Dolutegravir Sodium And Lamivudine

1 INDICATIONS AND USAGE DOVATO is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 25 kg with no antiretroviral treatment history or 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 with no history of treatment failure and no known substitutions associated with resistance to the individual components of DOVATO. DOVATO, a two-drug combination of dolutegravir (integrase strand transfer inhibitor [INSTI]) and lamivudine (nucleoside analogue reverse transcriptase inhibitor [NRTI]) is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 25 kg with no antiretroviral treatment history or 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 with no history of treatment failure and no known substitutions associated with resistance to the individual components of DOVATO. ( 1 )

2 DOSAGE AND ADMINISTRATION • Prior to or when initiating DOVATO, test patients for hepatitis B virus (HBV) infection. ( 2.1 ) • One tablet taken orally once daily with or without food. ( 2.2 ) • The dolutegravir dose (50 mg) in DOVATO is insufficient when coadministered with carbamazepine or rifampin. If DOVATO is coadministered with carbamazepine or rifampin, take one tablet of DOVATO once daily, followed by an additional dolutegravir 50-mg tablet, approximately 12 hours from the dose of DOVATO. ( 2.3 ) 2.1 Testing Prior to or When Initiating Treatment with DOVATO Prior to or when initiating DOVATO, test patients for HBV infection [see Warnings and Precautions ( 5.1 )]. 2.2 Recommended Dosage DOVATO is a fixed-dose combination product containing 50 mg of dolutegravir and 300 mg of lamivudine. The recommended dosage regimen of DOVATO in adults and adolescents 12 years of age and older and weighing at least 25 kg is one tablet taken orally once daily with or without food [see Clinical Pharmacology ( 12.3 )] . 2.3 Recommended Dosage with Certain Coadministered Drugs The dolutegravir dose (50 mg) in DOVATO is insufficient when coadministered with drugs listed in Table 1 that may decrease dolutegravir concentrations; the following dolutegravir dosage regimen is recommended. Table 1. Dosing Recommendations for DOVATO with Coadministered Drugs Coadministered Drug Dosing Recommendation Carbamazepine, rifampin An additional dolutegravir 50-mg tablet, separated by 12 hours from DOVATO, should be taken. 2.4 Not Recommended in Patients with Renal Impairment Because DOVATO is a fixed-dose tablet and cannot be dose adjusted, DOVATO is not recommended in patients with creatinine clearance less than 30 mL/min [see Use in Specific Populations ( 8.6 )] . 2.5 Not Recommended in Patients with Severe Hepatic Impairment DOVATO is not recommended in patients with severe hepatic impairment (Child-Pugh Score C) [see Use in Specific Populations ( 8.7 )] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Patients co-infected with HIV-1 and HBV [see Warnings and Precautions ( 5.1 )] • Hypersensitivity reactions [see Warnings and Precautions ( 5.2 )] • Hepatotoxicity [see Warnings and Precautions ( 5.3 )] • Lactic acidosis and severe hepatomegaly with steatosis [see Warnings and Precautions ( 5.4 )] • Immune reconstitution syndrome [see Warnings and Precautions ( 5.6 )] The most common adverse reactions (all grades) observed in ≥2% (in those receiving DOVATO) were headache, nausea, diarrhea, insomnia, fatigue, and anxiety. ( 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 clinical practice. Clinical Trials in Adults with No Antiretroviral Treatment History The safety assessment of DOVATO in HIV-1–infected adults with no antiretroviral treatment history and with a plasma viral load ≤500,000 HIV-1 