Efavirenz

1 INDICATIONS & USAGE Efavirenz in combination with other antiretroviral agents is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg. Efavirenz is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 infection in adults and in pediatric patients at least 3 months old and weighing at least 3.5 kg.( 1 )

2 DOSAGE & ADMINISTRATION • Efavirenz should be taken orally once daily on an empty stomach, preferably at bedtime. ( 2 ) • Recommended adult dose: 600 mg. ( 2.2 ) • With rifampin, increase efavirenz dose to 800 mg once daily for patients weighing 50 kg or more. ( 2.2 ) • Pediatric dosing is based on weight. ( 2.3 ) 2.1 Hepatic Function Monitor hepatic function prior to and during treatment with efavirenz [ see Warnings and Precautions ( 5.9 ) ]. Efavirenz is not recommended in patients with moderate or severe hepatic impairment (Child Pugh B or C) [ see Warnings and Precautions ( 5.9 ) and Use in Specific Populations ( 8.6 ) ]. 2.2 Adults The recommended dosage of efavirenz is 600 mg orally, once daily, in combination with a protease inhibitor and/or nucleoside analogue reverse transcriptase inhibitors (NRTIs). It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. The increased efavirenz concentrations observed following administration of efavirenz with food may lead to an increase in frequency of adverse reactions [see Clinical Pharmacology ( 12.3 )]. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions ( 5.6 ), Adverse Reactions ( 6.1 ), and Patient Counseling Information ( 17 )]. Efavirenz capsules or tablets should be swallowed intact with liquid. Concomitant Antiretroviral Therapy Efavirenz must be given in combination with other antiretroviral medications [see Indications and Usage ( 1 ), Warnings and Precautions ( 5.3) , Drug Interactions ( 7.1 ), and Clinical Pharmacology ( 12.3 )]. Dosage Adjustment If efavirenz is coadministered with voriconazole, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz dose should be decreased to 300 mg once daily using the capsule formulation (one 200 mg and two 50 mg capsules or six 50 mg capsules). Efavirenz tablets must not be broken. [See Drug Interactions ( 7.1 , Table 5) and Clinical Pharmacology ( 12.3 , Tables 7 and 8] . If efavirenz is coadministered with rifampin to patients weighing 50 kg or more, an increase in the dose of efavirenz to 800 mg once daily is recommended [see Drug Interactions ( 7.1 , Table 5) and Clinical Pharmacology ( 12.3 , Table 8)]. 2.3 Pediatric Patients It is recommended that efavirenz be taken on an empty stomach, preferably at bedtime. Table 1 describes the recommended dose of efavirenz for pediatric patients 3 months of age or older and weighing between 3.5 kg and 40 kg [see Clinical Pharmacology ( 12.3 )] . The recommended dosage of efavirenz for pediatric patients weighing 40 kg or greater is 600 mg once daily. For pediatric patients who cannot swallow capsules, the capsule contents can be administered with a small amount of food or infant formula using the capsule sprinkle method of administration . Table 1: Efavirenz Dosing in Pediatric Patients Patient Body Weight Efavirenz Daily Dose Number of Capsules a or Tablets b and Strength to Administer 3.5 kg to less than 5 kg 100 mg two 50 mg capsules 5 kg to less than 7.5 kg 150 mg three 50 mg capsule 7.5 kg to less than 15 kg 200 mg one 200 mg capsule 15 kg to less than 20 kg 250 mg one 200 mg + one 50 mg capsule 20 kg to less than 25 kg 300 mg one 200 mg + two 50 mg capsules 25 kg to less than 32.5 kg 350 mg one 200 mg + three 50 mg capsules 32.5 kg to less than 40 kg 400 mg two 200 mg capsules at least 40 kg 600 mg one 600 mg tablet OR three 200 mg capsules a Capsules can be administered intact or as sprinkles [see Dosage and Administration (2.4)]. b Tablets must not be crushed

