Tivicay

1 INDICATIONS AND USAGE 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) weighing at least 2 kg [see Microbiology ( 12.4 )] . 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) weighing at least 2 kg. ( 1 ) 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. ( 1 )

2 DOSAGE AND ADMINISTRATION • May be taken without regard to food. ( 2.2 ) 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 ( 2.1 ) 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 weighing at least 2 kg. See Tables 2 , 3 , and 4 for complete pediatric dosing recommendations. ( 2.3 ). • TIVICAY and TIVICAY PD are not bioequivalent and are not substitutable on a milligram-per-milligram basis. • Pediatric Patients ≥4 weeks of age: if certain UGT1A or CYP3A inducers are coadministered, then adjust the weight-based dose of TIVICAY or TIVICAY PD to twice daily. ( 2.3 , 7.2 , 7.3 ) TIVICAY PD Tablets for Oral Suspension ( Table 2 and Table 3 ): Term Neonates ≥2 kg (from birth to <4 weeks of age): • Birth to 14 Days: 1 tablet every other day • 15 Days to <4 Weeks: 1 tablet once daily Pediatric Population (≥4 Weeks of Age) Body Weight Recommended Dose TIVICAY PD Tablets for Oral Suspension 3 kg to less than 6 kg 1 tablet once daily 6 kg to less than 10 kg 3 tablets once daily 10 kg to less than 14 kg 4 tablets once daily 14 kg to less than 20 kg 5 tablets once daily 20 kg and greater 6 tablets once daily TIVICAY Tablets ( Table 4 ): Alternative dosing recommendations for TIVICAY tablets for patients weighing at least 14 kg: • 14 kg to less than 20 kg: 4 x 10 mg tablets once daily. • 20 kg and greater: 1 x 50 mg tablet once daily. 2.1 Overview of Different Dosage Forms and Important Dosage Considerations TIVICAY is available in two dosage forms: • TIVICAY o Available as 10 mg, 25 mg, and 50 mg tablets. o Recommended for adults and pediatric patients weighing at least 14 kg. o Do not use TIVICAY tablets in patients weighing less than 14 kg [see Dosage and Administration ( 2.3 )] . • TIVICAY PD o See Instructions for Use for details on preparation and administration of TIVICAY PD [see Dosage and Administration ( 2.4 )] . o Available as 5 mg tablets for oral suspension. o Recommended for pediatric patients weighing at least 2 kg. TIVICAY PD is the only recommended dosage form for pediatric patients weighing less than 14 kg. o TIVICAY PD is preferred over TIVICAY tablets in patients weighing at least 14 kg to less than 20 kg [see Dosage and Administration ( 2.3 )] . Do not substitute TIVICAY tablets and TIVICAY PD tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.5 ), Clinical Pharmacology ( 12.3 )] . 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 [see Dosage and Administration ( 2.4 )] . Take TIVICAY and TIVICAY PD with or without food in combination with other antiretrovirals [see Dosage and Administration ( 2.2 , 2.3 ), Clinical Pharmacology ( 12.3 )] . 2.2 Recommended Dosage in Adults TIVICAY tablets may be taken with or without food in combination with other antiretrovirals [see Clinical Pharmacology ( 12.3 )]. Refer to Table 1 for dosage recommendation for adults using TIVICAY tablets. 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 [see Drug Interactions ( 7.3 )] . 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 [see Drug Interactions ( 7.2 , 7.3 )] 50 mg twice daily INSTI-experienced with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance b [see Microbiology ( 12.4 )] 50 mg twice daily 2.3 Recommended Dosage in Pediatric Patients The recommended dosages of TIVICAY PD tablets for oral suspension and TIVICAY tablets in pediatric patients (in treatment-naïve, or treatment-experienced but naïve to INSTI treatment) are displayed in Tables 2 , 3 , and 4 . In pediatric patients weighing 14 kg or greater , either TIVICAY PD tablets for oral suspension ( Table 3 ) or TIVICAY tablets ( Table 4 ) can be used. Note that TIVICAY PD is preferred over TIVICAY tablets in pediatric patients weighing at least 14 kg to less than 20 kg. Do not use TIVICAY tablets in patients weighing less than 14 kg . See administration instructions in Dosage and Administration ( 2.4 ) . No data are available in preterm neonates. TIVICAY PD Tablets for Oral Suspension Table 2. Recommended Dosage of TIVICAY PD in Pediatric Patients Including Term Neonatesa (at Least 37 Weeks of Gestation) Less Than 4 Weeks of Age and Weighing at Least 2 kg Pediatric Patient Population TIVICAY PD Tablets for Oral Suspension Total Daily Dosage Birth to 14 days 1 tablet every other day 5 mg every other day 15 days to less than 4 weeks 1 tablet once daily 5 mg once daily a No data are available in preterm neonates Table 3. Recommended Dosage of TIVICAY PD in Pediatric Patients at Least 4 Weeks of Age and Weighing at Least 3 kg Body Weight TIVICAY PD Tablets for Oral Suspension Total Daily Dosage 3 kg to less