Triumeq

1 INDICATIONS AND USAGE TRIUMEQ and TRIUMEQ PD are indicated for the treatment of HIV-1 infection in adults and in pediatric patients aged at least 3 months and weighing at least 6 kg. Limitations of Use: TRIUMEQ and TRIUMEQ PD alone are not recommended in patients with resistance‑associated integrase substitutions or clinically suspected integrase strand transfer inhibitor (INSTI) resistance because the dose of dolutegravir in TRIUMEQ and TRIUMEQ PD is insufficient in these subpopulations. See full prescribing information for TIVICAY (dolutegravir).

TRIUMEQ and TRIUMEQ PD are a combination of dolutegravir (integrase strand transfer inhibitor [INSTI]), abacavir, and lamivudine (both nucleoside analogue reverse transcriptase inhibitors) indicated for the treatment of HIV-1 infection in adults and in pediatric patients aged at least 3 months and weighing at least 6 kg. Limitations of Use: TRIUMEQ and TRIUMEQ PD alone are not recommended in patients with resistance-associated integrase substitutions or clinically suspected INSTI resistance because the dose of dolutegravir in TRIUMEQ and TRIUMEQ PD is insufficient in these subpopulations. See the dolutegravir prescribing information.

2 DOSAGE AND ADMINISTRATION • Before initiating TRIUMEQ or TRIUMEQ PD, screen for the HLA‑B*5701 allele because TRIUMEQ and TRIUMEQ PD contain abacavir.. • Prior to or when initiating TRIUMEQ or TRIUMEQ PD, test patients for HBV infection. • TRIUMEQ and TRIUMEQ PD may be taken with or without food. ( 2.4 , 2.5 ) • Adults: One tablet of TRIUMEQ daily. ABC = abacavir, DTG = dolutegravir, 3TC = lamivudine. Pediatric Population Body Weight Number of Tablets (once daily) Recommended Daily Dose TRIUMEQ PD Tablets (6 kg to <25 kg) 6 kg to <10 kg 3 180 mg ABC, 15 mg DTG, and 90 mg 3TC 10 kg to <14 kg 4 240 mg ABC, 20 mg DTG, and 120 mg 3TC 14 kg to <20 kg 5 300 mg ABC, 25 mg DTG, and 150 mg 3TC 20 kg to <25 kg 6 360 mg ABC, 30 mg DTG, and 180 mg 3TC TRIUMEQ Tablets (≥25 kg) ≥25 kg 1 600 mg ABC, 50 mg DTG, and 300 mg 3TC • Do not substitute TRIUMEQ and TRIUMEQ PD on a milligram-per-milligram basis. • If dosing with certain UGT1A or CYP3A inducers, then the recommended dolutegravir dosage regimen should be adjusted. See Table 2 for complete dosing recommendations. • Because TRIUMEQ and TRIUMEQ PD are fixed-dose tablets and cannot be dose adjusted, TRIUMEQ and TRIUMEQ PD are not recommended in patients with creatinine clearance <30 mL/min and pediatric patients with a similar degree of renal impairment based on age-appropriate assessment of renal function, or patients with hepatic impairment. ( 2.7 , 4 )

2.1Screening for HLA−B*5701 Allele

prior to Initiating TRIUMEQ Screen for the HLA‑B*5701 allele prior to initiating therapy with TRIUMEQ or TRIUMEQ PD .

2.2Testing

prior to or When Initiating Treatment with TRIUMEQ Prior to or when initiating TRIUMEQ or TRIUMEQ PD, test patients for HBV infection .

2.3Overview of

TRIUMEQ Dosage Forms TRIUMEQ is available in two dosage forms. Do not substitute TRIUMEQ tablets and TRIUMEQ PD tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles for the dolutegravir component . • TRIUMEQ tablets: 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. TRIUMEQ is recommended in adults and pediatric patients weighing at least 25 kg . • TRIUMEQ PD tablets for oral suspension: 60 mg of abacavir, 5 mg of dolutegravir, and 30 mg of lamivudine.

TRIUMEQ PD is recommended in pediatric patients weighing 6 kg to less than 25 kg . • Because TRIUMEQ PD is a fixed-dose tablet and the dosage of individual components cannot be adjusted, it may lead to a suboptimal dosing for patients weighing ≥25 kg. TRIUMEQ PD is not recommended in patients weighing 25 kg or more .