RNA copies/mL at the screening visit, is based on the pooled Week 144 analyses of data from 2 identical, multicenter, double-blind, controlled trials, GEMINI-1 and GEMINI-2. A total of 1,433 HIV-1–infected adults with no antiretroviral treatment history received either dolutegravir (TIVICAY) 50 mg plus lamivudine (EPIVIR) 300 mg, as a complete regimen once daily, or TIVICAY 50 mg plus fixed-dose combination tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (TRUVADA), administered once daily. The rates of adverse events leading to discontinuation in the pooled analysis were 4% of subjects who received TIVICAY plus EPIVIR and 5% in subjects who received TIVICAY plus TRUVADA. The most common adverse events leading to discontinuation were psychiatric disorders: 2% of subjects who received TIVICAY plus EPIVIR and 1% in subjects who received TIVICAY plus TRUVADA. Adverse reactions (all grades) observed in at least 2% of subjects in either treatment arm of the Week 144 pooled analysis from GEMINI-1 and GEMINI-2 trials are provided in Table 2 . The adverse reactions observed for TIVICAY plus EPIVIR in the Week 144 analysis of the pooled data from GEMINI-1 and GEMINI-2 were generally consistent with the adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents. Table 2. Adverse Reactions (All Grades) Reported in ≥2% of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in GEMINI-1 and GEMINI-2 (Week 144 Pooled Analysis) a Fatigue: includes fatigue, asthenia, and malaise. Adverse Reaction TIVICAY plus EPIVIR (n = 716) TIVICAY plus TRUVADA (n = 717) Headache 3% 4% Nausea 2% 6% Diarrhea 2% 3% Insomnia 2% 3% Fatigue a 2% 2% Anxiety 2% 1% Dizziness 1% 2% Adverse reactions of at least Grade 2 occurring in ≥1% of subjects treated with TIVICAY plus EPIVIR were headache, anxiety, suicidal ideation, and insomnia (all at 1%). Less Common Adverse Reactions: The following adverse reactions (all grades) occurred in <2% of subjects receiving dolutegravir plus lamivudine or are from studies described in the prescribing information of the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine). Some events have been included because of their seriousness and assessment of potential causal relationship. Blood and Lymphatic Systems Disorders: Anemia, neutropenia, thrombocytopenia. Gastrointestinal Disorders: Abdominal discomfort, abdominal pain, flatulence, upper abdominal pain, vomiting. General: Fever. Hepatobiliary Disorders: Hepatitis. Immune System Disorders: Hypersensitivity, immune reconstitution syndrome. Musculoskeletal Disorders: Myositis. Nervous System Disorders: Somnolence. Psychiatric Disorders: Abnormal dreams, depression. 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, rash. Clinical Trials in Virologically Suppressed Adults The safety of DOVATO in virologically suppressed adults was based on Week 144 data from 740 subjects in a randomized, parallel-group, open-label, multicenter, non-inferiority controlled trial (TANGO). Subjects who were on a stable suppressive tenofovir alafenamide-based regimen (TBR) were randomized to receive DOVATO once daily or continue with their TBR for up to 148 weeks; at Week 148, the subjects randomized to continue with their TBR were switched to DOVATO once daily. All subjects are followed up to Week 200. Overall, the safety profile of DOVATO in virologically suppressed adult subjects in the TANGO trial was similar to that of TIVICAY plus EPIVIR in subjects with no antiretroviral treatment history in the GEMINI trials [see Clinical Studies ( 14.3 )]. Adverse reactions observed in at least 2% of subjects in the TANGO trial who were treated with DOVATO