Etravirine

1 INDICATIONS AND USAGE Etravirine, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients and pediatric patients 2 years of age and older [see Microbiology (12.4) and Clinical Studies (14) ] Etravirine is a human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated for treatment of HIV-1 infection in treatment-experienced patients 2 years of age and older. (1)

2 DOSAGE AND ADMINISTRATION Adult patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. ( 2.1 , 2.2 , 2.4 ) Pregnant patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. ( 2.2 ) Pediatric patients (2 years to less than 18 years of age and weighing at least 10 kg): dosage of etravirine is based on body weight and should not exceed the recommended adult dose. Etravirine tablets should be taken following a meal. ( 2.3 ) 2.1 Recommended Dosage in Adult Patients The recommended oral dosage of etravirine for adult patients is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. The type of food does not affect the exposure to etravirine [see Clinical Pharmacology (12.3) ] . 2.2 Recommended Dosage During Pregnancy The recommended oral dosage of etravirine for pregnant individuals is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal [see Use in Specific Populations (8.1) ] 2.3 Recommended Dosage in Pediatric Patients (2 Years to Less Than 18 Years of Age) The recommended dosage of etravirine for pediatric patients 2 years to less than 18 years of age and weighing at least 10 kg is based on body weight (see Table 1) not exceeding the recommended adult dosage. Etravirine should be taken orally, following a meal. The type of food does not affect the exposure to etravirine [see Clinical Pharmacology (12.3) ] . Table 1: Recommended Dosage of Etravirine Tablets for Pediatric Patients 2 Years to Less Than 18 Years of Age Body Weight kilograms (kg) Dose greater than or equal to 10 kg to less than 20 kg 100 mg twice daily greater than or equal to 20 kg to less than 25 kg 125 mg twice daily greater than or equal to 25 kg to less than 30 kg 150 mg twice daily greater than or equal to 30 kg 200 mg twice daily 2.4 Method of Administration Instruct patients to swallow the etravirine tablet(s) whole with liquid such as water. Patients who are unable to swallow the etravirine tablet(s) whole may disperse the tablet(s) in water. Instruct the patient to do the following: place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication, stir well until the water looks milky, add approximately 15 mL (1 tablespoon) of liquid. Water may be used but other liquids, such as orange juice or milk, may improve taste. Patients should not place the tablets in orange juice or milk without first adding water. The use of warm (temperature greater than 104°F [greater than 40°C]) or carbonated beverages should be avoided. drink the mixture immediately, rinse the glass several times with orange juice, milk or water and completely swallow the rinse each time to make sure the patient takes the entire dose.

6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: Severe skin and hypersensitivity reactions [see Warnings and Precautions (5.1) ] . Immune reconstitution syndrome [see Warnings and Precautions (5.3) ] . The most common adverse drug reactions of moderate to severe intensity (at least 2%) which occurred at a higher rate than placebo in adults are rash and peripheral neuropathy. ( 6.1 ) The most common adverse drug reactions in at least 2% of pediatric patients are rash and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Carnegie Pharmaceuticals, LLC at 1-732-783-7010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Adults The safety assessment is based on all data from 1203 subjects in the Phase 3 placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received etravirine tablets (200 mg twice daily). In these pooled trials, the median exposure for subjects in the etravirine tablets arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the etravirine tablets arm and 2.6% in the placebo arm. The most frequently reported ADR at least Grade 2 in severity was rash (10.0%). Stevens-Johnson syndrome, drug hypersensitivity reaction and erythema multiforme were reported in less than 0.1% of subjects during clinical development with etravirine tablets [see Warnings and Precautions (5.1) ] . A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving etravirine tablets discontinued due to rash. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1 to 2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the etravirine tablets arm in the Phase 3 trials (rash ≥ Grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men) [see Warnings and Precautions (5.1) ] . Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of etravirine tablets-related rash compared to patients without a history of NNRTI- related rash. Common Adverse Reactions Clinical ADRs of moderate intensity or greater (greater than or equal to Grade 2) and reported in at least 2% of subjects treated with etravirine tablets and occurring at a higher rate compared to placebo (excess of 1%) are presented in Table 2. Laboratory abnormalities considered ADRs are included in Table 3. Table 2: Adverse Drug Reactions (Grades 2 to 4) in at Least 2% of Adult Subjects (Pooled TMC125-C206 and TMC125-C216 Trials) Preferred Term Etravirine tablets + BR N=599 % Placebo + BR N=604 % Rash 10% 3% Peripheral neuropathy 4% 2% N=total number of subjects per treatment group; BR=background regimen Less Common Adverse Reactions Treatment-emergent ADRs occurring in less than 2% of subjects (599 subjects) receiving etravirine tablets and of at least moderate intensity (greater than or equal to Grade 2) are listed below by body system: Cardiac Disorders : myocardial infarction, angina pectoris, atrial fibrillation Ear and Labyrinth Disorders : vertigo Eye Disorders : blurred vision Gastrointestinal Disorders : gastroesophageal reflux disease, flatulence, gastritis, abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitis General Disorders and Administration Site Conditions : sluggishness Hematologic Disorders : hemolytic anemia Hepatobiliary Disorders : hepatic failure, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis Immune System Disorders : drug hypersensitivity, immune reconstitution syndrome Metabolism and Nutrition Disorders : diabetes mellitus, anorexia, dyslipidemia Nervous System Disorders : paresthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor Psychiatric Disorders : anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness,, nightmares Renal and Urinary Disorders: acute renal failure Reproductive System and Breast Disorders : gynecomastia Respiratory, Thoracic and Mediastinal Disorders : exertional dyspnea, bronchospasm Skin and Subcutaneous Tissue Disorders : night sweats, lipohypertrophy, prurigo, hyperhidrosis, dry skin, swelling face Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and hemorrhagic stroke, each reported in no more than 0.5% of subjects. Laboratory Abnormalities in Treatment-Experienced Patients Selected Grade 2 to Grade 4 laboratory abnormalities that represent a worsening from baseline observed in adult subjects treated with etravirine tablets are presented in Table 3. Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Observed in Treatment-Experienced Subjects (Pooled TMC125-C206 and TMC125- C216 Trials) Laboratory Parameter DAIDS Toxicity Range Etravirine tablets + BR N=599 % Placebo + BR N=604 % GENERAL BIOCHEMISTRY Pancreatic amylase Grade 2 > 1.5–2 × ULN 7% 8% Grade 3 > 2–5 × ULN 7% 8% Grade 4 5 × ULN 2% 1% Lipase Grade 2 > 1.5–3 × ULN 4% 6% Grade 3 > 3–5 × ULN 2% 2% Grade 4 5 × ULN 1% < 1% Creatinine Grade 2 > 1.4–1.8 × ULN 6% 5% Grade 3 > 1.9–3.4 × ULN 2% 1% Grade 4 > 3.4 × ULN 0% < 1% HEMATOLOGY Decreased hemoglobin Grade 2 90–99 g/L 2% 4% Grade 3 70–89 g/L < 1% < 1% Grade 4 < 70 g/L < 1% < 1% White blood cell count Grade 2 1,500–1,999/mm 3 2% 3% Grade 3 1,000–1,499/mm 3 1% 4% Grade 4 < 1,000/mm 3 1% < 1% Neutrophils Grade 2 750–999/mm 3 5% 6% Grade 3 500–749/mm 3 4% 4% Grade 4 < 500/mm 3 2% 3% Platelet count Grade 2 50,000– 99,999/mm 3 3% 5% Grade 3 25,000– 49,999/mm 3 1% 1% Grade 4 < 25,000/mm 3 < 1% < 1% LIPIDS AND GLUCOSE Total