6 ADVERSE REACTIONS The most significant adverse reactions observed in patients treated with efavirenz are: •psychiatric symptoms [see Warnings and Precautions ( 5.5 )], •nervous system symptoms [see Warnings and Precautions ( 5.6 )], •rash [see Warnings and Precautions ( 5.8 )]. •hepatotoxicity [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (>5%, moderate-severe) are impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharmaceutical Ltd at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Adverse Reactions in Adults. The most common (>5% in either efavirenz treatment group) adverse reactions of at least moderate severity among patients in Study 006 treated with efavirenz in combination with zidovudine/lamivudine or indinavir were rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting Selected clinical adverse reactions of moderate or severe intensity observed in ≥2% of efavirenz-treated patients in two controlled clinical trials are presented in Table 2 Table 2: Selected Treatment-Emergent a Adverse Reactions of Moderate or Severe Intensity Reported in ≥2% of EFAVIRENZ TABLETS-Treated Patients in Studies 006 and ACTG 364 Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI- and Protease Inhibitor-Naive Patients Adverse Reactions Efavirenz b + ZDV/LAM (n=412) Efavirenz b + Indinavir (n=415) Indinavir + ZDV/LAM (n=401) Efavirenz b + Nelfinavir + NRTIs (n=64) Efavirenz b + NRTIs (n=65) Nelfinavir + NRTIs (n=66) 180 weeks c 102 weeks c 76 weeks c 71.1 weeks c 70.9 weeks c 62.7 weeks c Psychiatric Body as a Whole Fatigue 8% 5% 9% 0 2% 3% Pain 1% 2% 8% 13% 6% 17% Central and Peripheral Nervous System Dizziness 9% 9% 2% 2% 6% 6% Headache 8% 5% 3% 5% 2% 3% Insomnia 7% 7% 2% 0 0 2% Concentration impaired 5% 3% <1% 0 0 0 Abnormal dreams 3% 1% 0 — — — Somnolence 2% 2% <1% 0 0 0 Anorexia 1% <1% <1% 0 2% 2% Gastrointestinal Nausea 10% 6% 24% 3% 2% 2% Vomiting 6% 3% 14% — — — Diarrhea 3% 5% 6% 14% 3% 9% Dyspepsia 4% 4% 6% 0 0 2% Abdominal pain 2% 2% 5% 3% 3% 3% Anxiety 2% 4% <1% — — — Depression 5% 4% <1% 3% 0 5% Nervousness 2% 2% 0 2% 0 2% Skin & Appendages Rash d 11% 16% 5% 9% 5% 9% Pruritis <1% 1% 1% 9% 5% 9% a Includes adverse events at least possibly related to study drug or of unknown relationship for Study 006. Includes all adverse events regardless of relationship to study drug for Study ACTG 364. b Efavirenz tablets provided as 600 mg once daily. c Median duration of treatment. d Includes erythema multiforme, rash, rash erythematous, rash follicular, rash maculopapular, rash petechial, rash pustular, and urticaria for Study 006 and macules, papules, rash, erythema, redness, inflammation, allergic rash, urticaria, welts, hives, itchy, and pruritus for ACTG 364. — = Not Specified. ZDV = zidovudine, LAM=lamivudine. Pancreatitis has been reported, although a causal relationship with efavirenz has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of patients treated with efavirenz 600 mg than in control patients ( see Laboratory Abnormalities ). Nervous System Symptoms For 1008 patients treated with regimens containing efavirenz and 635 patients treated with a control regimen in controlled trials, Table 3 lists the frequency of symptoms of different degrees of severity and gives the discontinuation rates for one or more of the following nervous system symptoms: dizziness, insomnia, impaired concentration, somnolence, abnormal dreaming, euphoria, confusion, agitation, amnesia, hallucinations, stupor, abnormal