Dolutegravir Sodium

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 [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) aged at least 4 weeks and weighing at least 3 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 )

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 ( 3 ) TIVICAY PD tablets for oral suspension: 5 mg ( 3 )

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 )

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 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.

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.

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 Subjects Treatment-Naïve Subjects: The safety assessment of TIVICAY in HIV‑1–infected treatment-naïve subjects 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 subjects 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 subjects 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 subjects 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 subjects receiving TIVICAY 50 mg once daily + EPZICOM and 14% in subjects receiving ATRIPLA once daily. Treatment‑emergent adverse reactions of moderate to severe intensity observed in at least 2% of subjects 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 Subjects 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 subjects 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 subjects received TIVICAY 50 mg once daily versus 242 subjects 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 subjects included in the efficacy and safety analyses. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY and 6% in subjects 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 Subjects: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV‑1–infected, antiretroviral treatment-experienced adults were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY 50 mg once daily + background regimen and 4% in subjects 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 subjects receiving TIVICAY 50 mg once daily + background regimen and 1% (5 of 361) in subjects receiving raltegravir 400 mg twice daily + background regimen. Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: In a multicenter, open-label, single‑arm trial (ING112574, VIKING-3), 183 HIV‑1–infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. The rate of adverse events leading to discontinuation was 4% of subjects 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 Subjects: 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 HIV-1–infected, virologically suppressed subjects 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 subjects receiving TIVICAY plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen. In the pooled analyses, the proportion of subjects 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 subjects 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 subjects with a pre-existing history of depression or other psychiatric illness. […]

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 [ s ee 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, 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 [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, 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 ). […]

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).

8.2 Lactation Risk Summary Dolutegravir is present in human milk. It is not known whether dolutegravir affects human milk production or has effects on the breastfed infant. Potential risks of breastfeeding include: (1) HIV‑1 transmission (in HIV-1–negative infants), (2) developing viral resistance (in HIV-1–positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults.

8.4 Pediatric Use The safety, pharmacokinetics, and effectiveness of TIVICAY and TIVICAY PD were evaluated in 75 HIV-1–infected, treatment-naïve or treatment-experienced, INSTI-naïve pediatric and adolescent subjects aged 4 weeks to less than 18 years weighing at least 3 kg in an ongoing, open-label, multicenter, dose-finding clinical trial, IMPAACT P1093 [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.3 )] . Additional pharmacokinetics data were evaluated in 2 pharmacokinetic substudies in ODYSSEY, an ongoing open-label, randomized, non-inferiority trial to evaluate the safety, efficacy, and pharmacokinetic parameters of TIVICAY or TIVICAY PD plus two NRTIs compared with standard of care in HIV-1–infected pediatric subjects younger than 18 years [see Clinical Pharmacology ( 12.3 )] . Overall, the safety data in pediatric subjects from the IMPAACT P1093 trial were comparable to those observed in adults [see Adverse Reactions ( 6.1 )] . The pharmacokinetic parameters of TIVICAY or TIVICAY PD in pediatric subjects from IMPAACT P1093 and ODYSSEY were comparable to those of adults receiving 50 mg once daily or twice daily [see Clinical Pharmacology ( 12.3 )] . The effectiveness observed in IMPAACT P1093 is comparable to that of treatment-experienced adult subjects. Safety and effectiveness of TIVICAY or TIVICAY PD have not been established in pediatric patients aged less than 4 weeks or weighing less than 3 kg or in any pediatric patients who are INSTI-experienced with documented or clinically suspected resistance to other INSTIs (e.g., raltegravir, elvitegravir).

8.5 Geriatric Use Clinical trials of TIVICAY did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of TIVICAY in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology ( 12.3 )] .

8.6 Hepatic Impairment No clinically important pharmacokinetic differences between subjects with moderate hepatic impairment and matching healthy subjects were observed. […]

Dolutegravir is an HIV-1 antiretroviral agent [see Microbiology ( 12.4 )].