cholesterol Grade 2 > 6.20–7.77 mmol/L 240–300 mg/dL 20% 17% Grade 3 > 7.77 mmol/L 300 mg/dL 8% 5% Low density lipoprotein Grade 2 4.13–4.9 mmol/L 160–190 mg/dL 13% 12% Grade 3 > 4.9 mmol/L > 190 mg/dL 7% 7% Triglycerides Grade 2 5.65–8.48 mmol/L 500–750 mg/dL 9% 7% Grade 3 8.49–13.56 mmol/L 751–1200 mg/dL 6% 4% Grade 4 > 13.56 mmol/L > 1200 mg/dL 4% 2% Elevated glucose levels Grade 2 6.95–13.88 mmol/L 161–250 mg/dL 15% 13% Grade 3 13.89–27.75 mmol/L 251–500 mg/dL 4% 2% Grade 4 > 27.75 mmol/L > 500 mg/dL 0% < 1% HEPATIC PARAMETERS Alanine amino transferase Grade 2 2.6–5 × ULN 6% 5% Grade 3 5.1–10 × ULN 3% 2% Grade 4 > 10 × ULN 1% < 1% Aspartate amino transferase Grade 2 2.6–5 × ULN 6% 8% Grade 3 5.1–10 × ULN 3% 2% Grade 4 > 10 × ULN < 1% < 1% ULN=Upper Limit of Normal; BR=background regimen Patients Co-Infected With Hepatitis B and/or Hepatitis C Virus In Phase 3 trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1129 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis B and/or hepatitis C virus co-infected subjects for both treatment groups. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 27.8%, 25.0% and 7.1% respectively, of etravirine tablets-treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected etravirine tablets-treated subjects. In general, adverse events reported by etravirine tablets-treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to etravirine tablets-treated subjects without hepatitis B and/or hepatitis C virus co-infection. Clinical Trials Experience in Pediatric Subjects (2 Years to Less Than 18 years of age) The safety assessment in pediatric subjects is based on two single-arm trials. TMC125-C213 is a Phase 2 trial in which 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to less than 18 years of age received etravirine tablets in combination with other antiretroviral agents (Week 24 analysis). TMC125-C234/IMPAACT P1090 is a Phase 1/2 trial in which 20 antiretroviral treatment- experienced HIV-1 infected pediatric subjects 2 years to less than 6 years of age received etravirine tablets in combination with other antiretroviral agents (Week 24 analysis) [see Clinical Studies (14.2) ] . In TMC125-C213, the frequency, type and severity of adverse drug reactions in pediatric subjects 6 years to less than 18 years of age were comparable to those observed in adult subjects, except for rash which was observed more frequently in pediatric subjects. The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea. Rash was reported more frequently in female subjects than in male subjects (rash ≥ Grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males; discontinuations due to rash were reported in 4/64 [6.3%] females versus 0/37 [0%] males). Rash (greater than or equal to Grade 2) occurred in 15% of pediatric subjects from 6 years to less than 18 years of age. In the majority of cases, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was self-limiting and generally resolved within 1 week on continued therapy. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile for subjects who completed 24 weeks of treatment. In TMC125-C234/IMPAACT P1090, the frequency, type and severity of adverse drug reactions in pediatric subjects 2 years to less than 6 years of age through Week 24 were comparable to those observed in adults. The most common adverse drug reactions (any grade) of pediatric subjects were rash (50% [10/20]) and diarrhea (25% [5/20]). In this age group, no subjects had Grade 3 or Grade 4 rash and no subjects discontinued prematurely due to rash. One subject discontinued etravirine due to asymptomatic lipase elevation. 6.2 Postmarketing Experience The following events have been identified during postmarketing use of etravirine tablets. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders : Severe hypersensitivity reactions including DRESS and cases of hepatic failure have been reported [see Warnings and Precautions (5.1) ] . Musculoskeletal and Connective Tissue Disorders : rhabdomyolysis Skin and Subcutaneous Tissue Disorders : Fatal cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.1) ] .

