TRIUMEQ and TRIUMEQ PD TRIUMEQ and TRIUMEQ PD contain an INSTI (dolutegravir) and 2 nucleoside analogues (abacavir and lamivudine) with inhibitory activity against HIV. Each film-coated tablet of TRIUMEQ, for oral use, contains 600 mg of abacavir (present as 702 mg of abacavir sulfate), 50 mg of dolutegravir (present as 52.6 mg of dolutegravir sodium), and 300 mg of lamivudine. The inactive ingredients of TRIUMEQ tablets include D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet film‑coating contains the inactive ingredients iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol–part hydrolyzed, talc, and titanium oxide. Each film-coated tablet of TRIUMEQ PD for oral suspension contains 60 mg of abacavir (present as 70.2 mg of abacavir sulfate), 5 mg of dolutegravir (present as 5.26 mg of dolutegravir sodium), and 30 mg of lamivudine. The inactive ingredients of TRIUMEQ PD tablets include acesulfame potassium, crospovidone, mannitol, microcrystalline cellulose, povidone K29/32, silicified microcrystalline cellulose, sodium starch glycolate, sodium stearyl fumarate, strawberry cream flavor and sucralose. The tablet film-coating contains the inactive ingredients: ferric oxide yellow, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc and titanium dioxide. Abacavir Sulfate The chemical name of abacavir sulfate is ( 1 S,cis)- 4-[2-amino-6-(cyclopropylamino)-9 H -purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). It has a molecular formula of (C 14 H 18 N 6 O) 2• H 2 SO 4 and a molecular weight of 670.76 g/mol. It has the following structural formula: Abacavir sulfate is a white to off-white solid and is soluble in water. Dolutegravir Sodium The chemical name of dolutegravir sodium is sodium (4 R ,12a S )-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2 H -pyrido[1',2':4,5]pyrazino[2,1- b ][1,3]oxazin-7-olate. The empirical formula is C 20 H 18 F 2 N 3 NaO 5 and the molecular weight is 441.36 g/mol. It has the following structural formula: Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water. Lamivudine The 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 a dideoxy analogue of cytidine. Lamivudine has also been referred to as (‑)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C 8 H 11 N 3 O 3 S and a molecular weight of 229.3 g/mol. It has the following structural formula: Lamivudine is a white to off-white crystalline solid and is soluble in water. Abacavir sulfate chemical structure Dolutegravir sodium chemical structure Lamivudine chemical structure

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.

TRIUMEQ tablets are purple, biconvex, oval, and debossed with “572 Trı” on one side. Each film-coated tablet contains 600 mg of abacavir (as abacavir sulfate), 50 mg of dolutegravir (as dolutegravir sodium), and 300 mg of lamivudine . TRIUMEQ PD tablets for oral suspension are yellow, capsule-shaped, strawberry cream flavored, biconvex, film-coated tablets debossed with “SV WTU” on one side. Each film-coated tablet contains 60 mg of abacavir (as abacavir sulfate), 5 mg of dolutegravir (as dolutegravir sodium), and 30 mg of lamivudine . • TRIUMEQ tablets: 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. • TRIUMEQ PD tablets for oral suspension: 60 mg of abacavir, 5 mg of dolutegravir, and 30 mg of lamivudine.

• 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. • 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 ) 2.1 Screening 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

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

Overview 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

Recommended 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

Recommended 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

Dosage 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

Not 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 .

• 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. 5.1 Hypersensitivity 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

Patients 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

Hepatotoxicity 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

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 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

Risk 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

Immune 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

Different 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

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 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).

