUMEQ. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.. oIf you take too much TRIUMEQ, call your healthcare provider or go to the nearest hospital emergency room right away.. oSee What is the most important information should know about TRIUMEQ. oLiver problems. People with history of hepatitis or virus may have an increased risk of developing new or worsening changes in certain liver function tests during treatment with TRIUMEQ. Liver problems including liver failure have also happened with TRIUMEQ in people without history of liver disease or other risk factors. Liver failure resulting in liver transplant has also been reported with TRIUMEQ. Your healthcare provider may do blood tests to check your liver. Call your healthcare provider right away if you develop any of the signs or symptoms of liver problems listed below. oyour skin or the white part of your eyes turns yellow (jaundice). odark or tea-colored urine. olight colored stools (bowel movements). oloss of appetite. onausea or vomiting. opain, aching, or tenderness on the right side of your stomach area. oToo much lactic acid in your blood (lactic acidosis). Too much lactic acid is serious medical emergency that can lead to death. Call your healthcare provider right away if you get any of the following symptoms that could be signs of lactic acidosis: ofeel very weak or tired. ounusual (not normal) muscle pain. otrouble breathing. ostomach pain with nausea and vomiting. ofeel cold, especially in your arms and legs. ofeel dizzy or lightheaded. ohave fast or irregular heartbeat. oLactic acidosis can also lead to severe liver problems, which can lead to death. Your liver may become large (hepatomegaly) and you may develop fat in your liver (steatosis). Call your healthcare provider right away if you get any of the signs or symptoms of liver problems which are listed above under Liver problems. oYou may be more likely to get lactic acidosis or severe liver problems if you are female or very overweight (obese).. oChanges in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your healthcare provider right away if you start having new symptoms after you start taking TRIUMEQ.. oHeart attack. Some HIV-1 medicines including TRIUMEQ may increase your risk of heart attack.. oThe most common side effects of TRIUMEQ include:. otrouble sleeping. otiredness. oheadache. oStore TRIUMEQ at room temperature between 68F to 77F (20C to 25C).. oStore TRIUMEQ in the original bottle.. oKeep the bottle of TRIUMEQ tightly closed and protect it from moisture.. oThe bottle of TRIUMEQ contains desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle.

SPL UNCLASSIFIED SECTION.

2.1 Screening for HLA-B5701 Allele prior to Starting TRIUMEQ. Screen for the HLA-B5701 allele prior to initiating therapy with TRIUMEQ [see Boxed Warning, Warnings and Precautions (5.1)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oPregnancy: Assess the risks and benefits of TRIUMEQ and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. (2.2, 5.6, 8.1, 8.3)oLactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2)oFemales and males of reproductive potential: Pregnancy testing is recommended in adolescents and adults of childbearing potential. Patients should be counseled on the consistent use of effective contraception. (8.1, 8.3)oPediatrics: Not recommended for patients weighing less than 40 kg. (8.4)oTRIUMEQ is not recommended in patients with creatinine clearance less than 30 mL per min. (8.6)oIf dose reduction of abacavir, component of TRIUMEQ, is required for patients with mild hepatic impairment, then the individual components should be used. (8.7). oPregnancy: Assess the risks and benefits of TRIUMEQ and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. (2.2, 5.6, 8.1, 8.3). oLactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. (8.2). oFemales and males of reproductive potential: Pregnancy testing is recommended in adolescents and adults of childbearing potential. Patients should be counseled on the consistent use of effective contraception. (8.1, 8.3). oPediatrics: Not recommended for patients weighing less than 40 kg. (8.4). oTRIUMEQ is not recommended in patients with creatinine clearance less than 30 mL per min. (8.6). oIf dose reduction of abacavir, 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 RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TRIUMEQ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.Risk SummaryData from an ongoing birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir, component of TRIUMEQ, is administered at the time of conception. As defects related to closure of the neural tube occur from conception through the first weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first weeks of gestation are at potential risk. Advise adolescents and adults of childbearing potential, including those actively trying to become pregnant, of the potential risk of neural tube defects with use of TRIUMEQ. Assess the risks and benefits of TRIUMEQ and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester. benefit-risk assessment should consider factors such as feasibility of switching to another antiretroviral regimen, tolerability, ability to maintain viral suppression, and risk of HIV-1 transmission to the infant against the risk of neural tube defects associated with in utero dolutegravir exposure during critical periods of fetal development [see Warnings and Precautions (5.6)].There are insufficient human data on the use of TRIUMEQ during pregnancy to definitively assess drug-associated risk for birth defects and miscarriage. The background risk for major birth defects for the indicated population is unknown. In the U.S. general population, the estimated background rate for major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir at systemic exposures (AUC) less than (rabbits) and approximately 50 times (rats) the exposure in humans at the recommended human dose (RHD) (see Data). 