12.3 Pharmacokinetics The pharmacokinetic properties of etravirine tablets were determined in healthy adult subjects and in treatment-experienced HIV-1-infected adult and pediatric subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1-infected subjects (Table 5) than in healthy subjects. Table 5: Population Pharmacokinetic Estimates of Etravirine 200 mg Twice Daily in HIV-1-Infected Adult Subjects (Integrated Data from Phase 3 Trials at Week 48) All HIV- 1- infected subjects enrolled in Phase 3 clinical trials received darunavir/ritonavir 600/100 mg twice daily as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in Table 5 account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of etravirine tablets with darunavir/ritonavir. Parameter Etravirine N=575 AUC 12h (ng·h/mL) Geometric mean ± standard deviation 4522 ± 4710 Median (range) 4380 (458-59084) C 0h (ng/mL) Geometric mean ± standard deviation 297 ± 391 Median (range) 298 (2-4852) Note: The median protein binding adjusted EC50 for MT4 cells infected with HIV-1/IIIB in vitro equals 4 ng/mL. Absorption and Bioavailability Following oral administration, Etravirine was absorbed with a T max of about 2.5 to 4 hours. The absolute oral bioavailability of etravirine tablets are unknown. In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH. Effects of Food on Oral Absorption The systemic exposure (AUC) to etravirine was decreased by about 50% when etravirine tablets were administered under fasting conditions, as compared to when etravirine tablets were administered following a meal. Within the range of meals studied, the systemic exposures to etravirine were similar. The total caloric content of the various meals evaluated ranged from 345 kilocalories (17 grams fat) to 1160 kilocalories (70 grams fat). Distribution Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha 1-acid glycoprotein (97.66% to 99.02%) in vitro . The distribution of etravirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans. Metabolism In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes metabolism by CYP3A, CYP2C9, and CYP2C19 enzymes. The major metabolites, formed by methyl hydroxylation of the dimethylbenzonitrile moiety, were at least 90% less active than etravirine against wild-type HIV in cell culture. Elimination After single dose oral administration of 800 mg 14 C-etravirine, 93.7% and 1.2% of the administered dose of 14 C-etravirine was recovered in the feces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The mean (± standard deviation) terminal elimination half-life of etravirine was about 41 (±20) hours. Specific Populations Geriatric Patients Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different within the age range (18 to 77 years) evaluated [see Use in Specific Populations (8.5) ]. Pediatric Patients The pharmacokinetics of etravirine in 115 treatment-experienced HIV-1-infected pediatric subjects, 2 years to less than 18 years of age showed that the administered weight-based dosages resulted in etravirine exposure comparable to that in adults receiving etravirine tablets 200 mg twice daily [see Dosage and Administration (2.3) ]. The pharmacokinetic parameters for etravirine (AUC 12h and C 0h ) are summarized in Table 6. Table 6: Pharmacokinetic Parameters for Etravirine in Treatment- Experienced HIV-1-Infected Pediatric Subjects 2 Years to Less Than 18 Years of Age (TMC125-C213 [Population PK] and TMC125- C234/P1090) Study TMC125-C213 TMC125- C234/IMPAACT P1090 Age Range (years) (6 years to less than 18 years) (2 years to less than 6 years) Parameter N=101 N=14 AUC 12h (ng·h/mL) Geometric mean ± standard deviation 3742 ± 4314 3504 ± 2923 Median (range) 4499 (62-28865) 3579 (1221-11815) C 0h (ng/mL) Geometric mean ± standard deviation 