thinking, and depersonalization [see Warnings and Precautions ( 5.6 )]. The frequencies of specific central and peripheral nervous system symptoms are provided in Table 2 Table 3: Percent of Patients with One or More Selected Nervous System Symptoms a,b Percent of Patients with: EFAVIRENZ TABLETS 600 mg Once Daily (n=1008) Control Groups (n=635) % % Symptoms of any severity 52.7 24.6 Mild symptoms c 33.3 15.6 Moderate symptoms d 17.4 7.7 Severe symptoms e 2.0 1.3 Treatment discontinuation as a result of symptoms 2.1 1.1 a Includes events reported regardless of causality. b Data from Study 006 and three Phase 2/3 studies. c "Mild" = Symptoms which do not interfere with patient’s daily activities. d "Moderate" = Symptoms which may interfere with daily activities. e "Severe" = Events which interrupt patient’s usual daily activities. Psychiatric Symptoms Serious psychiatric adverse experiences have been reported in patients treated with efavirenz tablets. In controlled trials, psychiatric symptoms observed at a frequency of greater than 2% among patients treated with efavirenz or control regimens, respectively, were depression (19%, 16%), anxiety (13%, 9%), and nervousness (7%, 2%). Rash In controlled clinical trials, the frequency of rash (all grades, regardless of causality) was 26% for 1008 adults treated with regimens containing efavirenz and 17% for 635 adults treated with a control regimen. Most reports of rash were mild or moderate in severity. The frequency of Grade 3 rash was 0.8% for efavirenz -treated patients and 0.3% for control groups, and the frequency of Grade 4 rash was 0.1% for efavirenz and 0 for control groups. The discontinuation rates as a result of rash were 1.7% for efavirenz -treated patients and 0.3% for control groups [see Warnings and Precautions ( 5.8 )]. Experience with efavirenz in patients who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen patients who discontinued nevirapine because of rash have been treated with efavirenz. Nine of these patients developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these patients discontinued because of rash. Laboratory Abnormalities Selected Grade 3-4 laboratory abnormalities reported in greater than 2% of efavirenz tablets-treated patients in two clinical trials are presented in Table 4. Table 4: Selected Grade 3-4 Laboratory Abnormalities Reported in≥2% of EFAVIRENZ TABLETS-Treated Patients in Studies 006 and ACTG 364 Study 006 LAM-, NNRTI-, and Protease Inhibitor-Naive Patients Study ACTG 364 NRTI-experienced, NNRTI- and Protease Inhibitor-Naive Patients Variable Limit EFAVI RENZ a + ZDV/ LAM (n=412) EFAVI RENZ a + Indinavir (n=415) Indina vir + ZDV/ LAM (n=401) EFAVI RENZ a + Nelfinavir + NRTIs (n=64) EFAVI RENZ a + NRTIs (n=65) Nelfi navir + NRTIs (n=66) 180 weeks b 102 weeks b 76 weeks b 71.1 weeks b 70.9 weeks b 62.7 weeks b Chemistry ALT >5 x ULN 5% 8% 5% 2% 6% 3% AST >5 x ULN 5% 6% 5% 6% 8% 8% GGT c >5 x ULN 8% 7% 3% 5% 0 5% Amylase >2 x ULN 4% 4% 1% 0 6% 2% Glucose >250 mg/dL 3% 3% 3% 5% 2% 3% Triglyce rides d ≥751 mg/dL 9% 6% 6% 11% 8% 17% Hematology Neutrophils <750/mm 3 10% 3% 5% 2% 3% 2% a Efairenz tablets provided as 600 mg once daily. b Median duration of treatment. c Isolated elevations of GGT in patients receiving efavirenz may reflect enzyme induction not associated with liver toxicity. d Nonfasting. ZDV = zidovudine, LAM = lamivudine, ULN = Upper limit of normal, ALT = alanine aminotransferase, AST = aspartate aminotransferase, GGT = gamma-glutamyltransferase Patients Coinfected with Hepatitis B or C Liver function tests should be