2.4Recommended Dosage in Adults

TRIUMEQ is a fixed-dose combination product containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. The recommended dosage regimen of TRIUMEQ in adults is one tablet once daily orally with or without food. Do not use TRIUMEQ PD in adults.

2.5Recommended Dosage and Administration Instructions for Pediatric

Patients Weighing at Least 6 kg The dosage and dosage form recommended for pediatric patients varies by weight as shown in Table 1 below. Table 1. Recommended Dosage of TRIUMEQ Tablets and TRIUMEQ PD Tablets for Oral Suspension in Pediatric Patients a TRIUMEQ is a fixed-dose combination product containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. b TRIUMEQ PD is a fixed-dose combination product containing 60 mg of abacavir, 5 mg of dolutegravir, and 30 mg of lamivudine.

Body Weight TRIUMEQ Tablets a TRIUMEQ PD b Number of Tablets Total Daily Dose 6 kg to <10 kg Not recommended 3 tablets once daily 180 mg abacavir, 15 mg dolutegravir, and 90 mg lamivudine once daily 10 kg to <14 kg Not recommended 4 tablets once daily 240 mg abacavir, 20 mg dolutegravir, and 120 mg lamivudine once daily 14 kg to <20 kg Not recommended 5 tablets once daily 300 mg abacavir, 25 mg dolutegravir, and 150 mg lamivudine once daily 20 kg to <25 kg Not recommended 6 tablets once daily 360 mg abacavir, 30 mg dolutegravir, and 180 mg lamivudine once daily ≥25 kg 1 tablet once daily Not recommended 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine Administer TRIUMEQ PD tablets for oral suspension with or without food. Instruct patients (or instruct caregivers) to fully disperse the tablets for oral suspension in 20 mL of drinking water (if using 4, 5, or 6 tablets for oral suspension) or 15 mL (if using 3 tablets for oral suspension) in the supplied cup; swirl the suspension so that no lumps remain. After full dispersion, administer the oral suspension within 30 minutes of mixing . Do not swallow the tablets for oral suspension whole, and do not chew, cut, or crush the tablets.

For children unable to use the supplied cup, an appropriate-sized syringe may be used to administer the oral suspension. Administer TRIUMEQ tablet with or without food. Do not chew, cut, or crush the tablet.

2.6Dosage Recommendation with Certain Concomitant Medications

The dolutegravir dose in TRIUMEQ (50 mg) and TRIUMEQ PD (5 mg) is insufficient when coadministered with medications listed in Table 2 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended. Table 2. Dosing Recommendations for TRIUMEQ and TRIUMEQ PD with Coadministered Medications Coadministered Drug Dosing Recommendation Efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin In adults and in pediatric patients weighing at least 25 kg , the recommended dolutegravir dosage regimen is 50 mg twice daily.

Thus, an additional TIVICAY 50-mg tablet, separated by 12 hours from TRIUMEQ, should be taken. In pediatric patients weighing 6 kg to <25 kg , an additional weight-based dose of dolutegravir should be given separated by 12 hours from TRIUMEQ PD. • 6 to <10 kg: administer an additional 15-mg dose of dolutegravir (3 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD. • 10 to <14 kg: administer an additional 20-mg dose of dolutegravir (4 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD. • 14 to <20 kg: administer an additional 25-mg dose of dolutegravir (5 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD. • 20 to <25 kg: administer an additional 30-mg dose of dolutegravir (6 TIVICAY PD tablets for oral suspension), 12 hours after TRIUMEQ PD.

2.7Not Recommended Due to Lack of Dosage

Adjustment Because TRIUMEQ and TRIUMEQ PD are fixed-dose tablets and cannot be dose adjusted, TRIUMEQ and TRIUMEQ PD are not recommended in: • patients with creatinine clearance <30 mL/min and pediatric patients with a similar degree of renal impairment based on age-appropriate renal function assessment. There are no data available on the use of lamivudine, a component of TRIUMEQ and TRIUMEQ PD, in pediatric patients with renal impairment . • patients with mild hepatic impairment. TRIUMEQ and TRIUMEQ PD are contraindicated in patients with moderate or severe hepatic impairment .

