Dolutegravir Sodium

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) 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 )

2 DOSAGE AND ADMINISTRATION 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 ( 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 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. 2.1 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 [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 2.2 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 [see 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 in [Dosage and Administration ( 2.5 )] . 2.3 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 ( 2.5 )] . 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 [see Drug Interactions ( 7.2 , 7.3 )] . 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 [see Drug Interactions ( 7.2 , 7.3 )] . 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 [see Drug Interactions ( 7.2 , 7.3 )] . 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 [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] .

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 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. Renal and Urinary Disorders: Renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities: Treatment-Naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects 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 Subjects 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 Subjects in SPRING-2 (Week 96 Analysisa) and SINGLE Trials (Week 144 Analysis a ) HDL = High density lipoprotein; LDL = Low density lipoprotein; NRTI = Nucleoside Reverse Transcriptase Inhibitor. a Subjects on lipid-lowering agents at baseline were excluded from these analyses (19 subjects in each arm in SPRING-2, and in SINGLE: TIVICAY + EPZICOM n = 30 and ATRIPLA n = 27). Ninety-four subjects initiated a lipid-lowering agent post-baseline; their last fasted on-treatment values (prior to starting the agent) were used regardless of whether they discontinued the agent (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 Subjects: 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 Subjects: 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 subjects 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, subjects 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 subjects with hepatitis B and/or C virus co-infection was similar to that observed in subjects 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 subjects 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 subjects 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 subjects, 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 subjects. Clinical Trials Experience in Pediatric Subjects The safety and pharmacokinetics of TIVICAY and TIVICAY PD in HIV-1–infected pediatric subjects 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 an ongoing, multicenter, open-label, non-comparative trial of HIV‑1–infected pediatric subjects 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 subjects (n = 75) who received the recommended dose (determined by weight and age) through Week 24 showed that 11% of subjects experienced drug-related clinical adverse reactions. The only Grade 1 to 2 drug-related clinical adverse reactions reported by more than one subject 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 subject 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. 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.