monitored in patients with a history of hepatitis B and/or C. In the long-term data set from Study 006, 137 patients treated with efavirenz-containing regimens (median duration of therapy, 68 weeks) and 84 treated with a control regimen (median duration, 56 weeks) were seropositive at screening for hepatitis B (surface antigen positive) and/or C (hepatitis C antibody positive). Among these coinfected patients, elevations in AST to greater than five times ULN developed in 13% of patients in the efavirenz arms and 7% of those in the control arm, and elevations in ALT to greater than five times ULN developed in 20% of patients in the efavirenz arms and 7% of patients in the control arm. Among coinfected patients, 3% of those treated with efavirenz -containing regimens and 2% in the control arm discontinued from the study because of liver or biliary system disorders [see Warnings and Precautions ( 5.9 )]. Lipids Increases from baseline in total cholesterol of 10-20% have been observed in some uninfected volunteers receiving efavirenz. In patients treated with efavirenz + zidovudine + lamivudine, increases from baseline in nonfasting total cholesterol and HDL of approximately 20% and 25%, respectively, were observed. In patients treated with efavirenz + indinavir, increases from baseline in nonfasting cholesterol and HDL of approximately 40% and 35%, respectively, were observed. Nonfasting total cholesterol levels ≥240 mg/dL and ≥300 mg/dL were reported in 34% and 9%, respectively, of patients treated with efavirenz + zidovudine + lamivudine; 54% and 20%, respectively, of patients treated with efavirenz + indinavir; and 28% and 4%, respectively, of patients treated with indinavir + zidovudine + lamivudine. The effects of efavirenz on triglycerides and LDL in this study were not well characterized since samples were taken from nonfasting patients. The clinical significance of these findings is unknown [see Warnings and Precautions ( 5.11 )]. Adverse Reactions in Pediatric Patients Because clinical studies are conducted under widely varying conditions, the adverse reaction rates reported cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in clinical practice. Assessment of adverse reactions is based on three clinical trials in 182 HIV-1 infected pediatric patients (3 months to 21 years of age) who received efavirenz in combination with other antiretroviral agents for a median of 123 weeks. The adverse reactions observed in the three trials were similar to those observed in clinical trials in adults except that rash was more common in pediatric patients (32% for all grades regardless of causality) and more often of higher grade (ie, more severe). Two (1.1%) pediatric patients experienced Grade 3 rash (confluent rash with fever, generalized rash), and four (2.2%) pediatric patients had Grade 4 rash (all erythema multiforme). Five pediatric patients (2.7%) discontinued from the study because of rash [see Warnings and Precautions ( 5.8 )]. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of efavirenz tablets. Because these reactions 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. Body as a Whole : allergic reactions, asthenia, redistribution/accumulation of body fat [see Warnings and Precautions ( 5.13 )] Central and Peripheral Nervous System: abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor,vertigo Endocrine: gynecomastia Gastrointestinal: constipation, malabsorption Cardiovascular: flushing, palpitations Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia Musculoskeletal: arthralgia, myalgia, myopathy Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia Respiratory : dyspnea Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome Special Senses: abnormal vision, tinnitus

