Dolutegravir Sodium And Rilpivirine Hydrochloride

1 INDICATIONS AND USAGE JULUCA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (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 and no known substitutions associated with resistance to the individual components of JULUCA. JULUCA, a two-drug combination of dolutegravir, an HIV-1 integrase strand transfer inhibitor (INSTI), and rilpivirine, an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI), is indicated 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 and no known substitutions associated with resistance to the individual components of JULUCA. ( 1 )

2 DOSAGE AND ADMINISTRATION • One tablet taken orally once daily with a meal. ( 2.1 ) • Rifabutin coadministration: Take an additional 25-mg tablet of rilpivirine with JULUCA once daily with a meal for the duration of the rifabutin coadministration. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of JULUCA is one tablet taken orally once daily with a meal [see Clinical Pharmacology ( 12.3 )] . One tablet of JULUCA contains 50 mg of dolutegravir and 25 mg of rilpivirine. 2.2 Recommended Dosage with Rifabutin Coadministration If JULUCA is coadministered with rifabutin, take an additional 25-mg tablet of rilpivirine with JULUCA once daily with a meal for the duration of the rifabutin coadministration [see Drug Interactions ( 7.4 )] .

6 ADVERSE REACTIONS The following adverse reactions are described below and in other sections of the labeling: • Skin and hypersensitivity reactions [see Warnings and Precautions ( 5.1 )]. • Hepatotoxicity [see Warnings and Precautions ( 5.2 )]. • Depressive disorders [see Warnings and Precautions ( 5.3 )]. The most common adverse reactions (all grades) observed in at least 2% of subjects were diarrhea, headache, and nausea. ( 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. The safety assessment of JULUCA is based on the pooled primary Week 48 analyses of data from 2 identical, international, multicenter, open-label trials, SWORD-1 and SWORD-2, including additional follow up through Week 148. A total of 1,024 adult HIV-1-infected subjects who were on a stable suppressive antiretroviral regimen (containing 2 nucleoside reverse transcriptase inhibitors [NRTIs] plus either an integrase strand transfer inhibitor [INSTI], a non-nucleoside reverse transcriptase inhibitor [NNRTI], or a protease inhibitor [PI]) for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine, were randomized and received treatment. Subjects were randomized 1:1 to continue their current antiretroviral regimen or be switched to dolutegravir plus rilpivirine administered once daily. Subjects originally assigned to continue their current antiretroviral regimen and who remained virologically suppressed at Week 48 switched to dolutegravir plus rilpivirine at Week 52. In the pooled analyses, the proportion of subjects who discontinued treatment due to an adverse event through Week 48 was 4% in subjects receiving dolutegravir plus rilpivirine once daily and less than 1% in subjects who remained on their current antiretroviral regimen. The most common adverse events leading to discontinuation through Week 48 were psychiatric disorders: 2% of subjects receiving dolutegravir plus rilpivirine and less than 1% on the current antiretroviral regimen. In the pooled analyses, the proportion of subjects receiving dolutegravir plus rilpivirine who discontinued treatment due to an adverse event through Week 148 was 8%. The most common adverse reactions (ARs) (all grades) reported in at least 2% of subjects in the Week 48 pooled analyses from SWORD-1 and SWORD-2 are provided in Table 2 . Table 2. Adverse Reactions (Grades 1 to 4) Reported in at Least 2% of Virologically Suppressed Subjects with HIV-1 Infection in SWORD-1 and SWORD-2 Trials (Week 48 Pooled Analyses) Adverse Reaction Dolutegravir plus Rilpivirine (n = 513) Current Antiretroviral Regimen (n = 511) Diarrhea 2% <1% Headache 2% 0 In the Week 148 pooled analyses, the only adverse reaction (all grades) occurring in at least 2% of subjects who received dolutegravir plus rilpivirine and that was not observed during the Week 48 analyses was nausea (2%). Less Common Adverse Reactions The following ARs occurred in less than 2% of subjects receiving dolutegravir plus rilpivirine or are from studies described in the prescribing information of the individual components, TIVICAY (dolutegravir) and EDURANT (rilpivirine). Some events have been included because of their seriousness and assessment of potential causal relationship. General Disorders: Fatigue. Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, nausea, upper abdominal pain, vomiting. Hepatobiliary Disorders: Cholecystitis, cholelithiasis, hepatitis. Immune System Disorders: Immune reconstitution syndrome. Metabolism and Nutrition Disorders: Decreased appetite. Musculoskeletal Disorders: Myositis. Nervous System Disorders: Dizziness, somnolence. Psychiatric Disorders: Depressive disorders including depressed mood; 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. Other reported psychiatric adverse reactions include anxiety, insomnia, sleep disorders, and abnormal dreams. Renal and Urinary Disorders: Glomerulonephritis membranous, glomerulonephritis mesangioproliferative, nephrolithiasis, renal impairment. Skin and Subcutaneous Tissue Disorders: Pruritus, rash. Laboratory Abnormalities Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects in the Week 48 pooled analysis are presented in Table 3 . Table 3. Selected Laboratory Abnormalities (Grades 2 and 3 to 4; Week 48 Pooled Analyses) in SWORD-1 and SWORD-2 Trials ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; ULN = Upper limit of normal. Laboratory Parameter Preferred Term Dolutegravir plus Rilpivirine (n = 513) Current Antiretroviral Regimen (n = 511) ALT Grade 2 (>2.5-5.0 x ULN) 2% <1% Grade 3 to 4 (>5.0 x ULN) <1% <1% AST Grade 2 (>2.5-5.0 x ULN) <1% 2% Grade 3 to 4 (>5.0 x ULN) <1% <1% Total Bilirubin Grade 2 (1.6-2.5 x ULN) 2% 4% Grade 3 to 4 (>2.5 x ULN) 0 3% Creatine kinase Grade 2 (6.0-9.9 x ULN) <1% <1% Grade 3 to 4 (≥10.0 x ULN) 1% 2% Hyperglycemia Grade 2 (126-250 mg/dL) 4% 5% Grade 3 to 4 (>250 mg/dL) <1% <1% Lipase Grade 2 (>1.5-3.0 x ULN) 5% 5% Grade 3 to 4 (>3.0 x ULN) 2% 2% In the Week 148 pooled analyses, there were no additional selected laboratory abnormalities with dolutegravir plus rilpivirine compared with those shown in Table 3 . Changes in Serum Creatinine: Dolutegravir and rilpivirine have 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 with dolutegravir plus rilpivirine and remained stable through 148 weeks. Mean changes from baseline of 0.093 mg/dL (range: -0.30 to 0.58 mg/dL) and 0.112 mg/dL (range: -0.24 to 0.81 mg/dL) were observed after 48 and 148 weeks of treatment with dolutegravir plus rilpivirine, respectively. These changes are not considered to be clinically relevant. Serum Lipids: At 48 weeks, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and total cholesterol to HDL ratio were similar between the treatment arms, with no further notable changes beyond Week 48. Bone Mineral Density Effects Mean bone mineral density (BMD) increased from baseline to Week 48 in subjects who switched from an antiretroviral treatment (ART) regimen containing tenofovir disoproxil fumarate (TDF) to dolutegravir plus rilpivirine (1.34% total hip and 1.46% lumbar spine) compared with those who continued on treatment with a TDF-containing antiretroviral regimen (0.05% total hip and 0.15% lumbar spine) in a dual-energy X-ray absorptiometry (DXA) substudy. BMD declines of 5% or greater at the lumbar spine were experienced by 2% of subjects receiving JULUCA and 5% of subjects who continued their TDF-containing regimen. In subjects who received dolutegravir plus rilpivirine from study start and were continuing JULUCA at Week 148, mean BMD increases from baseline were 0.98% (total hip) and 0.53% (lumbar spine). The long-term clinical significance of these BMD changes is not known. Fractures (excluding fingers and toes) were reported in 3 (0.6%) subjects who switched to dolutegravir plus rilpivirine and 9 (1.8%) subjects who continued their current antiretroviral regimen through 48 weeks. Adrenal Function In the pooled Phase 3 trials results analysis of rilpivirine, at Week 96, there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the rilpivirine group and of -0.02 (-0.48, 0.44) micrograms/dL in the efavirenz group. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the rilpivirine group is not known. Refer to the EDURANT (rilpivirine) Prescribing Information for additional information. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving a dolutegravir- or rilpivirine-containing regimen. 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 Disorders Arthralgia, myalgia. Renal and Genitourinary Disorders Nephrotic syndrome. Skin and Subcutaneous Tissue Disorders Severe skin and hypersensitivity reactions, including DRESS .