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 times the human exposure (AUC) at the RHD. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at 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). DataHuman Data: Dolutegravir: In birth outcome surveillance study in Botswana, there were cases of neural tube defects reported out of 3,591 deliveries (0.19%) to women who were exposed to dolutegravir-containing regimens at the time of conception. In comparison, the neural tube defect prevalence rates were 0.11% (21/19,361 deliveries) in the non-dolutegravir arm and 0.07% (87/119,630 deliveries) in the HIV-uninfected arm. Seven cases reported with dolutegravir included cases of myelomeningocele, cases of encephalocele, and one case each of anencephaly and iniencephaly. In the same study, no increased risk of neural tube defects was identified in women who started dolutegravir during pregnancy. Two infants out of 4,448 (0.04%) deliveries to women who started dolutegravir during pregnancy had neural tube defect, compared with infants out of 6,748 (0.07%) deliveries to women who started non-dolutegravir-containing regimens during pregnancy. The reported risks of neural tube defects by treatment groups were based on interim analyses from the ongoing surveillance study in Botswana. It is unknown if baseline characteristics were balanced between the study treatment groups. The observed trends of association could change as data accumulate.Data analyzed to date from other sources including the APR, clinical trials, and postmarketing data are insufficient to definitively address the risk of neural tube defects with dolutegravir.Data from the birth outcome surveillance study described above and postmarketing sources with more than 1,000 pregnancy outcomes from second and third trimester exposure in pregnant women indicate no evidence of increased risk of adverse birth outcomes.Based on prospective reports to the APR of 842 exposures to dolutegravir during pregnancy resulting in live births (including 512 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 1.9% to 5.3%) following first-trimester exposure to dolutegravir-containing regimens and 4.8% (95% CI: 2.8% to 7.8%) following second-/third-trimester exposure to dolutegravir-containing regimens. In the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP), the background birth defect rate was 2.7%. Abacavir: Based on prospective reports to the APR of exposures to abacavir during pregnancy resulting in live births (including over 1,300 exposed in the first trimester and over 1,300 exposed in the second/third 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 3.2% (95% CI: 2.3% to 4.3%) following first trimester exposure to abacavir-containing regimens and 2.9% (95% CI: 2.1% to 4.0%) 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 exposures to lamivudine during pregnancy resulting in live births (including over 5,300 exposed in the first trimester and over 7,400 exposed in the second/third 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: 2.7% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudine-containing regimens.Lamivudine pharmacokinetics were studied in pregnant women during 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 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 to 17 and to 18, respectively, and to rats on Gestation Day 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 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 through 17 and 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 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 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 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 through 16 [rat] and 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. Risk SummaryThe 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 breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving TRIUMEQ.DataAnimal Data: Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following 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 hours postdose.. 8.3 Females and Males of Reproductive Potential In adolescents and adults of childbearing potential currently on TRIUMEQ who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing TRIUMEQ and discuss with the patient if an alternative treatment should be considered [see Warnings and Precautions (5.6), Use in Specific Populations (8.1)].Pregnancy TestingPregnancy testing is recommended in adolescents and adults of childbearing potential before initiation of TRIUMEQ [see Dosage and Administration (2.2)].ContraceptionAdolescents and adults of childbearing potential who are taking TRIUMEQ should be counseled on the consistent use of effective contraception.. 