12.3 Pharmacokinetics Absorption Peak efavirenz plasma concentrations of 1.6-9.1 μM were attained by 5 hours following single oral doses of 100 mg to 1600 mg administered to uninfected volunteers. Dose-related increases in C max and AUC were seen for doses up to 1600 mg; the increases were less than proportional suggesting diminished absorption at higher doses. In HIV-1-infected patients at steady state, mean C max , mean C min , and mean AUC were dose proportional following 200 mg, 400 mg, and 600 mg daily doses. Time-to-peak plasma concentrations were approximately 3-5 hours and steady-state plasma concentrations were reached in 6-10 days. In 35 patients receiving efavirenz 600 mg once daily, steady-state C max was 12.9 ± 3.7 μM (mean ± SD), steady-state C min was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μMh. Effect of Food on Oral Absorption: Tablets : Administration of a single 600 mg efavirenz tablet with a high-fat/high-caloric meal (approximately 1000 kcal, 500-600 kcal from fat) was associated with a 28% increase in mean AUC∞ of efavirenz and a 79% increase in mean C max of efavirenz relative to the exposures achieved under fasted conditions. [see Dosage and Administration ( 2) and Patient Counseling Information ( 17 )]. Distribution Efavirenz is highly bound (approximately 99.5-99.75%) to human plasma proteins, predominantly albumin. In HIV-1 infected patients (n=9) who received efavirenz 200 to 600 mg once daily for at least one month, cerebrospinal fluid concentrations ranged from 0.26 to 1.19% (mean 0.69%) of the corresponding plasma concentration. This proportion is approximately 3-fold higher than the non-protein-bound (free) fraction of efavirenz in plasma. Metabolism Studies in humans and in vitro studies using human liver microsomes have demonstrated that efavirenz is principally metabolized by the cytochrome P450 system to hydroxylated metabolites with subsequent glucuronidation of these hydroxylated metabolites. These metabolites are essentially inactive against HIV-1. The in vitro studies suggest that CYP3A and CYP2B6 are the major isozymes responsible for efavirenz metabolism. Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism. Multiple doses of 200-400 mg per day for 10 days resulted in a lower than predicted extent of accumulation (22-42% lower) and a shorter terminal half-life of 40-55 hours (single dose half-life 52-76 hours). Elimination Efavirenz has a terminal half-life of 52-76 hours after single doses and 40-55 hours after multiple doses. A one-month mass balance/excretion study was conducted using 400 mg per day with a 14C-labeled dose administered on Day 8. Approximately 14-34% of the radiolabel was recovered in the urine and 16-61% was recovered in the feces. Nearly all of the urinary excretion of the radiolabeled drug was in the form of metabolites. Efavirenz accounted for the majority of the total radioactivity measured in feces. Special Populations Pediatric : The pharmacokinetic parameters for efavirenz at steady state in pediatric patients were predicted by a population pharmacokinetic model and are summarized in Table 6 by weight ranges that correspond to the recommended doses. Table 6: Predicted Steady-State Pharmacokinetics of Recommended Doses of Efavirenz (Capsules/Capsule Sprinkles) in HIV-Infected Pediatric Patients Body Weight Dose Mean AUC(0-24) μM·h Mean C max μg/mL Mean C min μg/mL 3.5-5 kg 100 mg 220.52 5.81 2.43 5-7.5 kg 150 mg 262.62 7.07 2.71 7.5-10 kg 200 mg 284.28 