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity has been reported in patients receiving a dolutegravir-containing regimen. Monitoring for hepatotoxicity is recommended. • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. • Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. • TRIUMEQ tablets and TRIUMEQ PD tablets for oral suspension are not substitutable. ( 2.3 , 5.7 )

5.1Hypersensitivity Reactions Hypersensitivity

reactions have been reported with the use of abacavir or dolutegravir, components of TRIUMEQ and TRIUMEQ PD. Abacavir Serious and sometimes fatal hypersensitivity reactions have occurred with abacavir-containing regimens. See full prescribing information for ZIAGEN (abacavir). Abacavir hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment . Patients who carry the HLA‑B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA‑B*5701 allele have developed hypersensitivity reactions.

Hypersensitivity to abacavir was reported in approximately 206 (8%) of 2,670 patients in 9 clinical trials with abacavir-containing products where HLA‑B*5701 screening was not performed. The incidence of suspected abacavir hypersensitivity reactions in clinical trials was 1% when subjects carrying the HLA-B*5701 allele were excluded. In any patient treated with abacavir, the clinical diagnosis of hypersensitivity reaction must remain the basis of clinical decision making.

Due to the potential for severe, serious, and possibly fatal hypersensitivity reactions with abacavir: • All patients should be screened for the HLA‑B*5701 allele prior to initiating therapy with TRIUMEQ or TRIUMEQ PD or reinitiation of therapy with TRIUMEQ or TRIUMEQ PD, unless patients have a previously documented HLA‑B*5701 allele assessment. • TRIUMEQ and TRIUMEQ PD are contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA‑B*5701‑positive patients. • Before starting TRIUMEQ or TRIUMEQ PD, review medical history for prior exposure to any abacavir-containing product. NEVER restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing product following a hypersensitivity reaction to abacavir, regardless of HLA‑B*5701 status. • To reduce the risk of a life‑threatening hypersensitivity reaction, regardless of HLA‑B*5701 status, discontinue TRIUMEQ or TRIUMEQ PD immediately if a hypersensitivity reaction is suspected, even when other diagnoses are possible (e.g., acute onset respiratory diseases such as pneumonia, bronchitis, pharyngitis, or influenza; gastroenteritis; or reactions to other medications). Clinical status, including liver chemistries, should be monitored and appropriate therapy initiated. • If a hypersensitivity reaction cannot be ruled out, do not restart TRIUMEQ or TRIUMEQ PD or any other abacavir-containing products because more severe symptoms, which may include life-threatening hypotension and death, can occur within hours. • Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ or TRIUMEQ PD would be caused by abacavir or dolutegravir.

Therefore, never restart TRIUMEQ or TRIUMEQ PD or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ or TRIUMEQ PD due to a hypersensitivity reaction. • If a hypersensitivity reaction is ruled out, patients may restart TRIUMEQ or TRIUMEQ PD. Rarely, patients who have stopped abacavir for reasons other than symptoms of hypersensitivity have also experienced life-threatening reactions within hours of reinitiating abacavir therapy. Therefore, reintroduction of TRIUMEQ or TRIUMEQ PD, or any other abacavir-containing product, is recommended only if medical care can be readily accessed. • A Medication Guide and Warning Card that provide information about recognition of abacavir hypersensitivity reactions should be dispensed with each new prescription and refill. Dolutegravir Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury.

The events were reported in <1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TRIUMEQ or TRIUMEQ PD and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated.

Delay in stopping treatment with TRIUMEQ or TRIUMEQ PD or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. Clinically, it is not possible to determine whether a hypersensitivity reaction with TRIUMEQ or TRIUMEQ PD would be caused by abacavir or dolutegravir. Therefore, never restart TRIUMEQ or TRIUMEQ PD or any other abacavir- or dolutegravir-containing product in patients who have stopped therapy with TRIUMEQ or TRIUMEQ PD due to a hypersensitivity reaction.