than 6 kg 1 tablet once daily 5 mg once daily 6 kg to less than 10 kg 3 tablets once daily 15 mg once daily 10 kg to less than 14 kg 4 tablets once daily 20 mg once daily 14 kg to less than 20 kg 5 tablets once daily 25 mg once daily 20 kg or greater 6 tablets once daily 30 mg once daily TIVICAY Tablets Table 4. Recommended Dosage of TIVICAY in Pediatric Patients Weighing at Least 14 kg Body Weight TIVICAY Tablets Total Daily Dosage 14 kg to less than 20 kg 4 x 10 mg tablets once daily 40 mg once daily 20 kg and greater 1 x 50 mg tablet once daily 50 mg once daily Dosage Modifications for Co-administration with Certain UGT1A or CYP3A Inducers in Pediatric Patients at Least 4 Weeks of Age If certain uridine diphosphate glucuronosyltransferase (UGT)1A or cytochrome P450 (CYP)3A inducers are co‑administered, then administer the corresponding dose of TIVICAY PD (see Table 3 ) or TIVICAY (see Table 4 ) twice daily instead of once daily (i.e., double the total daily dosage) [see Drug Interactions ( 7.2 , 7.3 )] . 2.4 Preparation and Administration Instructions for TIVICAY PD Take TIVICAY PD daily with or without food in combination with other antiretrovirals [see Clinical Pharmacology ( 12.3 )] . Do not chew, cut, or crush TIVICAY PD [see Instructions for Use] . 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 [see Instructions for Use] .

4 CONTRAINDICATIONS TIVICAY and TIVICAY PD are contraindicated in patients: • with previous hypersensitivity reaction to dolutegravir [see Warnings and Precautions ( 5.1 )] . • receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events [see Drug Interactions ( 7 )] . • Previous hypersensitivity reaction to dolutegravir. ( 4 ) • Coadministration with dofetilide. ( 4 )

5 WARNINGS AND PRECAUTIONS • 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. ( 5.1 ) • 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. ( 5.2 ) • Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. ( 5.4 ) • TIVICAY tablets and TIVICAY PD tablets for oral suspension are not substitutable. ( 2.2 , 5.5 ) 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 participants 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. 5.2 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 [see Adverse Reactions ( 6.1 )] . 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. 5.3 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 [see Contraindications ( 4 ), Drug Interactions ( 7.3 )] : • 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. 5.4 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. 5.5 Different Formulations Are Not Substitutable TIVICAY and TIVICAY PD are not bioequivalent and are not substitutable on a milligram-per-milligram basis [see Clinical Pharmacology ( 12.3 )] . If a pediatric patient switches from one formulation to the other, the dose must be adjusted for the new dosage formulation [see Dosage and Administration ( 2.2 )] . 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.

7 DRUG INTERACTIONS • 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. ( 7.2 , 7.3 ) • 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. ( 7.3 ) 7.1 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 ) [see Contraindications ( 4 ), Drug Interactions ( 7.3 )] . 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. 7.2 Effect of Other Agents on the Pharmacokinetics of Dolutegravir Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma 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 ) [see Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.3 )] . In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3. 7.3 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 [see Dosage and Administration ( 2 ), Clinical Pharmacology ( 12.3 )] . 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 [see Dosage and Administration ( 2 )] INSTI = integrase strand transfer inhibitor. a See Clinical Pharmacology ( 12.3 ) 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 [see Microbiology ( 12.4 )] ) 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 (at least 4 weeks of age), increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 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 (at least 4 weeks of age), increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 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 [see Contraindications ( 4 )] . Carbamazepine a ↓Dolutegravir Adjust dose of TIVICAY to twice daily in treatment-naïve or treatment-experienced, INSTI-naïve adult patients. In pediatric patients (at least 4 weeks of age), increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 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 (at least 4 weeks of age), increase the weight-based dose of TIVICAY or TIVICAY PD to twice daily (Tables 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 [see Clinical Pharmacology ( 12.3 )] .