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:oThe safety and efficacy of once-daily abacavir and lamivudine were established with randomized, multicenter trial (ARROW [COL105677]) in HIV-1-infected, treatment-naive subjects aged months to 17 years with 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)].oThe safety and antiviral activity (efficacy) of dolutegravir was established through 48-week, open-label, multicenter, dose-finding clinical trial (IMPAACT P1093), in which treatment-experienced, INSTI-naive, HIV-1-infected subjects aged 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 fixed-dose combination tablet which cannot be adjusted for patients weighing less than 40 kg [see Clinical Pharmacology (12.3)].. oThe safety and efficacy of once-daily abacavir and lamivudine were established with randomized, multicenter trial (ARROW [COL105677]) in HIV-1-infected, treatment-naive subjects aged months to 17 years with 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)].. oThe safety and antiviral activity (efficacy) of dolutegravir was established through 48-week, open-label, multicenter, dose-finding clinical trial (IMPAACT P1093), in which treatment-experienced, INSTI-naive, HIV-1-infected subjects aged 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)].. 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 30 mL per min because TRIUMEQ is fixed-dose combination and the dosage of the individual components cannot be adjusted. If dose reduction of lamivudine, component of TRIUMEQ, is required for patients with creatinine clearance less than 30 mL per min, then the individual components should be used [see Clinical Pharmacology (12.3)].Patients with creatinine clearance between 30 and 49 mL per min receiving TRIUMEQ may experience 1.6- to 3.3-fold higher lamivudine exposure (AUC) than patients with creatinine clearance >=50 mL per min. There are no safety data from randomized, controlled trials comparing TRIUMEQ to the individual components in patients with creatinine clearance between 30 and 49 mL per min who received dose-adjusted lamivudine. In the original lamivudine registrational trials in combination with zidovudine, higher lamivudine exposures were associated with higher rates of hematologic toxicities (neutropenia and anemia), although discontinuations due to neutropenia or anemia each occurred in <1% of subjects. Patients with sustained creatinine clearance between 30 and 49 mL per min who receive TRIUMEQ should be monitored for hematologic toxicities. If new or worsening neutropenia or anemia develop, dose adjustment of lamivudine, per lamivudine prescribing information, is recommended. If lamivudine dose adjustment is indicated, TRIUMEQ should be discontinued and the individual components should be used to construct the treatment regimen.. 8.7 Patients with Impaired Hepatic Function. TRIUMEQ is fixed-dose combination and the dosage of the individual components cannot be adjusted. If dose reduction of abacavir, 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oHepatotoxicity has been reported in patients receiving dolutegravir-containing regimen. Monitoring for hepatotoxicity is recommended. (5.4)oLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. (5.5)oEmbryo-fetal toxicity may occur when used at the time of conception and in early pregnancy. Assess the risks and benefits of TRIUMEQ and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception. (2.2, 5.6, 8.1, 8.3)oImmune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. (5.8) oHepatotoxicity has been reported in patients receiving dolutegravir-containing regimen. Monitoring for hepatotoxicity is recommended. (5.4). oLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. (5.5). oEmbryo-fetal toxicity may occur when used at the time of conception and in early pregnancy. Assess the risks and benefits of TRIUMEQ and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester due to the risk of neural tube defects. Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception. (2.2, 5.6, 8.1, 8.3). oImmune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. (5.8) 5.1 Hypersensitivity Reactions. Hypersensitivity reactions have been reported with the use of abacavir or dolutegravir, components of TRIUMEQ.AbacavirSerious 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 weeks of treatment with abacavir (median time to onset was days); although abacavir hypersensitivity reactions have occurred any time during treatment [see Adverse Reactions (6.1)]. Patients who carry the HLA-B5701 allele are at higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B5701 allele have developed hypersensitivity reactions. Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in clinical trials with abacavir-containing products where HLA-B5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B5701 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:oAll patients should be screened for the HLA-B5701 allele prior to initiating therapy with TRIUMEQ or reinitiation of therapy with TRIUMEQ, unless patients have previously documented HLA-B5701 allele assessment. oTRIUMEQ is contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients. oBefore starting TRIUMEQ, review medical history for prior exposure to any abacavir-containing product. NEVER restart TRIUMEQ or any other abacavir-containing product following hypersensitivity reaction to abacavir, regardless of HLA-B5701 status.oTo reduce the risk of life-threatening hypersensitivity reaction, regardless of HLA-B5701 status, discontinue TRIUMEQ immediately if 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.oIf hypersensitivity reaction cannot be ruled out, do not restart TRIUMEQ or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours.oClinically, it is not possible to determine whether hypersensitivity reaction with TRIUMEQ would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ due to hypersensitivity reaction.oIf hypersensitivity reaction is ruled out, patients may restart TRIUMEQ. 