TIVICAY contains dolutegravir, as dolutegravir sodium, an HIV INSTI. 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. Each film-coated tablet of TIVICAY for oral administration contains 10.5, 26.3, or 52.6 mg of dolutegravir sodium, which is equivalent to 10, 25, or 50 mg dolutegravir free acid, respectively, and the following inactive ingredients: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet film‑coating contains the inactive ingredients iron oxide yellow (25-mg and 50-mg tablets only), macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide. Each TIVICAY PD tablet for oral suspension contains 5.26 mg of dolutegravir sodium, which is equivalent to 5 mg dolutegravir free acid, and the following inactive ingredients: calcium sulfate dihydrate, crospovidone, mannitol, microcrystalline cellulose, povidone K29/32, silicified microcrystalline cellulose, sodium starch glycolate, strawberry cream flavor, sucralose, and sodium stearyl fumarate. The tablet film-coating contains hypromellose, polyethylene glycol, and titanium dioxide. Dolutegravir chemical structure

TIVICAY and TIVICAY PD are indicated in combination with other antiretroviral agents for the treatment of HIV‑1 infection in adults (treatment-naïve or -experienced) and in pediatric patients (treatment-naïve or -experienced but integrase strand transfer inhibitor [INSTI]-naïve) aged at least 4 weeks and weighing at least 3 kg . TIVICAY is indicated in combination with rilpivirine as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/ mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent. TIVICAY and TIVICAY PD are an HIV-1 integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults (treatment-naïve or -experienced) and in pediatric patients (treatment-naïve or -experienced but INSTI- naïve) aged at least 4 weeks and weighing at least 3 kg. TIVICAY is indicated in combination with rilpivirine as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure or known substitutions associated with resistance to either antiretroviral agent.

TIVICAY Tablets: 10 mg: Each tablet contains 10 mg of dolutegravir (as dolutegravir sodium). Tablets are white, round, film-coated, biconvex tablets debossed with “SV 572” on one side and “10” on the other side. 25 mg: Each tablet contains 25 mg of dolutegravir (as dolutegravir sodium). Tablets are pale yellow, round, film-coated, biconvex tablets debossed with “SV 572” on one side and “25” on the other side. 50 mg: Each tablet contains 50 mg of dolutegravir (as dolutegravir sodium). Tablets are yellow, round, film-coated, biconvex tablets debossed with “SV 572” on one side and “50” on the other side. TIVICAY PD Tablets for Oral Suspension: Each tablet contains 5 mg of dolutegravir (as dolutegravir sodium). Tablets are white, round, strawberry cream flavored, film-coated, biconvex tablets debossed with “SV H7S” on one side and “5” on the other side. TIVICAY tablets: 10 mg, 25 mg, and 50 mg TIVICAY PD tablets for oral suspension: 5 mg

May be taken without regard to food. ( 2.2 , 2.6) UGT = uridine diphosphate glucuronosyltransferase; CYP = cytochrome P450. a Rilpivirine dose is 25 mg once daily for those switching to dolutegravir plus rilpivirine. b Alternative combinations that do not include metabolic inducers should be considered where possible. Adult Population Recommended Dose Treatment-naïve or treatment-experienced INSTI-naïve or virologically suppressed (HIV-1 RNA <50 copies per mL) adults switching to dolutegravir plus rilpivirine a 50 mg once daily Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with certain UGT1A or CYP3A inducers ( 2.1 , 7.2 , 7.3 ) 50 mg twice daily INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance b ( 2.1 , 12.4 ) 50 mg twice daily Pediatric Patients: Treatment-naïve or treatment-experienced INSTI-naïve patients aged at least 4 weeks and weighing at least 3 kg. See Tables 2 , 3 , and 4 for complete pediatric dosing recommendations. ( 2.3 , 2.4 , 2.5 ). TIVICAY and TIVICAY PD are not bioequivalent and are not substitutable on a milligram-per-milligram basis. a If certain UGT1A or CYP3A inducers are coadministered, then adjust the weight-based dose of TIVICAY to twice daily. ( 2.3 , 2.4 , 7.2 , 7.3 ) Pediatric Population Body Weight Recommended Dose a TIVICAY PD Tablets for Oral Suspension 3 kg to less than 6 kg 5 mg once daily 6 kg to less than 10 kg 15 mg once daily 10 kg to less than 14 kg 20 mg once daily 14 kg to less than 20 kg 25 mg once daily 20 kg and greater 30 mg once daily Alternative dosing recommendations for TIVICAY tablets for patients weighing at least 14 kg ( Table 4 ): 14 kg to less than 20 kg: 40 mg once daily. 20 kg and greater: 50 mg once daily