6 ADVERSE REACTIONS The following serious adverse drug reactions are discussed in other sections of the labeling: • Hypersensitivity reactions [see Warnings and Precautions ( 5.1 )] . • Hepatotoxicity [see Warnings and Precautions ( 5.2 )] . • Immune Reconstitution Syndrome [see Warnings and Precautions ( 5.4 )] . The most common adverse reactions of moderate to severe intensity and incidence at least 2% (in those receiving TIVICAY in any one adult trial) are insomnia, fatigue, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ViiV Healthcare at 1-877-844-8872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adult Participants Treatment-Naïve Participants: The safety assessment of TIVICAY in treatment naïve participants with HIV‑1 is based on the analyses of data from 2 international, multicenter, double-blind trials, SPRING‑2 (ING113086) and SINGLE (ING114467) and data from the international, multicenter, open-label FLAMINGO (ING114915) trial. In SPRING‑2, 822 participants were randomized and received at least 1 dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine [EPZICOM] or emtricitabine/tenofovir [TRUVADA]). There were 808 participants included in the efficacy and safety analyses. Through 96 weeks, the rate of adverse events leading to discontinuation was 2% in both treatment arms. In SINGLE, 833 participants were randomized and received at least 1 dose of either TIVICAY 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA) once daily (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rates of adverse events leading to discontinuation were 4% in participants receiving TIVICAY 50 mg once daily + EPZICOM and 14% in participants receiving ATRIPLA once daily. Treatment‑emergent adverse reactions of moderate to severe intensity observed in at least 2% of participants in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 5 . Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. Table 5. Treatment-Emergent Adverse Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-Naïve Participants in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis) NRTI = Nucleoside Reverse Transcriptase Inhibitor. a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption. System Organ Class/ Preferred Term SPRING-2 SINGLE TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Psychiatric Insomnia <1% <1% 3% 3% Depression <1% <1% 1% 2% Abnormal dreams <1% <1% <1% 2% Nervous System Dizziness <1% <1% <1% 5% Headache <1% <1% 2% 2% Gastrointestinal Nausea 1% 1% <1% 3% Diarrhea <1% <1% <1% 2% Skin and Subcutaneous Tissue Rash a 0 <1% <1% 6% General Disorders Fatigue <1% <1% 2% 2% Ear and Labyrinth Vertigo 0 <1% 0 2% In addition, Grade 1 insomnia was reported by 1% and less than 1% of participants receiving TIVICAY and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for TIVICAY and ATRIPLA, respectively. These events were not treatment limiting. In a multicenter, open-label trial (FLAMINGO), 243 participants received TIVICAY 50 mg once daily versus 242 participants who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either EPZICOM or TRUVADA). There were 484 participants included in the efficacy and safety analyses. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in participants receiving TIVICAY and 6% in participants receiving darunavir/ritonavir. The adverse reactions observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Participants: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 participants with HIV‑1, 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. Participants were antiretroviral treatment-experienced adults. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in participants receiving TIVICAY 50 mg once daily + background regimen and 4% in participants receiving raltegravir 400 mg twice daily + background regimen. The only treatment‑emergent adverse reaction of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in participants receiving TIVICAY 50 mg once daily + background regimen and 1% (5 of 361) in participants receiving raltegravir 400 mg twice daily + background regimen. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Participants: In a multicenter, open-label, single‑arm trial (ING112574, VIKING-3), 183 participants with HIV‑1 received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. Participants were antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance. The rate of adverse events leading to discontinuation was 4% of participants at Week 48. Treatment‑emergent adverse reactions in VIKING-3 were generally similar compared with observations with the 50‑mg once-daily dose in adult Phase III trials. Virologically Suppressed Participants: The adverse reactions observed for TIVICAY plus rilpivirine in the Week 48 analysis of pooled data from 2 