5.2Patients Co-infected with HIV-1 and HBV: Emergence

of Lamivudine-Resistant HBV and the Risk of Posttreatment Exacerbations of HBV All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating TRIUMEQ or TRIUMEQ PD. Emergence of Lamivudine Resistant HBV Safety and efficacy of lamivudine have not been established for treatment of chronic HBV in subjects dually infected with HIV-1 and HBV. Emergence of HBV variants associated with resistance to lamivudine has been reported in HIV‑1−infected subjects who have received lamivudine‑containing antiretroviral regimens in the presence of concurrent infection with HBV. If a decision is made to administer TRIUMEQ or TRIUMEQ PD to patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen. Severe Acute Exacerbations of HBV in Patients Co-infected with HIV-1 and HBV Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing lamivudine, and may occur with discontinuation of TRIUMEQ or TRIUMEQ PD. Patients who are co-infected with HIV-1 and HBV who discontinue TRIUMEQ or TRIUMEQ PD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with TRIUMEQ or TRIUMEQ PD. If appropriate, initiation of anti-HBV therapy may be warranted, especially in patients with advanced liver disease or cirrhosis since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.3Hepatotoxicity Hepatic

adverse events have been reported in patients receiving a dolutegravir-containing regimen . Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ or TRIUMEQ PD . In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure, have also been reported in patients, including pediatric patients receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ. Monitoring for hepatotoxicity is recommended.

5.4Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including abacavir and lamivudine (components of TRIUMEQ and TRIUMEQ PD). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues.

See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Treatment with TRIUMEQ or TRIUMEQ PD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

5.5Risk of Adverse Reactions or Loss of Virologic

Response Due to Drug Interactions The concomitant use of TRIUMEQ or TRIUMEQ PD and other drugs may result in known or potentially significant drug interactions, some of which may lead to : • Loss of therapeutic effect of TRIUMEQ or TRIUMEQ PD and possible development of resistance. • Possible clinically significant adverse reactions from greater exposures of concomitant drugs. See Table 6 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with TRIUMEQ or TRIUMEQ PD, review concomitant medications during therapy with TRIUMEQ or TRIUMEQ PD, and monitor for the adverse reactions associated with the concomitant drugs.

5.6Immune Reconstitution Syndrome Immune

reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIUMEQ or TRIUMEQ PD. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.7Different Formulations Are Not Substitutable

TRIUMEQ and TRIUMEQ PD are not bioequivalent and are not substitutable on a milligram-per-milligram basis . If a pediatric patient switches from the tablets for oral suspension to the tablets, the dosage must be adjusted . Incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure to the individual components.

5.8Myocardial Infarction Several

prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavir‑treated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk.

In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir and the risk of MI is inconclusive. As a precaution, the underlying risk of coronary heart disease should be considered when prescribing antiretroviral therapies, including abacavir, and action taken to minimize all modifiable risk factors (e.g., hypertension, hyperlipidemia, diabetes mellitus, smoking).

4 CONTRAINDICATIONS TRIUMEQ and TRIUMEQ PD are contraindicated in patients: • who have the HLA-B*5701 allele . • with prior hypersensitivity reaction to abacavir, dolutegravir , or lamivudine. • receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events with concomitant use of dolutegravir . • with moderate or severe hepatic impairment . • Presence of HLA-B*5701 allele. • Prior hypersensitivity reaction to abacavir, dolutegravir, or lamivudine. • Coadministration with dofetilide. • Moderate or severe hepatic impairment. ( 4 , 8.7 )

8.1Pregnancy Pregnancy Exposure Registry There

is a 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 Summary Data from two, ongoing birth outcome surveillance studies in Botswana and Eswatini which together include over 14,000 individuals evaluated during pregnancy show similar prevalence of neural tube defects among infants born to individuals taking dolutegravir at the time of conception compared to those born to individuals taking non-dolutegravir-containing regimens at conception or infants born to HIV-negative individuals . There are insufficient human data on the use of TRIUMEQ during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage.

However, available human data from the APR with the individual components of TRIUMEQ do not indicate an increased risk of birth defects . 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 (including neural tube defects) 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) . Oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the RHD. No adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis at exposures approximately 9 times the human exposure (AUC) at the RHD. Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryolethality at a human exposure (AUC) similar to the RHD; however, no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (C max ) 35 times the RHD . Data Human Data: Dolutegravir: Observational studies: The first interim analysis from an ongoing birth outcome surveillance study in Botswana identified 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.

A subsequent analysis was conducted based on a larger cohort from the birth outcome surveillance study in Botswana and included over 9,460 individuals exposed to dolutegravir at conception, 23,664 individuals exposed to non-dolutegravir-containing regimens, and 170,723 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.11% (95% CI: 0.05-0.19%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.11%, 95% CI: 0.07-0.16%), or to HIV-negative individuals (0.06%, 95% CI: 0.05-0.08%).