Coadministration of TRIUMEQ or TRIUMEQ PD with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of TRIUMEQ or TRIUMEQ PD. 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 (IC 50 = 1.93 microM) and multidrug and toxin extrusion transporter (MATE)1 (IC 50 = 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) . In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC 50 = 2.12 microM) and OAT3 (IC 50 = 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 (IC 50 >50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1, UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, or multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters. In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: 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

Effect of Other Agents on the Pharmacokinetics of Dolutegravir Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir and is expected to be mitigated by atazanavir/ritonavir ( Table 6 ) . In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3. Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir

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 and TRIUMEQ PD 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. Table 6. Established and Other Potentially Significant Drug Interactions for Dolutegravir: Alterations in Dose May Be Recommended Based on Drug Interaction Trials or Predicted Interactions a See Clinical Pharmacology Table 8 or Table 10 for magnitude of interaction. Concomitant Drug Class: Drug Name Effect on Concentration Clinical Comment HIV-1 Antiviral Agents Non-nucleoside reverse transcriptase inhibitor: Etravirine a ↓Dolutegravir Use of TRIUMEQ or TRIUMEQ PD with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended. Non-nucleoside reverse transcriptase inhibitor: Efavirenz a ↓Dolutegravir In adults and in pediatric patients weighing at least 25 kg , adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of TIVICAY should be taken, separated by 12 hours from TRIUMEQ. In pediatric patients weighing 6 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. Non-nucleoside reverse transcriptase inhibitor: Nevirapine ↓Dolutegravir Avoid coadministration with TRIUMEQ or TRIUMEQ PD because there are insufficient data to make dosing recommendations. Protease inhibitor: Fosamprenavir/ritonavir a Tipranavir/ritonavir a ↓Dolutegravir In adults and in pediatric patients weighing at least 25 kg , adjust dolutegravir dose to 50 mg twice daily. An additional TIVICAY 50-mg dose should be taken, separated by 12 hours from TRIUMEQ. In pediatric patients weighing 10 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. Other Agents Antiarrhythmic: Dofetilide ↑Dofetilide Coadministration is contraindicated with TRIUMEQ and TRIUMEQ PD . Potassium channel blocker: Dalfampridine ↑Dalfampridine Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with TRIUMEQ or TRIUMEQ PD should be considered against the risk of seizures in these patients. Carbamazepine a ↓Dolutegravir In adults and in pediatric patients weighing at least 25 kg , adjust dolutegravir dose to 50 mg twice daily. An additional TIVICAY 50-mg dose should be taken, separated by 12 hours from TRIUMEQ. In pediatric patients weighing 6 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. Oxcarbazepine Phenytoin Phenobarbital St. John’s wort ( Hypericum perforatum ) ↓Dolutegravir Avoid coadministration with TRIUMEQ or TRIUMEQ PD because there are insufficient data to make dosing recommendations. Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing antacids a or laxatives Sucralfate Buffered medications ↓Dolutegravir Administer TRIUMEQ or TRIUMEQ PD 2 hours before or 6 hours after taking medications containing polyvalent cations. Oral calcium and iron supplements, including multivitamins containing calcium or iron a ↓Dolutegravir When taken with food, TRIUMEQ or TRIUMEQ PD and supplements or multivitamins containing calcium or iron can be taken at the same time. Under fasting conditions, TRIUMEQ or TRIUMEQ PD should be taken 2 hours before or 6 hours after taking supplements containing calcium or iron. Metformin a ↑Metformin Refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of TRIUMEQ or TRIUMEQ PD and metformin. Rifampin a ↓Dolutegravir In adults and in pediatric patients weighing at least 25 kg , adjust dolutegravir dose to 50 mg twice daily. An additional 50-mg dose of TIVICAY should be taken, separated by 12 hours from TRIUMEQ. In pediatric patients weighing 6 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. Methadone Abacavir: In a trial of 11 HIV-1–infected subjects receiving methadone-maintenance therapy with 600 mg of abacavir twice daily (twice the currently recommended dose), oral methadone clearance increased . This alteration will not result in a methadone dose modification in the majority of patients; however, an increased methadone dose may be required in a small number of patients. Sorbitol Lamivudine: Coadministration of single doses of lamivudine and sorbitol resulted in a sorbitol dose-dependent reduction in lamivudine exposures. When possible, avoid use of sorbitol-containing medicines with lamivudine-containing medicines . Riociguat Abacavir: Coadministration with TRIUMEQ resulted in increased riociguat exposure, which may increase the risk of riociguat adverse reactions . The riociguat dose may need to be reduced. See full prescribing information for ADEMPAS (riociguat).