were weight increased (3%) and insomnia (2%). Laboratory Abnormalities Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity are presented in Table 3 . The mean change from baseline observed for selected lipid values is presented in Table 4 . Table 3. Selected Laboratory Abnormalities (Grades 2 to 4; Week 144 Pooled Analyses) in GEMINI-1 and GEMINI-2 Trials ULN = Upper limit of normal. Laboratory Parameter Abnormality TIVICAY plus EPIVIR (n = 716) TIVICAY plus TRUVADA (n = 717) Alanine aminotransferase (ALT) Grade 2 (2.5 to <5.0 x ULN) 4% 4% Grade 3 to 4 (≥5.0 x ULN) 4% 3% Aspartate aminotransferase (AST) Grade 2 (2.5 to <5.0 x ULN) 5% 5% Grade 3 to 4 (≥5.0 x ULN) 3% 4% Total bilirubin Grade 2 (1.6 to <2.6 x ULN) 3% 4% Grade 3 to 4 (≥2.6 x ULN) 1% 1% Creatine kinase Grade 2 (6.0 to <10 x ULN) 5% 5% Grade 3 to 4 (≥10.0 x ULN) 8% 9% Hyperglycemia (glucose) Grade 2 (126 to 250 mg/dL) 11% 8% Grade 3 to 4 (>250 mg/dL) 1% 1% Hypophosphatemia (phosphate) Grade 2 (1.4 to <2.0 mg/dL) 11% 12% Grade 3 to 4 (<1.4 mg/dL) 1% 2% Lipase Grade 2 (1.5 to <3.0 x ULN) 7% 8% Grade 3 to 4 (≥3.0 x ULN) 3% 5% Table 4. Mean Change from Baseline in Fasted Lipid Values (Week 144 Pooled Analyses a ) in GEMINI 1 and GEMINI 2 Trials HDL = High density lipoprotein; LDL = Low density lipoprotein. a Subjects on lipid-lowering agents at baseline are excluded (TIVICAY plus EPIVIR, n = 30; TIVICAY plus TRUVADA, n = 23). The last available fasted, on-treatment lipid value prior to initiation of a lipid-lowering agent was carried forward in place of observed values after initiation of a lipid-lowering agent. A total of 51 and 28 subjects receiving TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively, initiated lipid-lowering agents post-baseline. Laboratory Parameter Preferred Term TIVICAY plus EPIVIR (n = 716) TIVICAY plus TRUVADA (n = 717) Cholesterol (mg/dL) 15 -2 HDL cholesterol (mg/dL) 7 4 LDL cholesterol (mg/dL) 7 -4 Triglycerides (mg/dL) 10 -9 Total cholesterol/HDL cholesterol ratio -0.2 -0.4 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 in both arms and remained stable through 144 weeks. A mean change from baseline of 0.144 mg/dL and 0.176 mg/dL was observed after 144 weeks of treatment with TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively. These changes are not considered to be clinically relevant. Clinical Trial Experience in Adolescents The safety of DOVATO was evaluated in HIV‑1–infected treatment-naïve subjects between 12 to less than 18 years of age and weighing at least 25 kg (N = 32) through Week 48, in an open label clinical trial, DANCE (Trial 205861). Overall, the observed safety profile in adolescent subjects was similar to those seen in adults [see Use in Specific Populations ( 8.4 ), and Clinical Studies ( 14.4 )] . 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving a dolutegravir- or lamivudine-containing regimen. Because postmarketing 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. Body as a Whole Redistribution/accumulation of body fat. Endocrine and Metabolic Hyperglycemia. General Weakness. Hemic and Lymphatic Anemia (including pure red cell aplasia, sideroblastic anemia, and severe anemias progressing on therapy). Hepatic and Pancreatic Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbations of HBV [see Warnings and Precautions ( 5.1 , 5.4 )] . Hepatobiliary Disorders Acute liver failure, hepatotoxicity. Hypersensitivity Anaphylaxis, urticaria. Investigations Weight increased. Musculoskeletal Arthralgia, creatinine phosphokinase (CPK) elevation, muscle weakness, myalgia, rhabdomyolysis. Nervous System Paresthesia, peripheral neuropathy. Skin Alopecia.