12.3 Pharmacokinetics Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic (PK) properties of the components of JULUCA are provided in Table 5 . The multiple-dose pharmacokinetic parameters are provided in Table 6 . Table 5. Pharmacokinetic Properties of the Components of JULUCA UGT = uridine diphosphate glucuronosyltransferase; CYP = Cytochrome P450. a Geometric mean ratio (fed/fasted) in PK parameters and (90% confidence interval). High-calorie/high-fat meal = ~900 kcal, 56% fat. Moderate-fat meal = ~625 kcal, 32% fat. When rilpivirine was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal. b Dosing in mass balance studies: single-dose administration of [ 14 C] dolutegravir or [ 14 C] rilpivirine. Dolutegravir Rilpivirine Absorption T max (h) 3 4 Effect of moderate-fat meal (relative to fasting) a AUC Ratio 1.87 (1.54, 2.26) AUC Ratio 1.57 (1.24, 1.98) Effect of high-fat meal (relative to fasting) a AUC Ratio 1.87 (1.53, 2.29) AUC Ratio 1.72 (1.36, 2.16) Distribution % Bound to human plasma proteins ~99 ~99 Source of protein binding data in vitro in vitro Blood-to-plasma ratio 0.5 0.7 Metabolism Primarily metabolized UGT1A1 CYP3A (minor) CYP3A Elimination Major route of elimination Metabolism Metabolism t 1/2 (h) 14 50 % of dose excreted as total 14 C (unchanged drug) in urine b 31 (<1) 6.5 (<1) % of dose excreted as total 14 C (unchanged drug) in feces b 64 (53) 85 (25) Table 6. Multiple-Dose Pharmacokinetic Properties of the Components of JULUCA a Based on population pharmacokinetic analyses using pooled data from ART treatment-naïve adults receiving 50 mg dolutegravir once daily or 25 mg rilpivirine once daily. b Observed C max in a pharmacokinetic substudy in ART treatment-naïve adults receiving 25 mg rilpivirine once daily. Parameter Mean (CV%) Dolutegravir a Rilpivirine a C max (mcg/mL) 3.67 (20) 0.13 (54) b AUC tau (mcg/h/mL) 53.6 (27) 2.2 (38) C trough (mcg/mL) 1.11 (46) 0.08 (44) Specific Populations Pediatric Patients: The pharmacokinetics of dolutegravir plus rilpivirine has not been studied in pediatric subjects [see Use in Specific Populations ( 8.4 )] . Geriatric Patients: Population pharmacokinetic analyses from studies with the individual components indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine. Pharmacokinetic data in subjects 65 years of age and older are limited [see Use in Specific Populations ( 8.5 )] . Patients with Renal Impairment: Population pharmacokinetic analyses indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. Dolutegravir AUC, C max , and C 24 were lower by 40%, 23%, and 43%, respectively, in subjects (n = 8) with severe renal impairment (creatinine clearance less than 30 mL/min) as compared with matched healthy controls. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis [see Use in Specific Populations ( 8.6 )] . Population pharmacokinetic analyses indicated that mild renal impairment had no clinically relevant effect on the exposure of rilpivirine. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment, end-stage renal disease, or patients requiring dialysis. Patients with Hepatic Impairment: Dolutegravir exposures were similar in subjects (n = 8) with moderate hepatic impairment (Child-Pugh Score B) as compared with matched healthy controls. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied. Rilpivirine exposure was 47% higher in subjects (n = 8) with mild hepatic impairment (Child-Pugh Score A) and 5% higher in subjects (n = 8) with moderate hepatic impairment (Child-Pugh Score B) compared with matched controls. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of rilpivirine has not been studied [see Use in Specific Populations ( 8.7 )] . Patients with HBV/HCV Co-infection: Population pharmacokinetic analyses indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure of dolutegravir or rilpivirine. Subjects with hepatitis B co-infection were excluded from studies with dolutegravir plus rilpivirine. Gender and Race: Population pharmacokinetic analyses from studies with the individual components revealed that gender and race had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine. Pregnancy and Postpartum: Rilpivirine: The exposure (C 0h and AUC 24h ) to total rilpivirine after taking rilpivirine 25 mg once daily as part of an antiretroviral regimen was 30% to 40% lower during pregnancy (similar for the second and third trimesters) compared with postpartum (see Table 7 ). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials of rilpivirine-containing regimens. Based on the exposure-response relationship for rilpivirine, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and postpartum. Table 7. Pharmacokinetic Results of Rilpivirine during the 2nd and 3rd Trimesters of Pregnancy and Postpartum Period a a Total rilpivirine exposure after administration of rilpivirine 25 mg once daily as part of an antiretroviral regimen. Pharmacokinetics of Total Rilpivirine (mean ± SD) Postpartum (6 to 12 Weeks) (n = 11) 2nd Trimester of Pregnancy (n = 15) 3rd Trimester of Pregnancy (n = 13) C 0h (ng/mL) 111 ± 69.2 65.0 ± 23.9 63.5 ± 26.2 C min (ng/mL) 84.0 ± 58.8 54.3 ± 25.8 52.9 ± 24.4 C max (ng/mL) 167 ± 101 121 ± 45.9 123 ± 47.5 T max (h), median (range) 4.00 (2.03-25.08) 4.00 (1.00-9.00) 4.00 (2.00-24.93) AUC 24h (ng•h/mL) 2,714 ± 1,535 1,792 ± 711 1,762 ± 662 Drug Interaction Studies Drug interaction trials were conducted with dolutegravir or rilpivirine as individual components and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. In vitro, dolutegravir did not inhibit (IC 50 greater than 50 microM) the following: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P‑gp, 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. In vitro, dolutegravir inhibited the renal OCT2 (IC 50 = 1.93 microM) and MATE1 (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 such as dofetilide, dalfampridine, and metformin [see Contraindications ( 4 ), Drug Interactions ( 7.4 )] . 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. Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3. Rilpivirine is primarily metabolized by CYP3A. Rilpivirine 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Dosing recommendations as a result of established and other potentially significant drug-drug interactions with dolutegravir or rilpivirine are provided in Table 4 [see Drug Interactions ( 7.4 )] . Table 8. 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 Dolutegravir 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 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) 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) Table 9. Summary of 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. c The number of subjects represents the maximum number of subjects that were evaluated. Coadministered Drug(s) and Dose(s) Dose of Dolutegravir 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 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 c 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 a 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 b 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) Table 10. Summary of Effect of Rilpivirine on the Pharmacokinetics of Coadministered Drugs n = Maximum number of subjects with data; NA = Not available. a This interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the coadministered drug. b N (maximum number of subjects with data) for AUC (0-∞) = 15. c AUC (0-last) . Coadministered Drug(s) and Dose(s) Dose of Rilpivirine n Geometric Mean Ratio (90% CI) of Coadministered Drug Pharmacokinetic Parameters with/without EDURANT No Effect = 1.00 C max AUC C min Acetaminophen 500 mg single dose 150 mg once daily a 16 0.97 (0.86 to 1.10) 0.91 (0.86 to 0.97) NA