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 any other abacavir-containing product, is recommended only if medical care can be readily accessed.oA Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill.DolutegravirHypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving TIVICAY in Phase clinical trials. Discontinue TRIUMEQ 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 other suspect agents after the onset of hypersensitivity may result in life-threatening reaction.Clinically, it is not possible to determine whether hypersensitivity reaction with TRIUMEQ would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ due to hypersensitivity reaction.. oAll patients should be screened for the HLA-B5701 allele prior to initiating therapy with TRIUMEQ or reinitiation of therapy with TRIUMEQ, unless patients have previously documented HLA-B5701 allele assessment. oTRIUMEQ is contraindicated in patients with prior hypersensitivity reaction to abacavir and in HLA-B5701-positive patients. oBefore starting TRIUMEQ, review medical history for prior exposure to any abacavir-containing product. NEVER restart TRIUMEQ or any other abacavir-containing product following hypersensitivity reaction to abacavir, regardless of HLA-B5701 status.. oTo reduce the risk of life-threatening hypersensitivity reaction, regardless of HLA-B5701 status, discontinue TRIUMEQ immediately if 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.. oIf hypersensitivity reaction cannot be ruled out, do not restart TRIUMEQ or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours.. oClinically, it is not possible to determine whether hypersensitivity reaction with TRIUMEQ would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ due to hypersensitivity reaction.. oIf hypersensitivity reaction is ruled out, patients may restart TRIUMEQ. 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 any other abacavir-containing product, is recommended only if medical care can be readily accessed.. oA Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill.. 5.2 Posttreatment Exacerbations of Hepatitis in Patients with Hepatitis Co-infection. Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.. 5.3 Emergence of Lamivudine-Resistant HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis virus 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 hepatitis virus. See full prescribing information for EPIVIR-HBV (lamivudine).. 5.4 Hepatotoxicity. Hepatic adverse events have been reported in patients receiving dolutegravir-containing regimen [see Adverse Reactions (6.1)]. Patients with underlying hepatitis or may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ [see Adverse Reactions (6.1)]. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis 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 receiving 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.. 5.5 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). 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 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.. 5.6 Embryo-Fetal Toxicity. An ongoing observational study showed an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. As there is limited understanding of the association of reported types of neural tube defects with dolutegravir use, inform adolescents and adults of childbearing potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with TRIUMEQ. Assess the risks and benefits of TRIUMEQ and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester [see Use in Specific Populations 8.1, 8.3)].Pregnancy testing is recommended before initiation of TRIUMEQ in adolescents and adults of childbearing potential [see Dosage and Administration 2.2)]. Adolescents and adults of childbearing potential should be counseled on the consistent use of effective contraception [see Use in Specific Populations 8.1, 8.3)].TRIUMEQ may be considered during the second and third trimesters of pregnancy if the expected benefit justifies the potential risk to the pregnant woman and the fetus.. 5.7 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions. The concomitant use of TRIUMEQ 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)]: oLoss of therapeutic effect of TRIUMEQ and possible development of resistance. oPossible clinically significant adverse reactions from greater exposures of concomitant drugs. See Table 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; review concomitant medications during therapy with TRIUMEQ; and monitor for the adverse reactions associated with the concomitant drugs.. oLoss of therapeutic effect of TRIUMEQ and possible development of resistance. oPossible clinically significant adverse reactions from greater exposures of concomitant drugs. 5.8 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIUMEQ. 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, and Guillain-Barre syndrome) 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.. 5.9 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 potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for causal relationship between abacavir and the risk of MI is inconclusive.As 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).

INSTRUCTIONS FOR USE SECTION.