12.3 Pharmacokinetics The C max , C trough, and AUC tau parameters of the components of DOVATO are provided in Table 6 . Table 6. Multiple-Dose Pharmacokinetic Parameters of the Components of DOVATO C max = Maximum concentration; C trough = Lowest concentration before administration of the next dose; AUC tau = Area under the concentration-time curve integrated across the dosing interval. a Based on dolutegravir 50-mg once-daily dosage administered to antiretroviral treatment-naive adults. b Based on lamivudine 300-mg once-daily dosage administered to healthy subjects. Parameter Mean (%CV) Dolutegravir a Lamivudine b C max (mcg/mL) 3.67 (20%) 2.04 (26%) C trough (mcg/mL) 1.11 (46%) 0.042 (38%) AUC tau (mcg · h/mL) 53.6 (27%) 8.87 (21%) The absorption, distribution, and elimination pharmacokinetic parameters of the components of DOVATO are provided in Table 7 . Table 7. Pharmacokinetic Properties of the Components of DOVATO T max = Time to maximum concentration (C max ); t 1/2 = Elimination half-life; UGT = Uridine diphosphate glucuronosyl transferase; CYP = Cytochrome P450; OCT = Organic cation transporter. a After administration of DOVATO (fasted state). b High-fat meal is approximately 900 kcal, 56% fat. c The geometric mean (90% confidence interval) AUC ratio (fed/fasted) of dolutegravir and lamivudine is 1.33 (1.18, 1.48) and 0.91 (0.87, 0.96), respectively. d Based on in vitro data. e Based on single-dose, mass balance study of radiolabeled dolutegravir. f Based on 24-hour urine collection obtained after oral or IV administration. Pharmacokinetic Parameters Dolutegravir Lamivudine Absorption T max (h), median a 2.5 1 Effect of Food High-fat meal b (relative to fasting) No clinically significant differences in the pharmacokinetics of either component (after administration of DOVATO) were observed c . Distribution Plasma protein binding d Approximately 99% 36% Blood-to-plasma ratio 0.44 - 0.54 1.1 - 1.2 Elimination t 1/2 (h) Approximately 14 13 - 19 Metabolism Metabolic pathways UGT1A1 (primary) CYP3A (minor) Not significantly metabolized Excretion Major route of elimination Metabolism Renal, by OCT system Urine (unchanged) 31% (<1%) e Approximately 70% f Feces (unchanged) 64% (53%) e − Specific Populations No clinically significant differences in the pharmacokinetics of the components of DOVATO were observed based on age, sex, or race. Pharmacokinetic data for dolutegravir and lamivudine in subjects 65 years of age and older are limited. Patients with Renal Impairment: The pharmacokinetics for the individual components of DOVATO have been evaluated in patients with renal impairment. See the U.S. prescribing information for the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine). Patients with Hepatic Impairment: The pharmacokinetics for the individual components of DOVATO have been evaluated in patients with varying degrees of hepatic impairment. See the U.S. prescribing information for the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine). Pediatric Subjects: In adolescents receiving DOVATO, dolutegravir and lamivudine exposures were higher as compared to adults; however, the differences in exposure were not considered clinically significant. Lamivudine and dolutegravir exposures were within the observed ranges at the recommended doses in adults and pediatrics receiving the individual components of DOVATO ( Table 8 ). Table 8. Pharmacokinetic Parameters Following Dovato in Adolescent Subjects 12 to Less than 18 Years of Age Weighing at Least 25 kg (n = 32) Age/weight Dose Pharmacokinetic Parameter Estimates Geometric Mean (CV%) AUC (0-24) mcg·h/mL C max mcg/mL C 24 mcg/mL 12 to <18 years of age and ≥25 kg Dolutegravir 50 mg once daily 78.2 (91.6) 6.71 (69.5) 1.46 (154) 12 to <18 years of age and ≥25 kg Lamivudine 300 mg once daily 14.7 (112) 2.95 (82.8) 0.106 (312) Pregnant women: Lamivudine: Lamivudine pharmacokinetics were studied in 36 pregnant women during 2 clinical trials conducted in South Africa. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. Drug Interaction Studies Clinical Studies: No drug interaction studies were conducted with DOVATO. The drug interaction studies described below were conducted with dolutegravir or lamivudine when used alone. Table 9 summarizes the effects of dolutegravir on the pharmacokinetics of coadministered drugs. Table 10 summarizes the effect of other drugs on the pharmacokinetics of dolutegravir when used alone and Table 11 summarizes the effect of sorbitol on the pharmacokinetics of lamivudine when used alone. Table 9. Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs a Organic cation transporter (OCT)2 or multidrug and toxin extrusion (MATE)1 substrate. b Norelgestromin is the active metabolite of norgestimate. Coadministered Drug(s) and Dose(s) Dose of Dolutegravir Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00 C max AUC C tau or C 24 Ethinyl estradiol 0.035 mg 50 mg twice daily 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 0.64 (0.44, 0.93) 0.81 (0.67, 0.97) 0.86 (0.79, 0.93) Metformin a 500 mg twice daily 50 mg once daily 1.66 (1.53 to 1.81) 1.79 (1.65 to 1.93) _ Metformin a 500 mg twice daily 50 mg twice daily 2.11 (1.91 to 2.33) 2.45 (2.25 to 2.66) _ Methadone 16 to 150 mg 50 mg twice daily 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 _ 0.95 (0.79 to 1.15) _ Norelgestromin b 0.25 mg 50 mg twice daily 0.89 (0.82 to 0.97) 0.98 (0.91 to 1.04) 0.93 (0.85 to 1.03) Sofosbuvir 400 mg once daily Metabolite (GS-331007) 50 mg once daily 0.88 (0.80, 0.98) 1.01 (0.93, 1.10) 0.92 (0.85, 0.99) 0.99 (0.97, 1.01) NA 0.99 (0.97, 1.01) Velpatasvir 100 mg once daily 50 mg once daily 0.94 (0.86, 1.02) 0.91 (0.84, 0.98) 0.88 (0.82, 0.94) No clinically significant differences in the pharmacokinetics of tenofovir (organic anion transporter [OAT]1 and OAT3 substrates) or para-amino hippurate (OAT1 and OAT3 substrates) were observed when coadministered with dolutegravir. No clinically significant differences in the pharmacokinetics of trimethoprim/sulfamethoxazole were observed when coadministered with lamivudine. Table 10. Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir a Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. b 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 Dolutegravir Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 C max AUC C τau or C 24 Antacid (MAALOX) simultaneous administration 50-mg single dose 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 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 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 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 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 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 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 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 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 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 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 1.06 (0.99 to 1.14) 1.11 (1.03 to 1.20) 1.17 (1.06 to 1.28) Rifampin a 600 mg once daily 50 mg twice daily 0.57 (0.49 to 0.65) 0.46 (0.38 to 0.55) 0.28 (0.23 to 0.34) Rifampin b 600 mg once daily 50 mg twice daily 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 1.16 (0.98 to 1.37) 0.95 (0.82 to 1.10) 0.70 (0.57 to 0.87) Table 11. Effect of Sorbitol on the Pharmacokinetics of Lamivudine C max = Maximum concentration; AUC(0-24) = Area under the concentration-time curve integrated from time of administration to 24 hours; AUC(inf) = Area under the concentration-time curve from the time of administration to infinity. a Coadministered with a single dose of lamivudine 300 mg. Coadministered Drug and Dose a Lamivudine Pharmacokinetic Parameters (% Decreased) C max AUC 0-24 AUC inf Sorbitol (Excipient) 3.2 grams 28% 20% 14% 10.2 grams 52% 39% 32% 13.4 grams 55% 44% 36% No clinically significant differences in the pharmacokinetics of lamivudine were observed when coadministered with trimethoprim (MATE1, MATE2-K, and OCT2 inhibitor)/sulfamethoxazole, interferon alfa, or ribavirin. In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically: Dolutegravir: Dolutegravir does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A. Dolutegravir does not induce CYP1A2, CYP2B6, or CYP3A4. Dolutegravir is a substrate of UGT1A3 and UGT1A9. Dolutegravir does not inhibit UGT1A1 or UGT2B7. Dolutegravir is a substrate of BCRP and P-gp. Dolutegravir does not inhibit P‑gp, BCRP, bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. Dolutegravir is not a substrate of OATP1B1 or OATP1B3. Lamivudine : Lamivudine is a substrate of P-gp and BCRP. Lamivudine does not inhibit OATP1B1/3, BCRP, P-gp, MATE1, MATE2-K, OCT1, OCT2, or OCT3.