Recommended Dosage in Adults TIVICAY tablets may be taken with or without food. Table 1. Dosing Recommendations for TIVICAY Tablets in Adult Patients INSTI = integrase strand transfer inhibitor. a Rilpivirine dose is 25 mg once daily for those switching to dolutegravir plus rilpivirine. b Alternative combinations that do not include metabolic inducers should be considered where possible . Population Recommended Dosage Treatment-naïve or treatment-experienced INSTI-naïve or virologically suppressed (HIV‑1 RNA <50 copies/mL) adults switching to dolutegravir plus rilpivirine a 50 mg once daily Treatment-naïve or treatment-experienced INSTI-naïve when coadministered with certain uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A) or cytochrome P450 (CYP)3A inducers 50 mg twice daily INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance b 50 mg twice daily 2.2 General Dosing and Administration Instructions for Pediatric Patients Do not substitute TIVICAY tablets and TIVICAY PD tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles . If switching from the tablets to the tablets for oral suspension, follow the recommended dosage in Table 3 . If switching from the tablets for oral suspension to the tablets, follow the recommended dosage in Table 4 . See administration instructions in [Dosage and Administration]

Recommended Dosage in Pediatric Patients Weighing 3 to 14 kg The recommended weight-based dosage of TIVICAY PD tablets for oral suspension in pediatric patients weighing 3 to 14 kg (4 weeks and older, treatment-naïve, or treatment-experienced but naïve to INSTI treatment) is described in Table 2 . Do not use TIVICAY tablets in patients weighing 3 to 14 kg. See administration instructions in [Dosage and Administration] . Table 2. Recommended Dosage of TIVICAY PD in Pediatric Patients 4 Weeks and Older Weighing 3 to 14 kg a If certain uridine diphosphate glucuronosyltransferase (UGT)1A or cytochrome P450 (CYP)3A inducers are coadministered, then administer TIVICAY PD twice daily . Body Weight TIVICAY PD Tablets for Oral Suspension Daily Dose a Number of 5-mg Tablets 3 kg to less than 6 kg 5 mg once daily 1 6 kg to less than 10 kg 15 mg once daily 3 10 kg to less than 14 kg 20 mg once daily 4 2.4 Recommended Dosage in Pediatric Patients Weighing 14 kg or Greater For pediatric patients weighing 14 kg or greater (4 weeks and older, treatment-naïve, or treatment-experienced but naïve to INSTI treatment) administer either: TIVICAY PD tablets for oral suspension (preferred in pediatric patients weighing less than 20 kg) ( Table 3 ), or TIVICAY tablets for oral use ( Table 4 ) Table 3. Recommended Dosage of TIVICAY PD Tablets for Oral Suspension in Pediatric Patients Weighing 14 kg or Greater a If certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY PD twice daily . Body Weight TIVICAY PD Tablets for Oral Suspension Daily Dose a Number of 5-mg Tablets 14 kg to less than 20 kg 25 mg once daily 5 20 kg and greater 30 mg once daily 6 Table 4. Recommended Dosage of TIVICAY Tablets in Pediatric Patients Weighing 14 kg or Greater a If certain UGT1A or CYP3A inducers are coadministered, then administer TIVICAY twice daily . Body Weight TIVICAY Tablets Daily Dose a Number of Tablets 14 kg to less than 20 kg 40 mg once daily 4 x 10-mg 20 kg and greater 50 mg once daily 1 x 50-mg 2.5 Additional Administration Instructions Administer TIVICAY tablets and TIVICAY PD tablets for oral suspension with or without food. Administration Instructions for TIVICAY PD Do not chew, cut, or crush TIVICAY PD . Instruct patients (or instruct caregivers) to either: Swallow the tablets for oral suspension whole (if more than one tablet is required, swallow one tablet at a time to reduce the risk of choking), or Fully disperse the tablets for oral suspension in 5 mL of drinking water (if using 1 or 3 tablets for oral suspension) or 10 mL (if using 4, 5, or 6 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 .

Hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury, have been reported. Discontinue TIVICAY or TIVICAY PD and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. Hepatotoxicity has been reported in patients receiving dolutegravir-containing regimens. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations. Monitoring for hepatotoxicity is recommended. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. TIVICAY tablets and TIVICAY PD tablets for oral suspension are not substitutable. 5.1 Hypersensitivity Reactions Hypersensitivity 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 III clinical trials. Discontinue TIVICAY or TIVICAY 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 TIVICAY or TIVICAY PD or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. TIVICAY and TIVICAY PD are contraindicated in patients who have experienced a previous hypersensitivity reaction to dolutegravir

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 TIVICAY or TIVICAY 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 been reported in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ (abacavir, dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of TIVICAY or TIVICAY PD and other drugs may result in known or potentially significant drug interactions, some of which may lead to : Loss of therapeutic effect of TIVICAY or TIVICAY PD and possible development of resistance. Possible clinically significant adverse reactions from greater exposures of concomitant drugs. For concomitant drugs for which the interaction can be mitigated, please see Table 8 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 TIVICAY or TIVICAY PD; review concomitant medications during therapy with TIVICAY or TIVICAY 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 TIVICAY or TIVICAY 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, and Guillain-Barré 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

Different Formulations Are Not Substitutable TIVICAY and TIVICAY PD are not bioequivalent and are not substitutable on a milligram-per-milligram basis . If a pediatric patient switches from one formulation to the other, the dose must be adjusted for the new dosage formulation . 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 of dolutegravir.