12.3 Pharmacokinetics The pharmacokinetic properties of dolutegravir have been evaluated in healthy adult subjects and HIV‑1–infected adult subjects. Exposure to dolutegravir was generally similar between healthy subjects and HIV‑1–infected subjects. The non-linear exposure of dolutegravir following 50 mg twice daily compared with 50 mg once daily in HIV‑1–infected subjects ( Table 9 ) was attributed to the use of metabolic inducers in the background antiretroviral regimens of subjects receiving dolutegravir 50 mg twice daily in clinical trials. Table 9. Dolutegravir Steady-State Pharmacokinetic Parameter Estimates in HIV-1–Infected Adults a Based on population pharmacokinetic analyses using data from SPRING-1 and SPRING-2. b Based on population pharmacokinetic analyses using data from VIKING (ING112961) and VIKING-3. Parameter 50 mg Once Daily Geometric Mean a (%CV) 50 mg Twice Daily Geometric Mean b (%CV) AUC (0-24) (mcg ∙ h/mL) 53.6 (27) 75.1 (35) C max (mcg/mL) 3.67 (20) 4.15 (29) C min (mcg/mL) 1.11 (46) 2.12 (47) TIVICAY tablets and TIVICAY PD tablets for oral suspension are not bioequivalent. The relative bioavailability of TIVICAY PD is approximately 1.6-fold higher than TIVICAY; therefore, the 2 dosage forms are not substitutable on a milligram-per-milligram basis [see Dosage and Administration ( 2.3 )]. Absorption Following oral administration of dolutegravir, peak plasma concentrations were observed 1 to 3 hours postdose. With once-daily dosing, pharmacokinetic steady state is achieved within approximately 5 days with average accumulation ratios for AUC, C max , and C 24 h ranging from 1.2 to 1.5. Dolutegravir plasma concentrations increased in a less than dose-proportional manner above 50 mg. Dolutegravir is a P‑gp substrate in vitro. The absolute bioavailability of dolutegravir has not been established. Effect of Food: TIVICAY or TIVICAY PD may be taken with or without food. Food increased the extent of absorption and slowed the rate of absorption of dolutegravir following a 50-mg dose of TIVICAY. Low-, moderate-, and high-fat meals increased dolutegravir AUC (0-∞) by 33%, 41%, and 66%; increased C max by 46%, 52%, and 67%; and prolonged T max to 3, 4, and 5 hours from 2 hours under fasted conditions, respectively. Distribution Dolutegravir is highly bound (greater than or equal to 98.9%) to human plasma proteins based on in vivo data and binding is independent of plasma concentration of dolutegravir. The apparent volume of distribution (Vd/F) following 50-mg once-daily administration is estimated at 17.4 L based on a population pharmacokinetic analysis. Cerebrospinal Fluid (CSF): In 12 treatment-naïve subjects on dolutegravir 50 mg daily plus abacavir/lamivudine, the median dolutegravir concentration in CSF was 13.2 ng/mL (range: 3.74 ng/mL to 18.3 ng/mL) 2 to 6 hours postdose after 16 weeks of treatment. The clinical relevance of this finding has not been established. Elimination Dolutegravir has a terminal half-life of approximately 14 hours and an apparent clearance (CL/F) of 1.0 L/h based on population pharmacokinetic analyses. Metabolism: Dolutegravir is primarily metabolized via UGT1A1 with some contribution from CYP3A. Polymorphisms in Drug ‑ Metabolizing Enzymes: In a meta-analysis of healthy subject trials, subjects with UGT1A1 (n = 7) genotypes conferring poor dolutegravir metabolism had a 32% lower clearance of dolutegravir and 46% higher AUC compared with subjects with genotypes associated with normal metabolism via UGT1A1 (n = 41). Excretion: After a single oral dose of [ 14 C] dolutegravir, 53% of the total oral dose was excreted unchanged in feces. Thirty-one percent of the total oral dose was excreted in urine, represented by an ether glucuronide of dolutegravir (18.9% of total dose), a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose), and its hydrolytic N-dealkylation product (3.6% of total dose). Renal elimination of unchanged drug was low (less than 1% of the dose). Specific Populations Pediatric Patients: The pharmacokinetics of dolutegravir were evaluated in the IMPAACT P1093 trial and in 2 weight-band-based pharmacokinetic substudies from the ODYSSEY trial. Steady-state plasma exposure at doses by weight band are summarized in Table 10 [see Clinical Studies ( 14.3 )] . Mean dolutegravir AUC 0-24h and C 24h in HIV-1–infected pediatric subjects were comparable to those in adults after 50 mg once daily or 50 mg twice daily. Mean C max is higher in pediatrics, but the increase is not considered clinically significant as the safety profiles were similar in pediatric and adult subjects [see Use in Specific Populations ( 8.4 )] . Table 10. Summary of Pharmacokinetic