The Eswatini birth outcome surveillance study includes 9,743 individuals exposed to dolutegravir at conception, 1,838 individuals exposed to non-dolutegravir-containing regimens, and 32,259 HIV-negative pregnant individuals. The prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.08% (95% CI: 0.04-0.16%). The observed prevalence rate did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.22%, 95% CI: 0.06-0.56%) or to HIV-negative individuals (0.08%, 95% CI: 0.06-0.12%).

The observed prevalence of neural tube defects in infants delivered to individuals taking non-dolutegravir-containing regimens had a wide confidence interval due to low sample size. Limitations of these birth outcome surveillance studies include insufficient data to determine if baseline characteristics were balanced between the study groups or to assess other factors such as the use of folic acid during the preconception or first trimester periods. Antiretroviral Pregnancy Registry: Based on prospective reports to the APR, of over 1,300 exposures to dolutegravir during pregnancy resulting in live births (including 874 exposed in the first trimester), the prevalence of defects in live births was 3.3% (95% CI: 2.2% to 4.7%) following first-trimester exposure to dolutegravir-containing regimens and 5.0% (95% CI: 3.2% to 7.3%) 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%. Dolutegravir has been shown to cross the placenta. In a clinical trial in Uganda and South Africa in women during the last trimester of pregnancy receiving dolutegravir 50 mg once daily, the ratio of median dolutegravir concentration in fetal umbilical cord to that in maternal peripheral plasma was 1.21 (range 0.51-2.11) (n = 15). Abacavir: Based on prospective reports to the APR of over 2,800 exposures to abacavir during pregnancy resulting in live births (including 1,455 exposed in the first trimester), there was no difference between the overall risk of birth defects for abacavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.2% (95% CI: 2.4% to 4.3%) following first trimester exposure to abacavir-containing regimens and 3.0% (95% CI: 2.2% to 4.1%) 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 . Lamivudine: Based on prospective reports to the APR of over 13,000 exposures to lamivudine during pregnancy resulting in live births (including 5,613 exposed in the first trimester), there was no difference between the overall risk of birth defects for lamivudine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 3.1% (95% CI: 2.6% to 3.6%) following first trimester exposure to lamivudine-containing regimens and 2.9% (95% CI: 2.5%, 3.3%) following second/third trimester exposure to lamivudine-containing regimens. Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trials assessed pharmacokinetics in 16 women at 36 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks’ gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks’ gestation using lamivudine 300 mg twice daily without other antiretrovirals.

These trials were not designed or powered to provide efficacy information. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, amniotic fluid specimens were collected following natural rupture of membranes and confirmed that lamivudine crosses the placenta in humans.

Based on limited data at delivery, median (range) amniotic fluid concentrations of lamivudine were 3.9-fold (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/kg/day) on Gestation Days 6 to 17 and 6 to 18, respectively, and to rats on Gestation Day 6 to lactation/post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed up to the highest dose tested.

During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the RHD and in rats were approximately 50 times the exposure in humans at the RHD. In the rat pre/post-natal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 50 times human exposure at the RHD). Abacavir: Abacavir was administered orally to pregnant rats (at 100, 300, and 1,000 mg/kg/day) and rabbits (at 125, 350, or 700 mg/kg/day) during organogenesis (on Gestation Days 6 through 17 and 6 through 20, respectively). Fetal malformations (increased incidences of fetal anasarca and skeletal malformations) or developmental toxicity (decreased fetal body weight and crown‑rump length) were observed in rats at doses up to 1,000 mg/kg/day, resulting in exposures approximately 35 times the human exposure (AUC) at the RHD. No developmental effects were observed in rats at 100 mg/kg/day, resulting in exposures (AUC) 3.5 times the human exposure at the recommended daily dose.

In a fertility and early embryo-fetal development study conducted in rats (at 60, 160, or 500 mg/kg/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/kg/day. No developmental effects were observed in rats at 60 mg/kg/day, resulting in exposures (AUC) approximately 4 times the human exposure at the RHD. Studies in pregnant rats showed that abacavir is transferred to the fetus through the placenta. In pregnant rabbits, no developmental toxicities and no increases in fetal malformations occurred at up to the highest dose evaluated, resulting in exposures (AUC) approximately 9 times the human exposure at the RHD. Lamivudine: Lamivudine was administered orally to pregnant rats (at 90, 600, and 4,000 mg/kg/day) and rabbits (at 90, 300 and 1,000 mg/kg/day and at 15, 40, and 90 mg/kg/day) during organogenesis (on Gestation Days 7 through 16 [rat] and 8 through 20 [rabbit]).