Atorvastatin 40 mg once daily 150 mg once daily a 16 1.35 (1.08 to 1.68) 1.04 (0.97 to 1.12) 0.85 (0.69 to 1.03) 2-hydroxy-atorvastatin 1.58 (1.33 to 1.87) 1.39 (1.29 to 1.50) 1.32 (1.10 to 1.58) 4-hydroxy-atorvastatin 1.28 (1.15 to 1.43) 1.23 (1.13 to 1.33) NA Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg once daily a 16 0.98 (0.85 to 1.13) 1.03 (0.95 to 1.13) NA Digoxin 0.5 mg single dose 25 mg once daily 22 1.06 (0.97 to 1.17) 0.98 (0.93 to 1.04) c NA Ethinylestradiol 0.035 mg once daily 25 mg once daily 17 1.17 (1.06 to 1.30) 1.14 (1.10 to 1.19) 1.09 (1.03 to 1.16) Norethindrone 1 mg once daily 0.94 (0.83 to 1.06) 0.89 (0.84 to 0.94) 0.99 (0.90 to 1.08) Ketoconazole 400 mg once daily 150 mg once daily a 14 0.85 (0.80 to 0.90) 0.76 (0.70 to 0.82) 0.34 (0.25 to 0.46) Methadone 60-100 mg once daily, individualized dose 25 mg once daily 13 R(‑) methadone 0.86 (0.78 to 0.95) 0.84 (0.74 to 0.95) 0.78 (0.67 to 0.91) S(+) methadone 0.87 (0.78 to 0.97) 0.84 (0.74 to 0.96) 0.79 (0.67 to 0.92) Metformin 850 mg single dose 25 mg once daily 20 1.02 (0.95 to -1.10) 0.97 (0.90 to 1.06) b NA Omeprazole 20 mg once daily 150 mg once daily a 15 0.86 (0.68 to 1.09) 0.86 (0.76 to 0.97) NA Rifampin 600 mg once daily 150 mg once daily a 16 1.02 (0.93 to 1.12) 0.99 (0.92 to 1.07) NA 25-desacetylrifampin 1.00 (0.87 to 1.15) 0.91 (0.77 to 1.07) NA Sildenafil 50 mg single dose 75 mg once daily a 16 0.93 (0.80 to 1.08) 0.97 (0.87 to 1.08) NA N -desmethyl-sildenafil 0.90 (0.80 to 1.02) 0.92 (0.85 to 0.99) c NA Simeprevir 150 mg once daily 25 mg once daily 21 1.10 (0.97 to 1.26) 1.06 (0.94 to 1.19) 0.96 (0.83 to 1.11) Table 11. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Rilpivirine n = Maximum number of subjects with data; NA = Not available; ↔ = No change. a This interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the coadministered drug. b Comparison based on historic controls. Coadministered Drug(s) and Dose(s) Dose of Rilpivirine n Geometric Mean Ratio (90% CI) of Rilpivirine Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00 C max AUC C min Acetaminophen 500 mg single dose 150 mg once daily a 16 1.09 (1.01 to 1.18) 1.16 (1.10 to 1.22) 1.26 (1.16 to 1.38) Atorvastatin 40 mg once daily 150 mg once daily a 16 0.91 (0.79 to 1.06) 0.90 (0.81 to 0.99) 0.90 (0.84 to 0.96) Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg once daily a 16 1.17 (1.08 to 1.27) 1.25 (1.16 to 1.35) 1.18 (1.09 to 1.28) Ethinylestradiol/ Norethindrone 0.035 mg once daily/ 1 mg once daily 25 mg once daily 15 ↔ b ↔ b ↔ b Famotidine 40 mg single dose taken 12 hours before rilpivirine 150 mg single dose a 24 0.99 (0.84 to 1.16) 0.91 (0.78 to 1.07) NA Famotidine 40 mg single dose taken 2 hours before rilpivirine 150 mg single dose a 23 0.15 (0.12 to 0.19) 0.24 (0.20 to 0.28) NA Famotidine 40 mg single dose taken 4 hours after rilpivirine 150 mg single dose a 24 1.21 (1.06 to 1.39) 1.13 (1.01 to 1.27) NA Ketoconazole 400 mg once daily 150 mg once daily b 15 1.30 (1.13 to 1.48) 1.49 (1.31 to 1.70) 1.76 (1.57 to 1.97) Methadone 60-100 mg once daily, individualized dose 25 mg once daily 12 ↔ b ↔ b ↔ b Omeprazole 20 mg once daily 150 mg once daily a 16 0.60 (0.48 to 0.73) 0.60 (0.51 to 0.71) 0.67 (0.58 to 0.78) Rifabutin 300 mg once daily 25 mg once daily 18 0.69 (0.62 to 0.76) 0.58 (0.52 to 0.65) 0.52 (0.46 to 0.59) Rifabutin 300 mg once daily 50 mg once daily 18 1.43 (1.30 to 1.56) 1.16 (1.06 to 1.26) 0.93 (0.85 to 1.01) (reference arm for comparison was 25-mg-once-daily rilpivirine administered alone) Rifampin 600 mg once daily 150 mg once daily a 16 0.31 (0.27 to 0.36) 0.20 (0.18 to 0.23) 0.11 (0.10 to 0.13) Sildenafil 50 mg single dose 75 mg once daily a 16 0.92 (0.85 to 0.99) 0.98 (0.92 to 1.05) 1.04 (0.98 to 1.09) Simeprevir 150 mg once daily 25 mg once daily 23 1.04 (0.95 to 1.13) 1.12 (1.05 to 1.19) 1.25 (1.16 to 1.35)