205 ± 342 183 ± 240 Median (range) 287 (2-2276) 162 (54-908) The pharmacokinetics and dose of etravirine in pediatric subjects less than 2 years of age have not been established [see Use in Specific Populations (8.4) ]. Male and Female Patients No significant pharmacokinetic differences have been observed between males and females. Racial or Ethnic Groups Population pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine. Patients with Renal Impairment The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from a mass balance study with 14 C-etravirine showed that less than 1.2% of the administered dose of etravirine is excreted in the urine as metabolites. No unchanged drug was detected in the urine. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis [see Use in Specific Populations (8.7) ]. Patients with Hepatic Impairment Etravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of etravirine tablets to subjects with normal hepatic function (16 subjects), mild hepatic impairment (Child-Pugh Class A, 8 subjects), and moderate hepatic impairment (Child-Pugh Class B, 8 subjects). The effect of severe hepatic impairment on the pharmacokinetics of etravirine has not been evaluated [see Use in Specific Populations (8.6) ]. Pregnancy and Postpartum After intake of etravirine tablets 200 mg twice daily in combination with other antiretroviral agents (13 subjects with 2 NRTIs, 1 subject with 2 NRTIs + lopinavir + ritonavir, 1 subject with 2 NRTIs + raltegravir), based on intra-individual comparison, the C max and AUC 12h of total etravirine were 23 to 42% higher during pregnancy compared with postpartum (612 weeks). The C min of total etravirine was 78 to 125% higher during pregnancy compared with postpartum (612 weeks), while two subjects had C min <10 ng/mL in the postpartum period (612 weeks) [C min of total etravirine was 11 to 16% higher when these 2 subjects are excluded] (see Table 7) [see Use in Specific Populations (8.1) ]. Increased etravirine exposures during pregnancy are not considered clinically significant. The protein binding of etravirine was similar (>99%) during the second trimester, third trimester, and postpartum period. Table 7: Pharmacokinetic Results of Total Etravirine After Administration of Etravirine 200 mg Twice Daily as Part of an Antiretroviral Regimen, During the 2 nd Trimester of Pregnancy, the 3 rd Trimester of Pregnancy, and Postpartum. Parameter Mean ± SD (median) Postpartum N=10 2nd Trimester N=13 3rd Trimester N=10 n=9 for AUC 12h C min , ng/mL 269 ± 182 (284) Two subjects had C min <10 ng/mL, C min was 334 ± 135 (315) in the postpartum period when these subjects were excluded from the descriptive analysis (N=8). 383 ± 210 (346) 349 ± 103 (371) C max , ng/mL 569 ± 261 (528) 774 ± 300 (828) 785 ± 238 (694) AUC 12h , ng·h/mL 5004 ± 2521 6617 ± 2766 6846 ± 1482 (5246) (6836) (6028) Patients with Hepatitis B and/or Hepatitis C Virus Co-Infection Population pharmacokinetic analysis of the TMC125-C206 and TMC125-C216 trials showed reduced clearance for etravirine in HIV-1-infected subjects with hepatitis B and/or C virus co-infection. Based upon the safety profile of etravirine tablets [see Adverse Reactions (6)] , no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus. Drug Interactions Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of etravirine tablets with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine tablets. Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-gp. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with etravirine tablets may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s). Drug interaction studies were performed with etravirine tablets and other drugs likely to be co- administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the AUC, C max , and C min values of etravirine are summarized in Table 8 (effect of other drugs on etravirine tablets). The effect of co-administration of etravirine tablets on the AUC, C max , and C min values of other drugs are summarized in Table 9 (effect of etravirine tablets on other drugs). For information regarding clinical recommendations, [see Drug Interactions (7) ]. Table 8: Drug Interactions: Pharmacokinetic Parameters for Etravirine in the Presence of Co-administered Drugs Co-administered Drug Dose/Schedule of Co-administered Drug N Exposure Mean Ratio of Etravirine Pharmacokinetic Parameters 90% CI; No Effect = 1.00 C max AUC C min CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change Co-administration with HIV protease inhibitors (PIs) Atazanavir 400 mg once daily 14 ↑ 1.47 (1.36 1.59) 1.50 (1.41 1.59) 1.58 (1.46 1.70) Atazanavir/ritonavir The systemic exposure of etravirine when co-administered with atazanavir/ritonavir in HIV infected subjects is similar to exposures of etravirine observed in the Phase 3 trials after co-administration of etravirine tablets and darunavir/ritonavir (as part of the background regimen). 300/100 mg once daily 14 ↑ 1.30 (1.17 1.44) 1.30 (1.18 1.44) 1.26 (1.12 1.42) Darunavir/ritonavir 600/100 mg twice daily 14 ↓ 0.68 (0.57 0.82) 0.63 (0.54 0.73) 0.51 (0.44 0.61) Lopinavir/ritonavir (tablet) 400/100 mg twice daily 16 ↓ 0.70 (0.64 0.78) 0.65 (0.59 0.71) 0.55 (0.49 0.62) Ritonavir 600 mg twice daily 11 ↓ 0.68 (0.55 0.85) 0.54 (0.41 0.73) N.A. Saquinavir/ritonavir 1000/100 mg twice daily 14 ↓ 0.63 (0.53 0.75) 0.67 (0.56 0.80) 0.71 (0.58 0.87) Tipranavir/ritonavir 500/200 mg twice daily 19 ↓ 0.29 (0.22 0.40) 0.24 (0.18 0.33) 0.18 (0.13 0.25) Co-administration with nucleoside reverse transcriptase inhibitors (NRTIs) Didanosine 400 mg once daily 15 ↔ 1.16 (1.02 1.32) 1.11 (0.99 1.25) 1.05 (0.93 1.18) Tenofovir disoproxil fumarate 300 mg once daily 23 ↓ 0.81 (0.75 0.88) 0.81 (0.75 0.88) 0.82 (0.73 0.91) Co-administration with CCR5 antagonists Maraviroc 300 mg twice daily 14 ↔ 1.05 (0.95 1.17) 1.06 (0.99 1.14) 1.08 (0.98 1.19) Maraviroc (when co- administered with darunavir/ritonavir) The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir. 150/600/100 mg twice daily 10 ↔ 1.08 (0.98 1.20) 1.00 (0.86 1.15) 0.81 (0.65 1.01) Co-administration with integrase strand transfer inhibitors Raltegravir 400 mg twice daily 19 ↔ 1.04 (0.971.12) 1.10 (1.031.16) 1.17 (1.101.26) Co-administration with other drugs Artemether/lumefantrine 80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours 14 ↔ 1.11 (1.06 1.17) 1.10 (1.06 1.15) 1.08 (1.04 1.14) Atorvastatin 40 mg once daily 16 ↔ 0.97 (0.93 1.02) 1.02 (0.97 1.07) 1.10 (1.02 1.19) Clarithromycin 500 mg twice daily 15 ↑ 1.46 (1.38 1.56) 1.42 (1.34 1.50) 1.46 (1.36 1.58) Fluconazole 200 mg once daily in the morning 16 ↑ 1.75 (1.60 1.91) 1.86 (1.73 2.00) 2.09 (1.90 2.31) Omeprazole 40 mg once daily 18 ↑ 1.17 (0.96 1.43) 1.41 (1.22 1.62) N.A. Paroxetine 20 mg once daily 16 ↔ 1.05 (0.96 1.15) 1.01 (0.93 1.10) 1.07 (0.98 1.17) Ranitidine 150 mg twice daily 18 ↓ 0.94 (0.75 1.17) 0.86 (0.76 0.97) N.A. Rifabutin 300 mg once daily 12 ↓ 0.63 (0.53 0.74) 0.63 (0.54 0.74) 0.65 (0.56 0.74) Voriconazole 200 mg twice daily 16 ↑ 1.26 (1.16 1.38) 1.36 (1.25 1.47) 1.52 (1.41 1.64) Table 9: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Etravirine Tablets Co-administered Drug Dose/Schedule of Co-administered Drug N Exposure Mean Ratio of Co-administered Drug Pharmacokinetic Parameters 90% CI; No effect = 1.00 C max AUC C min CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change Co-administration with HIV protease inhibitors (PIs) Atazanavir 400 mg once daily 14 ↓ 0.97 (0.73 1.29) 0.83 (0.63 1.09) 0.53 (0.38 