No evidence of fetal malformations due to lamivudine was observed in rats and rabbits at doses producing plasma concentrations (C max ) 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 (C max ) 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/kg/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.

The following adverse reactions are discussed in other sections of the labeling: • Serious and sometimes fatal hypersensitivity reaction . • Exacerbations of hepatitis B . • Hepatotoxicity . • Lactic acidosis and severe hepatomegaly with steatosis . • Immune reconstitution syndrome . • Myocardial infarction . 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. 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 .

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Clinical Trials in Adults Serious and Fatal Abacavir-Associated Hypersensitivity Reactions: In clinical trials, serious and sometimes fatal hypersensitivity reactions have occurred with abacavir, a component of TRIUMEQ and TRIUMEQ PD . These reactions have been characterized by 2 or more of the following signs or symptoms: fever; rash; gastrointestinal symptoms (including nausea, vomiting, diarrhea, or abdominal pain); constitutional symptoms (including generalized malaise, fatigue, or achiness); respiratory symptoms (including dyspnea, cough, or pharyngitis). Almost all abacavir hypersensitivity reactions include fever and/or rash as part of the syndrome.

Other signs and symptoms have included lethargy, headache, myalgia, edema, arthralgia, and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with these hypersensitivity reactions. Physical findings have included lymphadenopathy, mucous membrane lesions (conjunctivitis and mouth ulcerations), and maculopapular or urticarial rash (although some patients had other types of rashes and others did not have a rash).

There were reports of erythema multiforme. Laboratory abnormalities included elevated liver chemistries, elevated creatine phosphokinase, elevated creatinine, and lymphopenia and abnormal chest x‑ray findings (predominantly infiltrates, which were localized). Serious Dolutegravir Hypersensitivity Reactions: In clinical trials, hypersensitivity reactions have occurred with dolutegravir, a component of TRIUMEQ and TRIUMEQ PD . These hypersensitivity reactions have been characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury.

Additional Treatment-Emergent Adverse Drug Reactions (ADRs) with Use of TRIUMEQ: The safety assessment of TRIUMEQ is primarily based on the analyses of data from a randomized, international, multicenter, double-blind, active-controlled trial, SINGLE (ING114467) and supported by data in treatment-experienced, INSTI-naive subjects from SAILING (ING111762) and by data from other treatment-naive trials. See full prescribing information for TIVICAY. Treatment-Naive Subjects: In SINGLE, 833 adult subjects were randomized and received at least one dose of either dolutegravir (TIVICAY) 50 mg with fixed-dose abacavir and lamivudine (EPZICOM) once daily (n = 414) or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA) once daily (n = 419) (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rate of adverse events leading to discontinuation was 4% in subjects receiving TIVICAY + EPZICOM and 14% in subjects receiving ATRIPLA once daily.

Treatment‑emergent ADRs of moderate to severe intensity observed in at least 2% of subjects in either treatment arm of SINGLE are provided in Table 3 . Table 3. Treatment-Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-Naive Subjects in SINGLE (Week 144 Analysis) a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption. Adverse Reaction TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Psychiatric Insomnia 3% 3% Depression 1% 2% Abnormal dreams <1% 2% Nervous System Dizziness <1% 5% Headache 2% 2% Gastrointestinal Nausea <1% 3% Diarrhea <1% 2% General Disorders Fatigue 2% 2% Skin and Subcutaneous Tissue Rash a <1% 6% Ear and Labyrinth Vertigo 0 2% Treatment-Experienced Subjects: SAILING is an international, double-blind trial in INSTI-naive, antiretroviral treatment-experienced adult subjects.

Subjects were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rate of adverse events leading to discontinuation was consistent with that seen in the overall treatment-naive patient population. See full prescribing information for TIVICAY. The ADRs observed in the subset of subjects who received TIVICAY + EPZICOM were generally consistent with those seen in the overall treatment-naive patient population.