Refer to the full prescribing information for important drug interactions with TIVICAY or TIVICAY PD. ( 4 , 7 ) Drugs that are metabolic inducers may decrease the plasma concentrations of dolutegravir. TIVICAY or TIVICAY PD should be taken 2 hours before or 6 hours after taking cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. When taken with food, TIVICAY and supplements containing calcium or iron can be taken at the same time

Effect of Dolutegravir on the Pharmacokinetics of Other Agents In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (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, Table 8 ) . 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 greater than 50 microM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate glucuronosyltransferase (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, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or 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

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 concentration and reduce the therapeutic effect of dolutegravir. Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration. 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 8 ) . In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3

Established and Other Potentially Significant Drug Interactions Table 8 provides clinical recommendations as a result of drug interactions with TIVICAY or TIVICAY PD. 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 [ s ee Dosage and Administration, Clinical Pharmacology]. Table 8. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions INSTI = integrase strand transfer inhibitor. a See Clinical Pharmacology Table 11 or Table 12 for magnitude of interaction. b The lower dolutegravir exposures observed in INSTI-experienced patients (with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance ) upon coadministration with certain inducers may result in loss of therapeutic effect and development of resistance to TIVICAY or other coadministered antiretroviral agents. Concomitant Drug Class: Drug Name Effect on Concentration of Dolutegravir and/or Concomitant Drug Clinical Comment HIV-1 Antiviral Agents Non-nucleoside reverse transcriptase inhibitor: Etravirine a ↓Dolutegravir Use of TIVICAY or TIVICAY PD with etravirine without coadministration of atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir is not recommended. Non-nucleoside reverse transcriptase inhibitor: Efavirenz a ↓Dolutegravir Adjust dose of TIVICAY to twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2 , 3 , and 4 ). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b Non-nucleoside reverse transcriptase inhibitor: Nevirapine ↓Dolutegravir Avoid coadministration with nevirapine because there are insufficient data to make dosing recommendations. Protease inhibitors: Fosamprenavir/ritonavir a Tipranavir/ritonavir a ↓Dolutegravir Adjust dose of TIVICAY to twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2 , 3 , and 4 ). Use alternative combinations that do not include metabolic inducers where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b Other Agents Dofetilide ↑Dofetilide Coadministration is contraindicated with TIVICAY or TIVICAY PD . Carbamazepine a ↓Dolutegravir Adjust dose of TIVICAY to twice daily in treatment-naïve or treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2 , 3 , and 4 ). Use alternative treatment that does not include carbamazepine where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b Oxcarbazepine Phenytoin Phenobarbital St. John’s wort ( Hypericum perforatum ) ↓Dolutegravir Avoid coadministration with TIVICAY or TIVICAY 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 TIVICAY or TIVICAY PD 2 hours before or 6 hours after taking medications containing polyvalent cations. Oral calcium or iron supplements, including multivitamins containing calcium or iron a ↓Dolutegravir When taken with food, TIVICAY and supplements or multivitamins containing calcium or iron can be taken at the same time. Under fasting conditions, TIVICAY or TIVICAY PD should be taken 2 hours before or 6 hours after taking supplements containing calcium or iron. Potassium channel blocker: Dalfampridine ↑Dalfampridine Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with TIVICAY or TIVICAY PD should be considered against the risk of seizures in these patients. Metformin ↑Metformin Refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of TIVICAY or TIVICAY PD and metformin. Rifampin a ↓Dolutegravir Adjust dose of TIVICAY to twice daily for treatment-naïve and treatment-experienced, INSTI-naïve adult patients. In pediatric patients, increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 2 , 3 , and 4 ). Use alternatives to rifampin where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance. b 7.4 Drugs without Clinically Significant Interactions with Dolutegravir Based on drug interaction trial results, the following drugs can be coadministered with dolutegravir without a dose adjustment: atazanavir/ritonavir, darunavir/ritonavir, elbasvir/grazoprevir, methadone, midazolam, omeprazole, oral contraceptives containing norgestimate and ethinyl estradiol, prednisone, rifabutin, rilpivirine, sofosbuvir/velpatasvir, and tenofovir .