identical, international, multicenter, open‑label trials (SWORD‑1 and SWORD‑2) of 513 virologically suppressed participants with HIV‑1, switching from their current antiretroviral regimen to TIVICAY plus rilpivirine, were consistent with the adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents. There were no adverse reactions (Grades 2 to 4) with an incidence of at least 2% in either treatment arm at Week 48. The safety profile during the additional follow-up period through Week 148 were consistent with Week 48. The rate of adverse events leading to discontinuation through Week 48 was 4% in participants receiving TIVICAY plus rilpivirine once daily and less than 1% in participants who remained on their current antiretroviral regimen. In the pooled analyses, the proportion of participants receiving TIVICAY plus rilpivirine who discontinued treatment due to an adverse event through Week 148 was 8%. Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Trials: The following adverse reactions occurred in less than 2% of treatment-naïve or treatment-experienced participants receiving TIVICAY in a combination regimen in any one trial. These events have been included because of their seriousness and assessment of potential causal relationship. Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, vomiting. Hepatobiliary Disorders: Hepatitis. Musculoskeletal Disorders: Myositis. Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in participants with a pre-existing history of depression or other psychiatric illness. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities: Treatment-Naïve Participants: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of participants are presented in Table 6 . The mean change from baseline observed for selected lipid values is presented in Table 7 . Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. Table 6. Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naïve Participants in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis) ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; NRTI = Nucleoside Reverse Transcriptase Inhibitor; ULN = Upper limit of normal. Laboratory Parameter Preferred Term SPRING-2 SINGLE TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) ALT Grade 2 (>2.5-5.0 x ULN) 4% 4% 3% 5% Grade 3 to 4 (>5.0 x ULN) 2% 2% 1% <1% AST Grade 2 (>2.5-5.0 x ULN) 5% 3% 3% 4% Grade 3 to 4 (>5.0 x ULN) 3% 2% 1% 3% Total Bilirubin Grade 2 (1.6-2.5 x ULN) 3% 2% <1% <1% Grade 3 to 4 (>2.5 x ULN) <1% <1% <1% <1% Creatine kinase Grade 2 (6.0-9.9 x ULN) 2% 5% 5% 3% Grade 3 to 4 (≥10.0 x ULN) 7% 4% 7% 8% Hyperglycemia Grade 2 (126-250 mg/dL) 6% 6% 9% 6% Grade 3 (>250 mg/dL) <1% 2% 2% <1% Lipase Grade 2 (>1.5-3.0 x ULN) 7% 7% 11% 11% Grade 3 to 4 (>3.0 x ULN) 2% 5% 5% 4% Total neutrophils Grade 2 (0.75-0.99 x 10 9 ) 4% 3% 4% 5% Grade 3 to 4 (<0.75 x 10 9 ) 2% 2% 3% 3% Table 7. Mean Change from Baseline in Fasted Lipid Values in Treatment-Naïve Participants in SPRING-2 (Week 96 Analysis a ) and SINGLE Trials (Week 144 Analysis a ) HDL = High density lipoprotein; LDL = Low density lipoprotein; NRTI = Nucleoside Reverse Transcriptase Inhibitor. a Participants on lipid-lowering agents at baseline were excluded from these analyses (19 participants in each arm in SPRING-2, and in SINGLE: TIVICAY + EPZICOM n = 30 and ATRIPLA n = 27). Ninety-four participants 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 (SPRING-2: TIVICAY n = 9, raltegravir n = 13; SINGLE: TIVICAY + EPZICOM n = 36, ATRIPLA n = 36). Laboratory Parameter Preferred Term SPRING-2 SINGLE TIVICAY 50 mg Once Daily + 2 NRTIs (n = 403) Raltegravir 400 mg Twice Daily + 2 NRTIs (n = 405) TIVICAY 50 mg + EPZICOM Once Daily (n = 414) ATRIPLA Once Daily (n = 419) Cholesterol (mg/dL) 8.1 10.1 24.0 26.7 HDL cholesterol (mg/dL) 2.0 2.3 5.4 7.2 LDL cholesterol (mg/dL) 5.1 6.1 16.0 14.6 Triglycerides (mg/dL) 6.7 6.6 13.6 31.9 Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Participants: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve (SPRING-2 and SINGLE) trials. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Participants: The most common treatment-emergent laboratory abnormalities (greater than 5% for Grades 2 to 4 combined) observed in VIKING-3 at Week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4 of 183) of participants had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% [3 of 183]) being the most frequently reported. Virologically Suppressed Adults: Laboratory abnormalities observed in SWORD-1 and SWORD-2 were generally similar compared with observations seen in the other Phase III trials. Hepatitis B and/or Hepatitis C Virus Co-infection: In Phase III trials, participants with hepatitis B and/or C virus co‑infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in participants with hepatitis B and/or C virus co‑infection was similar to that observed in participants without hepatitis B or C co‑infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C virus co‑infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or C co‑infected compared with HIV mono-infected participants receiving TIVICAY were observed in 18% vs. 3% with the 50‑mg once‑daily dose and 13% vs. 8% with the 50‑mg twice‑daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some participants with hepatitis B and/or C at the start of therapy with TIVICAY, particularly in the setting where anti-hepatitis therapy was withdrawn [see Warnings and Precautions ( 5.2 )] . Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see Clinical Pharmacology ( 12.2 )] . Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 96 weeks. In treatment-naïve participants, a mean change from baseline of 0.15 mg/dL (range: -0.32 mg/dL to 0.65 mg/dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced participants. Clinical Trials Experience in Pediatric Participants Children and Adolescent Participants with HIV‑1: The safety and pharmacokinetics of TIVICAY and TIVICAY PD in pediatric participants with HIV‑1 aged at least 4 weeks and weighing at least 3 kg was evaluated in the IMPAACT P1093 trial and 2 weight-band-based pharmacokinetic substudies of the ODYSSEY trial [see Use in Specific Populations ( 8.4 ), Clinical Pharmacology ( 12.3 )] . Overall, the safety data in these pediatric studies were similar to those seen in adults, and there was no clinically significant difference in dolutegravir exposure [see Clinical Pharmacology ( 12.3 )] . IMPAACT P1093 is a multicenter, open-label, non-comparative trial of pediatric participants with HIV‑1 aged 4 weeks to less than 18 years [see Use in Specific Populations ( 8.4 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.3 )] . The safety analysis based on participants (n = 75) who received the recommended dose (determined by weight and age) through Week 24 showed that 11% of participants experienced drug-related clinical adverse reactions. The only Grade 1 to 2 drug-related clinical adverse reactions reported by more than one participant was immune reconstitution inflammatory syndrome (IRIS) (n = 2). There were no Grade 3 or 4 drug‑related adverse reactions reported. No adverse reactions led to discontinuation. The Grade 3 or 4 laboratory abnormalities reported in more than one participant were decreased neutrophil count (n = 11), decreased blood bicarbonate (n = 4), decreased hemoglobin (n = 3), increased lipase (n = 2), and increased blood potassium (n = 2). These laboratory events were not considered to be drug-related. Median laboratory values were similar at baseline and Week 24. Changes in median serum creatinine were similar to those observed in adults. Neonates Exposed to HIV‑1: Forty‑eight term neonates exposed to HIV‑1 (from birth and weighing at least 2 kg) received dolutegravir for up to 6 weeks, and followed for a total of 16 weeks in IMPAACT 2023. The safety profile in neonates was similar to that observed in older populations and there were no new safety findings identified [see Use in Specific Populations ( 8.4 )] . 6.2 Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. 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 Sideroblastic anemia. Hepatobiliary Disorders Acute liver failure, hepatotoxicity. Investigations Weight increased. Musculoskeletal Arthralgia, myalgia. Psychiatric Anxiety.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to TIVICAY or TIVICAY PD 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. (see Data) . There are insufficient human data on the use of dolutegravir during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. However, available human data from the APR do not indicate an increased risk of birth defects (see Data) . 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 27 times (rats) the exposure in humans at the maximum recommended human dose (MRHD) of TIVICAY (see Data) . Data Human Data: 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 1,377 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 to 2.11) (n = 15). Animal Data: Dolutegravir was administered orally at up to 1,000 mg/kg daily to pregnant rats and rabbits on Gestation Days 6 to 17 and 6 to 18, respectively, and to rats on Gestation Day 6 to Lactation/Postpartum Day 20. No adverse effects on embryo-fetal (rats and rabbits) or pre/postnatal (rats) development were observed at up to the highest dose tested. During organogenesis, systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans at the MRHD and in rats were approximately 27 times the exposure in humans at the MRHD. In the rat pre/postnatal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 27 times human exposure at the MRHD).