Less Common Adverse Reactions Observed in Clinical Trials: The following adverse reactions occurred in <2% of treatment-naive or treatment-experienced subjects in any one trial. These events have been included because of their seriousness and/or assessment of potential causal relationship. Gastrointestinal Disorders: Abdominal pain, abdominal distention, abdominal discomfort, dyspepsia, flatulence, gastroesophageal reflux disease, upper abdominal pain, vomiting.

General Disorders: Fever, lethargy. Hepatobiliary Disorders: Hepatitis. Metabolism and Nutrition Disorders: Anorexia, hypertriglyceridemia. Musculoskeletal Disorders: Arthralgia, myositis. Nervous System Disorders: Somnolence. Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion.

These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. Nightmare and sleep disorder. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities: Treatment-Naive Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects in SINGLE are presented in Table 4 . The mean change from baseline observed for selected lipid values is presented in Table 5 . Table 4.

Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naive Subjects in SINGLE (Week 144 Analysis) ALT = Alanine aminotransferase, AST = Aspartate aminotransferase, ULN = upper limit of normal. Laboratory Abnormality TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) ALT Grade 2 (>2.5-5.0 x ULN) 3% 5% Grade 3 to 4 (>5.0 x ULN) 1% <1% AST Grade 2 (>2.5-5.0 x ULN) 3% 4% Grade 3 to 4 (>5.0 x ULN) 1% 3% Creatine kinase Grade 2 (6.0-9.9 x ULN) 5% 3% Grade 3 to 4 (≥10.0 x ULN) 7% 8% Hyperglycemia Grade 2 (126-250 mg/dL) 9% 6% Grade 3 (>250 mg/dL) 2% <1% Lipase Grade 2 (>1.5-3.0 x ULN) 11% 11% Grade 3 to 4 (>3.0 ULN) 5% 4% Total neutrophils Grade 2 (0.75-0.99 x 10 9 ) 4% 5% Grade 3 to 4 (<0.75 x 10 9 ) 3% 3% Table 5. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naive Subjects in SINGLE (Week 144 Analysis a ) HDL = High-density lipoprotein, LDL = Low-density lipoprotein. a Subjects on lipid-lowering agents at baseline were excluded from these analyses (TIVICAY + EPZICOM: n = 30 and ATRIPLA: n = 27).

Seventy-two subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless of whether they discontinued the agent (TIVICAY + EPZICOM: n = 36 and ATRIPLA: n = 36). Lipid TIVICAY + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Cholesterol (mg/dL) 24.0

26.7HDL

cholesterol (mg/dL) 5.4

7.2LDL

cholesterol (mg/dL) 16.0

14.6Triglycerides

(mg/dL) 13.6

31.9Treatment-Experienced Subjects: Laboratory

abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naive trials. Hepatitis C Virus Co-infection: In SINGLE, the pivotal Phase 3 trial, subjects with hepatitis C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal; subjects with hepatitis B co-infection were excluded. Overall, the safety profile in subjects with hepatitis C virus co-infection was similar to that observed in subjects without hepatitis C co-infection, although the rates of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) abnormalities were higher in the subgroup with hepatitis C virus co-infection for both treatment groups.

Grades 2 to 4 ALT abnormalities in hepatitis C co-infected compared with HIV mono-infected subjects receiving TRIUMEQ were observed in 15% and 2% (vs. 24% and 4% of subjects treated with ATRIPLA) (Week 96 analysis), respectively . See 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 . Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 144 weeks. In SINGLE, a mean change from baseline of 0.14 mg/dL (range: -0.25 mg/dL to 0.81 mg/dL) was observed after 144 weeks of treatment. Creatinine increases were similar in treatment-experienced subjects.

Abacavir and Lamivudine: Laboratory abnormalities observed in clinical trials of ZIAGEN (in combination with other antiretroviral treatment) were anemia, neutropenia, liver function test abnormalities, and elevations of creatine phosphokinase (CPK), blood glucose, and triglycerides. Additional laboratory abnormalities observed in clinical trials of EPIVIR (in combination with other antiretroviral treatment) were thrombocytopenia and elevated levels of bilirubin, amylase, and lipase. Clinical Trials Experience in Pediatric Subjects Abacavir, Dolutegravir and Lamivudine: The safety of TRIUMEQ PD and TRIUMEQ in pediatric subjects with HIV-1 infection weighing at least 6 kg was evaluated in the IMPAACT 2019 trial.