0.73) Atazanavir/ritonavir 300/100 mg once daily 13 ↓ 0.97 (0.89 1.05) 0.86 (0.79 0.93) 0.62 (0.55 0.71) Atazanavir/ritonavir HIV-infected subjectsHIV-infected subjects 300/100 mg once daily 20 ↓ 0.96 (0.80 1.16) 0.96 (0.76 1.22) 0.82 (0.55 1.22) Darunavir/ritonavir 600/100 mg twice daily 15 ↔ 1.11 (1.01 1.22) 1.15 (1.05 1.26) 1.02 (0.90 1.17) Fosamprenavir/ritonavir 700/100 mg twice daily 8 ↑ 1.62 (1.47 1.79) 1.69 (1.53 1.86) 1.77 (1.39 2.25) Lopinavir/ritonavir (tablet) 400/100 mg twice daily 16 ↔ 0.89 (0.82 0.96) 0.87 (0.83 0.92) 0.80 (0.73 0.88) Saquinavir/ritonavir 1000/100 mg twice daily 15 ↔ 1.00 (0.70 1.42) 0.95 (0.64 1.42) 0.80 (0.46 1.38) Tipranavir/ritonavir 500/200 mg twice daily 19 ↑ 1.14 (1.02 1.27) 1.18 (1.03 1.36) 1.24 (0.96 1.59) Co-administration with nucleoside reverse transcriptase inhibitors (NRTIs) Didanosine 400 mg once daily 14 ↔ 0.91 (0.58 1.42) 0.99 (0.79 1.25) N.A. Tenofovir disoproxil fumarate 300 mg once daily 19 ↔ 1.15 (1.04 1.27) 1.15 (1.09 1.21) 1.19 (1.13 1.26) Co-administration with CCR5 antagonists Maraviroc 300 mg twice daily 14 ↓ 0.40 (0.28 0.57) 0.47 (0.38 0.58) 0.61 (0.53 0.71) Maraviroc (when co- administered with darunavir/ritonavir) compared to maraviroc 150 mg twice dailycompared to maraviroc 150 mg twice daily 150/600/100 mg twice daily 10 ↑ 1.77 (1.20 2.60) 3.10 (2.57 3.74) 5.27 (4.51 6.15) Co-administration with integrase strand transfer inhibitors Dolutegravir 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) Dolutegravir (when co- administered with darunavir/ritonavir) 50 mg once daily + 600/100 mg twice daily 9 ↓ 0.88 (0.78 to 1.00) 0.75 (0.69 to 0.81) 0.63 (0.52 to 0.76) Dolutegravir (when co- administered with lopinavir/ritonavir 50 mg once daily + 400/100 mg twice daily 8 ↔ 1.07 (1.02 to 1.13) 1.11 (1.02 to 1.20) 1.28 (1.13 to 1.45) Raltegravir 400 mg twice 0.89 0.90 0.66 daily 19 ↓ (0.68 1.15) (0.68 1.18) (0.34 1.26) Co-administration with other drugs Artemether Dihydroartemisinin Lumefantrine 80/480 mg, 6 doses at 0, 8, 24, 36, 48, and 60 hours 15 15 15 ↓ ↓ ↓ 0.72 (0.55 0.94) 0.84 (0.71 0.99) 1.07 (0.94 1.23) 0.62 (0.48 0.80) 0.85 (0.75 0.97) 0.87 (0.77 0.98) 0.82 (0.67 1.01) 0.83 (0.71 0.97) 0.97 (0.83 1.15) Atorvastatin 2-hydroxy-atorvastatin 40 mg once daily 16 16 ↓ ↑ 1.04 (0.84 1.30) 1.76 (1.60 1.94) 0.63 (0.58 0.68) 1.27 (1.19 1.36) N.A. N.A. Buprenorphine Norbuprenorphine Individual dose regimen ranging from 4/1 mg to 16/4 mg once daily 16 16 ↓ ↔ 0.89 (0.76 1.05) 1.08 (0.95 1.23) 0.75 (0.66 0.84) 0.88 (0.81 0.96) 0.60 (0.52 0.68) 0.76 (0.67 0.87) Clarithromycin 14-hydroxy- clarithromycin 500 mg twice daily 15 15 ↓ ↑ 0.66 (0.57 0.77) 1.33 (1.13 1.56) 0.61 (0.53 0.69) 1.21 (1.05 1.39) 0.47 (0.38 0.57) 1.05 (0.90 1.22) Digoxin 0.5 mg single dose 16 ↑ 1.19 (0.96 1.49) 1.18 (0.90 1.56) N.A. Ethinylestradiol Norethindrone 0.035 mg once daily 1 mg once daily 16 16 ↑ ↔ 1.33 (1.21 1.46) 1.05 (0.98 1.12) 1.22 (1.13 1.31) 0.95 (0.90 0.99) 1.09 (1.01 1.18) 0.78 (0.68 0.90) Fluconazole 200 mg once daily in the morning 15 ↔ 0.92 (0.85 1.00) 0.94 (0.88 1.01) 0.91 (0.84 0.98) R(-) Methadone Individual dose regimen ranging from 60 to 130 mg/day 16 ↔ 1.02 (0.96 1.09) 1.06 (0.99 1.13) 1.10 (1.02 1.19) S(+) Methadone 16 ↔ 0.89 (0.83 0.97) 0.89 (0.82 0.96) 0.89 (0.81 0.98) Paroxetine 20 mg once daily 16 ↔ 1.06 (0.95 1.20) 1.03 (0.90 1.18) 0.87 (0.75 1.02) Rifabutin 25-O-desacetylrifabutin 300 mg once daily 300 mg once daily 12 12 ↓ ↓ 0.90 (0.78 1.03) 0.85 (0.72 1.00) 0.83 (0.75 0.94) 0.83 (0.74 0.92) 0.76 (0.66 0.87) 0.78 (0.70 0.87) Sildenafil N-desmethyl-sildenafil 50 mg single dose 15 15 ↓ ↓ 0.55 (0.40 0.75) 0.75 (0.59 0.96) 0.43 (0.36 0.51) 0.59 (0.52 0.68) N.A. N.A. Voriconazole 200 mg twice daily 14 ↑ 0.95 (0.75 1.21) 1.14 (0.88 1.47) 1.23 (0.87 1.75)