INSTRUCTIONS FOR USETRIUMEQ PD (TRI-u-meck Pe De)(abacavir, dolutegravir, and lamivudine)tablets for oral suspensionThis Instructions for Use contains information on how to take TRIUMEQ PD.Read this Instructions for Use before your child starts taking TRIUMEQ PD for the first time and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your childs medical condition or treatment. Talk to your healthcare provider or pharmacist if you have any questions on how to prepare or give the prescribed dose of TRIUMEQ PD.Important informationoGive TRIUMEQ PD exactly as your healthcare provider tells you.oEach time you receive your childs prescription, check the bottle to make sure that you received the correct dosage form of TRIUMEQ PD. Contact your pharmacist or healthcare provider if you did not receive the correct dosage form.oDo not chew, cut, or crush the tablets for oral suspension.oIf you forget to give dose of TRIUMEQ PD, give it as soon as you remember. Do not give doses at the same time or give more than your healthcare provider has prescribed.oIf your child does not or cannot take the full dose, call your healthcare provider.oIf you give too much TRIUMEQ PD, get emergency medical help right away.oFor more information about TRIUMEQ PD, read the Medication Guide.Your pack contains:oA bottle containing 90 TRIUMEQ PD tablets for oral suspensionoDosing cupYou will also need:oClean drinking water.Getting ReadyStep 1. Pour waterFigure AoPour 20 mL of clean drinking water into the cup.See Figure A.Use drinking water only.Do not use any other drink or food to prepare the dose.Step 2. Prepare the medicine Figure Figure CoAdd the prescribed number of tablet(s) to the water. See Figure B.oSwirl the cup gently for to minutes to disperse the tablet(s). The medicine will become cloudy. Take care not to spill any of the medicine. See Figure C.oCheck that the medicine is ready. If there are any lumps of tablet, swirl the cup until they are gone.If you spill any medicine, clean up the spill.Throw away the rest of the prepared medicine and make new dose.You must give the dose of medicine within 30 minutes of preparing the dose. If it has been more than 30 minutes, wash away all the dose in the cup using water and prepare new dose of medicine.Giving the medicineStep 3. Give the medicineFigure DoMake sure that the child is upright. Give all the prepared medicine to the child. See Figure D.oAdd another 15 mL of drinking water to the cup, swirl, and give it all to the child.oRepeat if any medicine remains in the cup to make sure the child gets the full dose.CleanStep 4. Clean the dosing cupFigure EoWash the cup with water. See Figure E.oThe cup will need to be clean before preparing the next dose.Storage InformationoStore TRIUMEQ PD tablets for oral suspension at room temperature between 68F to 77F (20C to 25C) in the original bottle. Keep the bottle tightly closed and protect from moisture. oThe TRIUMEQ PD bottle contains desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle.Keep TRIUMEQ PD and all medicines out of the reach of children.Disposal InformationWhen all the tablets in the bottle have been taken or are no longer needed, throw away the bottle and cup. Dispose of them using your local household waste guidelines.You will get new cup in your next pack.Manufactured for:ViiV HealthcareResearch Triangle Park, NC 27709by:GlaxoSmithKlineResearch Triangle Park, NC 27709Trademarks are owned by or licensed to the ViiV Healthcare group of companies.(C)2022 ViiV Healthcare group of companies or its licensor.TRM:1IFUThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Issued: 03/2022. oGive TRIUMEQ PD exactly as your healthcare provider tells you.. oEach time you receive your childs prescription, check the bottle to make sure that you received the correct dosage form of TRIUMEQ PD. Contact your pharmacist or healthcare provider if you did not receive the correct dosage form.. oDo not chew, cut, or crush the tablets for oral suspension.. oIf you forget to give dose of TRIUMEQ PD, give it as soon as you remember. Do not give doses at the same time or give more than your healthcare provider has prescribed.. oIf your child does not or cannot take the full dose, call your healthcare provider.. oIf you give too much TRIUMEQ PD, get emergency medical help right away.. oFor more information about TRIUMEQ PD, read the Medication Guide.. oA bottle containing 90 TRIUMEQ PD tablets for oral suspension. oDosing cup. oClean drinking water.. oPour 20 mL of clean drinking water into the cup.. Figure Figure C. oAdd the prescribed number of tablet(s) to the water. See Figure B.. oSwirl the cup gently for to minutes to disperse the tablet(s). The medicine will become cloudy. Take care not to spill any of the medicine. See Figure C.. oCheck that the medicine is ready. If there are any lumps of tablet, swirl the cup until they are gone.. oMake sure that the child is upright. Give all the prepared medicine to the child. See Figure D.. oAdd another 15 mL of drinking water to the cup, swirl, and give it all to the child.. oRepeat if any medicine remains in the cup to make sure the child gets the full dose.. oWash the cup with water. See Figure E.. oThe cup will need to be clean before preparing the next dose.. oStore TRIUMEQ PD tablets for oral suspension at room temperature between 68F to 77F (20C to 25C) in the original bottle. Keep the bottle tightly closed and protect from moisture. oThe TRIUMEQ PD bottle contains desiccant packet to help keep your medicine dry (protect it from moisture). Do not remove the desiccant packet from the bottle.. Bottle and Cup. Figure A. Figure and C. Figure D. Figure E.