7.75 2.87 10-15 kg 200 mg 238.14 6.54 2.32 15-20 kg 250 mg 233.98 6.47 2.3 20-25 kg 300 mg 257.56 7.04 2.55 25-32.5 kg 350 mg 262.37 7.12 2.68 32.5-40 kg 400 mg 259.79 6.96 2.69 >40 kg 600 mg 254.78 6.57 2.82 Gender and race : The pharmacokinetics of efavirenz in patients appear to be similar between men and women and among the racial groups studied. Renal impairment : The pharmacokinetics of efavirenz have not been studied in patients with renal insufficiency; however, less than 1% of efavirenz is excreted unchanged in the urine, so the impact of renal impairment on efavirenz elimination should be minimal. Hepatic impairment: A multiple-dose study showed no significant effect on efavirenz pharmacokinetics in patients with mild hepatic impairment (Child-Pugh Class A) compared with controls. There were insufficient data to determine whether moderate or severe hepatic impairment (Child-Pugh Class B or C) affects efavirenz pharmacokinetics. Drug Interaction Studies Efavirenz has been shown in vivo to cause hepatic enzyme induction, thus increasing the biotransformation of some drugs metabolized by CYP3A and CYP2B6. In vitro studies have shown that efavirenz inhibited CYP isozymes 2C9 and 2C19 with Ki values (8.5-17 μM) in the range of observed efavirenz plasma concentrations. In in vitro studies, efavirenz did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (Ki values 82-160 μM) only at concentrations well above those achieved clinically. Coadministration of efavirenz with drugs primarily metabolized by CYP2C9, CYP2C19, CYP3A, or CYP2B6 isozymes may result in altered plasma concentrations of the coadministered drug. Drugs which induce CYP3A and CYP2B6 activity would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations. Drug interaction studies were performed with efavirenz and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. The effects of coadministration of efavirenz on the C max , AUC, and C min are summarized in Table 7 (effect of efavirenz on other drugs) and Table 8 (effect of other drugs on efavirenz). For information regarding clinical recommendations see Drug Interactions ( 7.1 ) Table 7: Effect of Efavirenz on Coadministered Drug Plasma C max , AUC, and C min Coadministered Drug Dose Efavirenz Dose Number of Subjects Coadministered Drug (mean % change) C max (90% CI) AUC (90% CI) C min (90% CI) Atazanavir 400 mg qd with a light meal d 1‑20 600 mg qd with a light meal d 7‑20 27 ↓ 59% (49-67%) ↓ 74% (68-78%) ↓ 93% (90-95%) 400 mg qd d 1-6, then 300 mg qd d 7-20 with ritonavir 100 mg qd and a light meal 600 mg qd 2 h after atazanavir and ritonavir d 7-20 13 ↑ 14% a (↓ 17-↑ 58%) ↑ 39% a (2-88%) ↑ 48% a (24-76%) 300 mg qd/ritonavir 100 mg qd d 1-10 (pm), then 400 mg qd/ritonavir 100 mg qd d 11-24 (pm) (simultaneous with efavirenz) 600 mg qd with a light snack d 11-24 (pm) 14 ↑ 17% (8-27%) ↔ ↓ 42% (31-51%) Indinavir 1000 mg q8h x 10 days 600 mg qd x 10 days 20 After morning dose ↔ b ↓ 33% b (26-39%) ↓ 39% b (24-51%) After afternoon dose ↔ b ↓ 37% b (26-46%) ↓ 52% b (47-57%) After evening dose ↓ 29% b (11-43%) ↓ 46% b (37-54%) ↓ 57% b (50-63%) Lopinavir/ritonavir 400/100 mg capsule q12h x 9 days 600 mg qd x 9 days 11,7 c ↔ d ↓ 19% d (↓ 36-↑ 3%) ↓ 39% d (3-62%) 500/125 mg tablet q12h × 10 days with efavirenz compared to 400/100 mg q12h alone 600 mg qd × 9 days 19 ↑12% d (2-23%) ↔ d ↓ 10% d (↓22-↑4%) 600/150 mg tablet q12h x 10 days with efavirenz compared to 400/100 mg q12h alone 600 mg qd x 9 days 23 ↑ 36% d (28-44%) ↑ 36% d (28-44%) ↑ 32% d (21-44%) Nelfinavir 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↑ 21% (10-33%) ↑ 20% (8-34%) ↔ Metabolite AG-1402 ↓ 40% (30-48%) ↓ 37% (25-48%) ↓ 43% (21-59%) Ritonavir 500 mg q12h x 8 days 600 mg qd x 10 days 11 After AM dose ↑ 24% (12-38%) ↑ 18% (6-33%) ↑ 42% (9-86%) e After PM dose ↔ ↔ ↑ 24% (3-50%) e Saquinavir SGC f 1200 mg q8h x 10 days 600 mg qd x 10 days 12 ↓ 50% (28-66%) ↓ 62% (45-74%) ↓ 56% (16-77%) e Lamivudine 150 mg q12h x 14 days 600 mg qd x 14 days 9 ↔ ↔ ↑ 265% (37-873%) Tenofovir g 300 mg qd 600 mg qd x 14 days 29 ↔ ↔ ↔ Zidovudine 300 mg q12h x 14 days 600 mg qd x 14 days 9 ↔ ↔ ↑ 225% (43-640%) Maraviroc 100 mg bid 600 mg qd 12 ↓ 51% (37-62%) ↓ 45% (38-51%) ↓ 45% (28-57%) Raltegravir 400 mg single dose 600 mg qd 9 ↓ 36% (2-59%) ↓ 36% (20-48%) ↓ 21% (↓ 51-↑ 28%) Boceprevir 800 mg tid × 6 days 600 mg qd × 16 days NA ↓ 8% (↓ 22-↑ 8%) ↓ 19% (11-25%) ↓ 44% (26-58%) Simeprevir 150 mg qd × 14 days 600 mg qd × 14 days 23 ↓ 51% (↓ 46-↓ 56%) ↓ 71% (↓ 67-↓ 74%) ↓ 91% (↓ 88-↓ 92%) Azithromycin 600 mg single dose 400 mg qd x 7 days 14 ↑ 22% (4-42%) ↔ NA Clarithromycin 500 mg q12h x 7 days 400 mg qd x 7 days 11 ↓ 26% (15-35%) ↓ 39% (30-46%) ↓ 53% (42-63%) 14-OH metabolite ↑ 49% (32-69%) ↑ 34% (18-53%) ↑ 26% (9-45%) Fluconazole 200 mg x 7 days 400 mg qd x 7 days 10 ↔ ↔ ↔ Itraconazole 200 mg q12h x 28 days 600 mg x 14 days 18 ↓ 37% (20-51%) ↓ 39% (21-53%) ↓ 44% (27-58%) Hydroxy-itraconazole ↓ 35% (12-52%) ↓ 37% (14-55%) ↓ 43% (18-60%) Posaconazole 400 mg (oral suspension) bid × 10 and 20 days 400 mg qd × 10 and 20 days 11 ↓ 45% (34-53%) ↓ 50% (40-57%) NA Rifabutin 300 mg qd x 14 days 600 mg qd x 14 days 9 ↓ 32% (15-46%) ↓ 38% (28-47%) ↓ 45% (31-56%) Voriconazole 400 mg po q12h x 1 day, then 200 mg po q12h x 8 days 400 mg qd x 9 days NA ↓ 61% h ↓ 77% h NA 300 mg po q12h days 2‑7 300 mg qd x 7 days NA ↓ 36% i (21-49%) ↓ 55% i (45-62%) NA 400 mg po q12h days 2‑7 300 mg qd x 7 days NA ↑ 23% i (↓ 1-↑ 53%) ↓ 7% i (↓ 23-↑ 13%) NA Artemether/ lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) 600 mg qd × 26 days 12 Artemether ↓ 21% ↓ 51% NA dihydroartemisinin ↓ 38% ↓ 46% NA Lumefantrine ↔ ↓ 21% NA Atorvastatin 10 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 14% (1-26%) ↓ 43% (34-50%) ↓ 69% (49-81%) Total active (including metabolites) ↓ 15% (2-26%) ↓ 32% (21-41%) ↓ 48% (23-64%) Pravastatin 40 mg qd x 4 days 600 mg qd x 15 days 13 ↓ 32% (↓ 59-↑ 12%) ↓ 44% (26-57%) ↓ 19% (0-35%) Simvastatin 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 72% (63-79%) ↓ 68% (62-73%) ↓ 45% (20-62%) Total active (including metabolites) ↓ 68% (55-78%) ↓ 60% (52-68%) Na j Carbamazepine 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 29 days 600 mg qd x 14 days 12 ↓ 20% (15-24%) ↓ 27% (20-33%) ↓ 35% (24-44%) Epoxide metabolite ↔ ↔ ↓ 13% (↓ 30-↑ 7%) Cetirizine 10 mg single dose 600 mg qd x 10 days 11 ↓ 24% (18-30%) ↔ NA Diltiazem 240 mg x 21 days 600 mg qd x 14 days 13 ↓ 60% (50-68%) ↓ 69% (55-79%) ↓ 63% (44-75%) Desacetyl diltiazem ↓ 64% (57-69%) ↓ 75% (59-84%) ↓ 62% (44-75%) N-monodes-methyl diltiazem ↓ 28% (7-44%) ↓ 37% (17-52%) ↓ 37% (17-52%) Ethinyl estradiol/ Norgestimate 0.035 mg/ 0.25 mg x 14 days 600 mg qd x 14 days Ethinyl estradiol 21 ↔ ↔ ↔ Norelgestromin 21 ↓ 46% (39-52%) ↓ 64% (62-67%) ↓ 82% (79-85%) Levonorgestrel 6 ↓ 80% (77-83%) ↓ 83% (79-87%) ↓ 86% (80-90%) Lorazepam 2 mg single dose 600 mg qd x 10 days 12 ↑ 16% (2-32%) ↔ NA Methadone Stable maintenance 35- 100 mg daily 600 mg x 14-21 days 11 ↓ 45% (25-59%) ↓ 52% (33-66%) NA Bupropion 150 mg single dose (sustained-release) 600 mg qd × 14 days 13 ↓ 34% (21-47%) ↓ 55% (48-62%) NA Hydroxy - bupropion ↓ 50% (20-80%) ↔ NA Paroxetine 20 mg qd x 14 days 600 mg x 14 days 16 ↔ ↔ ↔ Sertraline 50 mg qd