This was a multicenter, open-label, non-comparative trial of pediatric subjects with HIV-1 infection, younger than 12 years of age. Fifty-seven subjects weighing at least 6 kg to less than 40 kg were enrolled in this trial . Overall, the safety data in this pediatric study was similar to that seen in adults. The safety analysis through Week 48 included 57 subjects weighing at least 6 kg at enrollment who received the recommended dose (determined by weight) and formulation.

This analysis showed that 26% of subjects experienced clinical adverse reactions. The most common adverse reactions were classified as laboratory abnormalities and included decreased glomerular filtration rate (n = 13, 23%), increased blood creatinine (n = 10, 18%), and increased ALT (n = 3, 5%). All other adverse reactions occurred at a rate of <2% of participants.

Two subjects reported Grade 3 or 4 adverse reactions. One subject, an 8-year-old female who weighed 22 kg at baseline, experienced Grade 3 increased blood creatinine and Grade 3 decreased glomerular filtration rate. By Week 48, the glomerular filtration rate was improving, and the events did not lead to drug discontinuation.

Another subject, a 7-year-old male who weighed 20 kg at baseline, experienced drug-induced liver injury with Grade 4 increased ALT and AST following 36 weeks of treatment with TRIUMEQ PD. Clinical signs or symptoms of hepatitis were not reported, and ALT and AST values normalized after TRIUMEQ PD was discontinued. Abacavir and Lamivudine: The safety of once-daily compared with twice-daily dosing of abacavir and lamivudine, administered as either single products or as EPZICOM, was assessed in the ARROW trial (n = 336). Primary safety assessment in the ARROW (COL105677) trial was based on Grade 3 and Grade 4 adverse events.

One event of Grade 4 hepatitis in the once-daily cohort was considered as uncertain causality by the investigator and all other Grade 3 or 4 adverse events were considered not related by the investigator. No additional safety issues were identified in pediatric subjects compared with historical data in adults. Dolutegravir: The safety of dolutegravir in pediatric subjects with HIV-1 infection weighing at least 6 kg was evaluated in the IMPAACT P1093 trial . Overall, the safety data in this pediatric study was similar to that seen in adults.

IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of pediatric subjects with HIV-1 infection, aged <18 years. One hundred and forty-two subjects weighing at least 6 kg were enrolled in this trial . The safety analysis through Week 24 included 60 subjects weighing at least 6 kg at enrollment who received the recommended dose (determined by weight and age) and formulation. This analysis showed that 13% of subjects experienced adverse reactions.

Grade 1 to 2 adverse reactions reported by more than one subject was immune reconstitution inflammatory syndrome (n = 2). There were no Grade 3 or 4 adverse reactions reported. No adverse reactions led to discontinuation. The Grade 3 or 4 laboratory abnormalities reported in more than one subject weighing at least 6 kg at enrollment were decreased neutrophil count (n = 5), decreased blood bicarbonate (n = 3), increased lipase (n = 2), and increased blood potassium (n = 2).

These laboratory events were not considered to be drug related. Changes in median serum creatinine were similar to those observed in adults.

6.2Postmarketing Experience In

addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use with one or more of the components of TRIUMEQ and TRIUMEQ PD. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic Systems Aplastic anemia, anemia (including pure red cell aplasia, sideroblastic anemia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly. Digestive Stomatitis.

Gastrointestinal Pancreatitis. General Weakness. Hepatobiliary Disorders Acute liver failure, liver transplant . Hypersensitivity Sensitization reactions (including anaphylaxis), urticaria . Investigations Weight increased. Metabolism and Nutrition Disorders Hyperlactemia. Musculoskeletal CPK elevation, muscle weakness, myalgia, rhabdomyolysis.

Nervous Paresthesia, peripheral neuropathy, seizures. Psychiatric Anxiety. Respiratory Abnormal breath sounds/wheezing. Skin Alopecia, erythema multiforme. Suspected Stevens‑Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving abacavir primarily in combination with medications known to be associated with SJS and TEN, respectively.

Because of the overlap of clinical signs and symptoms between hypersensitivity to abacavir and SJS and TEN, and the possibility of multiple drug sensitivities in some patients, abacavir should be discontinued and not restarted in such cases .