Parameters in Pediatric HIV-1–Infected Subjects (Pooled Analyses for IMPAACT P1093 and ODYSSEY a Trials) a Data from 2 weight-band-based pharmacokinetic substudies in the ODYSSEY trial. b The bioavailability of TIVICAY PD tablets for oral suspension is ~1.6-fold that of TIVICAY tablets. Weight Band Dose b of TIVICAY or TIVICAY PD n Pharmacokinetic Parameter Geometric Mean (%CV) C max (mcg/mL) AUC 0-24h (mcg∙h/mL) C 24h (ng/mL) 3 kg to <6 kg TIVICAY PD 5 mg once daily 8 3.80 (34) 49.37 (49) 962 (98) 6 kg to <10 kg TIVICAY PD 15 mg once daily 17 5.27 (50) 57.17 (76) 706 (177) 10 kg to <14 kg TIVICAY PD 20 mg once daily 13 5.99 (33) 68.75 (48) 977 (100) 14 kg to <20 kg TIVICAY PD 25 mg once daily 19 5.97 (42) 58.97 (44) 725 (75) 20 kg to <25 kg TIVICAY PD 30 mg once daily 9 7.16 (26) 71.53 (26) 759 (73) ≥20 kg TIVICAY 50 mg once daily 49 4.92 (40) 54.98 (43) 778 (62) Geriatric Patients: Population pharmacokinetic analysis indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir. Patients with Hepatic Impairment: In a trial comparing 8 subjects with moderate hepatic impairment (Child-Pugh Score B) with 8 matched healthy controls, exposure of dolutegravir from a single 50-mg dose was similar between the 2 groups. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Patients with Renal Impairment: In a trial evaluating the pharmacokinetics of a single 50-mg tablet of dolutegravir comparing 8 subjects with severe renal impairment (CrCl less than 30 mL/min) with 8 matched healthy controls, AUC, C max , and C 24 of dolutegravir were lower by 40%, 23%, and 43%, respectively, compared with those in matched healthy subjects. Population pharmacokinetic analysis using data from SAILING and VIKING-3 trials indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis. HBV or HCV Co-infected Patients: Population analyses using pooled pharmacokinetic data from adult trials indicated no clinically relevant effect of HCV co-infection on the pharmacokinetics of dolutegravir. There were limited data on HBV co-infection. Gender and Race: Population analyses using pooled pharmacokinetic data from adult trials indicated gender and race had no clinically relevant effect on the exposure of dolutegravir. Drug Interaction Studies Drug interaction trials were performed with TIVICAY and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of dolutegravir on the exposure of coadministered drugs are summarized in Table 11 and the effects of coadministered drugs on the exposure of dolutegravir are summarized in Table 12 . Dosing or regimen recommendations as a result of established and other potentially significant drug-drug interactions with TIVICAY are provided in Table 8 [see Dosage and Administration ( 2.2 ), Drug Interactions ( 7.3 )] . Table 11. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs a The number of subjects represents the maximum number of subjects that were evaluated. Coadministered Drug(s) and Dose(s) Dose of TIVICAY n Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00 C max AUC C τ or C 24 Elbasvir 50 mg once daily 50 mg single dose 12 0.97 (0.89, 1.05) 0.98 (0.93, 1.04) 0.98 (0.93, 1.03) Ethinyl estradiol 0.035 mg 50 mg twice daily 15 0.99 (0.91 to 1.08) 1.03 (0.96 to 1.11) 1.02 (0.93 to 1.11) Grazoprevir 200 mg once daily 50 mg single dose 12 0.64 (0.44, 0.93) 0.81 (0.67, 0.97) 0.86 (0.79, 0.93) Metformin 500 mg twice daily 50 mg once daily 15 a 1.66 (1.53 to 1.81) 1.79 (1.65 to 1.93) _ Metformin 500 mg twice daily 50 mg twice daily 15 a 2.11 (1.91 to 2.33) 2.45 (2.25 to 2.66) _ Methadone 16 to 150 mg 50 mg twice daily 11 1.00 (0.94 to 1.06) 0.98 (0.91 to 1.06) 0.99 (0.91 to 1.07) Midazolam 3 mg 25 mg once daily 10 _ 0.95 (0.79 to 1.15) _ Norelgestromin 0.25 mg 50 mg twice daily 15 0.89 (0.82 to 0.97) 0.98 (0.91 to 1.04) 0.93 (0.85 to 1.03) Rilpivirine 25 mg once daily 50 mg once daily 16 1.10 (0.99 to 1.22) 1.06 (0.98 to 1.16) 1.21 (1.07 to 1.38) Sofosbuvir 400 mg once daily Metabolite (GS-331007) 50 mg once daily 24 0.88 (0.80, 0.98) 0.92 (0.85, 0.99) NA 1.01 (0.93, 1.10) 0.99 (0.97, 1.01) 0.99 (0.97, 1.01) Tenofovir disoproxil fumarate 300 mg once daily 50 mg once daily 15 1.09 (0.97 to 1.23) 1.12 (1.01 to 1.24) 1.19 (1.04 to 1.35) Velpatasvir 100 mg once daily 50 mg once daily 24 0.94 (0.86, 1.02) 0.91 (0.84, 0.98) 0.88 (0.82, 0.94) Table 12. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir a The number of subjects represents the maximum number of subjects that were evaluated. b Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. c Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily. Coadministered Drug(s) and Dose(s) Dose of TIVICAY n Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 C max AUC C τ or C 24 Atazanavir 400 mg once daily 30 mg once daily 12 1.50 (1.40 to 1.59) 1.91 (1.80 to 2.03) 2.80 (2.52 to 3.11) Atazanavir/ritonavir 300/100 mg once daily 30 mg once daily 12 1.34 (1.25 to 1.42) 1.62 (1.50 to 1.74) 2.21 (1.97 to 2.47) Darunavir/ritonavir 600/100 mg twice daily 30 mg once daily 15 0.89 (0.83 to 0.97) 0.78 (0.72 to 0.85) 0.62 (0.56 to 0.69) Efavirenz 600 mg once daily 50 mg once daily 12 0.61 (0.51 to 0.73) 0.43 (0.35 to 0.54) 0.25 (0.18 to 0.34) Elbasvir/grazoprevir 50/200 mg once daily 50 mg single dose 12 1.22 (1.05, 1.40) 1.16 (1.00, 1.34) 1.14 (0.95, 1.36) Etravirine 200 mg twice daily 50 mg once daily 16 0.48 (0.43 to 0.54) 0.29 (0.26 to 0.34) 0.12 (0.09 to 0.16) Etravirine + darunavir/ritonavir 200 mg + 600/100 mg twice daily 50 mg once daily 9 0.88 (0.78 to 1.00) 0.75 (0.69 to 0.81) 0.63 (0.52 to 0.76) Etravirine + lopinavir/ritonavir 200 mg + 400/100 mg twice daily 50 mg once daily 8 1.07 (1.02 to 1.13) 1.11 (1.02 to 1.20) 1.28 (1.13 to 1.45) Fosamprenavir/ritonavir 700 mg/100 mg twice daily 50 mg once daily 12 0.76 (0.63 to 0.92) 0.65 (0.54 to 0.78) 0.51 (0.41 to 0.63) Lopinavir/ritonavir 400/100 mg twice daily 30 mg once daily 15 1.00 (0.94 to 1.07) 0.97 (0.91 to 1.04) 0.94 (0.85 to 1.05) Rilpivirine 25 mg once daily 50 mg once daily 16 1.13 (1.06 to 1.21) 1.12 (1.05 to 1.19) 1.22 (1.15 to 1.30) Tenofovir 300 mg once daily 50 mg once daily 15 0.97 (0.87 to 1.08) 1.01 (0.91 to 1.11) 0.92 (0.82 to 1.04) Tipranavir/ritonavir 500/200 mg twice daily 50 mg once daily 14 0.54 (0.50 to 0.57) 0.41 (0.38 to 0.44) 0.24 (0.21 to 0.27) Antacid (MAALOX) simultaneous administration 50 mg single dose 16 0.28 (0.23 to 0.33) 0.26 (0.22 to 0.32) 0.26 (0.21 to 0.31) Antacid (MAALOX) 2 h after dolutegravir 50 mg single dose 16 0.82 (0.69 to 0.98) 0.74 (0.62 to 0.90) 0.70 (0.58 to 0.85) Calcium carbonate 1,200 mg simultaneous administration (fasted) 50 mg single dose 12 0.63 (0.50 to 0.81) 0.61 (0.47 to 0.80) 0.61 (0.47 to 0.80) Calcium carbonate 1,200 mg simultaneous administration (fed) 50 mg single dose 11 1.07 (0.83 to 1.38) 1.09 (0.84 to 1.43) 1.08 (0.81 to 1.42) Calcium carbonate 1,200 mg 2 h after dolutegravir 50 mg single dose 11 1.00 (0.78 to 1.29) 0.94 (0.72 to 1.23) 0.90 (0.68 to 1.19) Carbamazepine 300 mg twice daily 50 mg once daily 16 a 0.67 (0.61 to 0.73) 0.51 (0.48 to 0.55) 0.27 (0.24 to 0.31) Ferrous fumarate 324 mg simultaneous administration (fasted) 50 mg single dose 11 0.43 (0.35 to 0.52) 0.46 (0.38 to 0.56) 0.44 (0.36 to 0.54) Ferrous fumarate 324 mg simultaneous administration (fed) 50 mg single dose 11 1.03 (0.84 to 1.26) 0.98 (0.81 to 1.20) 1.00 (0.81 to 1.23) Ferrous fumarate 324 mg 2 h after dolutegravir 50 mg single dose 10 0.99 (0.81 to 1.21) 0.95 (0.77 to 1.15) 0.92 (0.74 to 1.13) Multivitamin (One-A-Day) simultaneous administration 50 mg single dose 16 0.65 (0.54 to 0.77) 0.67 (0.55 to 0.81) 0.68 (0.56 to 0.82) Omeprazole 40 mg once daily 50 mg single dose 12 0.92 (0.75 to 1.11) 0.97 (0.78 to 1.20) 0.95 (0.75 to 1.21) Prednisone 60 mg once daily with taper 50 mg once daily 12 1.06 (0.99 to 1.14) 1.11 (1.03 to 1.20) 1.17 (1.06 to 1.28) Rifampin b 600 mg once daily 50 mg twice daily 11 0.57 (0.49 to 0.65) 0.46 (0.38 to 0.55) 0.28 (0.23 to 0.34) Rifampin c 600 mg once daily 50 mg twice daily 11 1.18 (1.03 to 1.37) 1.33 (1.15 to 1.53) 1.22 (1.01 to 1.48) Rifabutin 300 mg once daily 50 mg once daily 9 1.16 (0.98 to 1.37) 0.95 (0.82 to 1.10) 0.70 (0.57 to 0.87)