x 14 days 600 mg x 14 days 13 ↓ 29% (15-40%) ↓ 39% (27-50%) ↓ 46% (31-58%) ↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of <10%. a Compared with atazanavir 400 mg qd alone. b Comparator dose of indinavir was 800 mg q8h x 10 days. c Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for lopinavir/ritonavir alone. d Values are for lopinavir; the pharmacokinetics of ritonavir in this study were unaffected by concurrent efavirenz. e 95% CI. f Soft Gelatin Capsule. g Tenofovir disoproxil fumarate. h 90% CI not available. i Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). j Not available because of insufficient data. NA = not available. Table 8: Effect of Coadministered Drug on Efavirenz Plasma C max , AUC, and C min Efavirenz (mean % change) Coadministered Drug Dose Efavirenz Dose Number of Subjects C max (90% CI) AUC (90% CI) C min (90% CI) Indinavir 800 mg q8h x 14 days 200 mg qd x 14 days 11 ↔ ↔ ↔ Lopinavir/ ritonavir 400/100 mg q12h x 9 days 600 mg qd x 9 days 11,12 a ↔ ↓ 16% (↓ 38-↑ 15%) ↓ 16% (↓ 42-↑ 20%) Nelfinavir 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↓ 12% (↓ 32-↑ 13%) b ↓ 12% (↓ 35-↑ 18%) b ↓ 21% (↓ 53-↑ 33%) Ritonavir 500 mg q12h x 8 days 600 mg qd x 10 days 9 ↑ 14% (4-26%) ↑ 21% (10-34%) ↑ 25% (7-46%) b Saquinavir SGC c 1200 mg q8h x 10 days 600 mg qd x 10 days 13 ↓ 13% (5-20%) ↓ 12% (4-19%) ↓ 14% (2-24%) b Tenofovir d 300 mg qd 600 mg qd x 14 days 30 ↔ ↔ ↔ Boceprevir 800 mg tid x 6 days 600 mg qd x 16 days NA ↑ 11% (2-20%) ↓ 20% (15-26%) NA Simeprevir 150 mg qd x 14 days 600 mg qd x 14 days 23 ↔ ↓ 10% (5-15%) ↓ 13% (7-19%) Azithromycin 600 mg single dose 400 mg qd x 7 days 14 ↔ ↔ ↔ Clarithromycin 500 mg q12h x 7 days 400 mg qd x 7 days 12 ↑ 11% (3-19%) ↔ ↔ Fluconazole 200 mg x 7 days 400 mg qdx 7 days 10 ↔ ↑ 16% (6-26%) ↑ 22% (5-41%) Itraconazole 200 mg q12h x 14 days 600 mg qdx 28 days 16 ↔ ↔ ↔ Rifabutin 300 mg qd x 14 days 600 mg qdx 14 days 11 ↔ ↔ ↓ 12% (↓ 24-↑ 1%) Rifampin 600 mg x 7 days 600 mg qd x 7 days 12 ↓ 20% (11-28%) ↓ 26% (15-36%) ↓ 32% (15-46%) Voriconazole 400 mg po q12h x 1 day, then 200 mg po q12h x 8 days 400 mg qd x 9 days NA ↑ 38% e ↑ 44% e NA 300 mg po q12h days 2-7 300 mg qd x 7 days NA ↓ 14% f (7-21%) ↔ f NA 400 mg po q12h days 2-7 300 mg qd x 7 days NA ↔ f ↑ 17% f (6-29%) NA Artemether/Lumefantrine Aremether 20 mg/lumefantrine 120 mg tablets (64-tablets doses over 3 days) 600 mg qd x 26 days 12 ↔ ↓ 17% NA Atorvastatin 10 mg qd x 4 days 600 mg qd x 15 days 14 ↔ ↔ ↔ Pravastatin 40 mg qd x 4 days 600 mg qd x 15 days 11 ↔ ↔ ↔ Simvastatin 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 12% (↓ 28-↑ 8%) ↔ ↓ 12% (↓ 25-↑ 3%) Aluminum hydroxide 400 mg, magnesium hydroxide 400 mg, plus simethicone 40 mg 30 mL single dose 400 mg single dose 17 ↔ ↔ NA Carbamazepine 200 mg qd x 3 days, 200 mg bid x 3 days, then 400 mg qd x 15 days 600 mg qd x 35 days 14 ↓21% (15-26%) ↓36% (32-40%) ↓47% (41-53%) Cetirizine 10 mg single dose 600 mg qd x 10 days 11 ↔ ↔ ↔ Diltiazem 240 mg x 14 days 600 mg qd x 28 days 12 ↑ 16% (6-26%) ↑ 11% (5-18%) ↑ 13% (1-26%) Famotidine 40 mg single dose 400 mg single dose 17 ↔ ↔ NA Paroxetine 20 mg qd x 14 days 600 mg qd x 14 days 12 ↔ ↔ ↔ Sertraline 50 mg qd x 14 days 600 mg qd x 14 days 13 ↑ 11% (6-16%) ↔ ↔ ↑ Indicates increase ↓ Indicates decrease ↔ Indicates no change or a mean increase or decrease of <10%. a Parallel-group design; n for efavirenz + lopinavir/ritonavir, n for efavirenz alone. b 95% CI. c Soft Gelatin Capsule. d Tenofovir disoproxil fumarate. e 90% CI not available. f Relative to steady-state administration of efavirenz (600 mg once daily for 9 days). NA = not available.