Efavirenz, Emtricitabine And Tenofovir Disoproxil Fumarate

1 INDICATIONS AND USAGE Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg. Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is a three-drug combination of efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg. (1)

2 DOSAGE AND ADMINISTRATION Testing: Consult Full Prescribing Information for important testing recommendations prior to initiation and during treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. (2.1) Recommended dosage in adults and pediatric patients weighing at least 40 kg: One tablet once daily taken orally on an empty stomach, preferably at bedtime. (2.2) Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL/min. (2.3) Hepatic impairment: Not recommended in patients with moderate to severe hepatic impairment. (2.4) Dosage adjustment with rifampin coadministration: An additional 200 mg/day of efavirenz is recommended for patients weighing 50 kg or more. (2.5) 2.1 Testing Prior to Initiation and During Treatment with Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate Tablets Prior to or when initiating efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1) ]. Prior to initiation and during use of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.7) ]. Monitor hepatic function prior to and during treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions (5.3) ]. Perform pregnancy testing before initiation of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are in adolescents and adults of childbearing potential [see Warnings and Precautions (5.8) , Use in Specific Populations (8.1 , 8.3) ]. 2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is a three-drug fixed-dose combination product containing 600 mg of efavirenz (EFV), 200 mg of emtricitabine (FTC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in adults and pediatric patients weighing at least 40 kg is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Clinical Pharmacology (12.3) ] . 2.3 Not Recommended in Patients with Moderate or Severe Renal Impairment Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min) [see Warnings and Precautions (5.7) , Use in Specific Populations (8.6) ] . 2.4 Not Recommended in Patients with Moderate to Severe Hepatic Impairment Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate to severe hepatic impairment (Child-Pugh B or C) [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7) ] . 2.5 Dosage Adjustment with Rifampin If efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets are co-administered with rifampin in patients weighing 50 kg or more, take one tablet of efavirenz, emtricitabine and tenofovir disoproxil fumarate once daily followed by one additional 200 mg per day of efavirenz [see Drug Interactions (7.3) and Clinical Pharmacology (12.3) ] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B in Patients Coinfected with HIV-1 and HBV [see Warnings and Precautions (5.1) ] . Rash [see Warnings and Precautions (5.2) ]. Hepatotoxicity [see Warnings and Precautions (5.3) ]. Psychiatric Symptoms [see Warnings and Precautions (5.5) ]. Nervous System Symptoms [see Warnings and Precautions (5.6) ]. New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.7) ]. Embryo-Fetal Toxicity [see Warnings and Precautions (5.8) ]. Bone Loss and Mineralization Defects [see Warnings and Precautions (5.9) ]. Convulsions [see Warnings and Precautions (5.10) ]. Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.11) ]. Immune Reconstitution Syndrome [see Warnings and Precautions (5.12) ]. Fat Redistribution [see Warnings and Precautions (5.13) ]. Most common adverse reactions (incidence greater than or equal to 10%) observed in an active-controlled clinical trial of EFV, FTC, and TDF are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Subjects Study 934 was an open-label active-controlled trial in which 511 antiretroviral-naïve subjects received either FTC + TDF administered in combination with EFV (N=257) or zidovudine (AZT)/lamivudine (3TC) administered in combination with EFV (N=254). The most common adverse reactions (incidence greater than or equal to 10%, any severity) occurring in Study 934 include diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions observed in Study 934 were generally consistent with those seen in previous trials of the individual components (Table 1). Table 1 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Either Treatment Group in Study 934 (0 to 144 Weeks) FTC+TDF+EFV b AZT/3TC+EFV N=257 N=254 Fatigue 9% 8% Depression 9% 7% Nausea 9% 7% Diarrhea 9% 5% Dizziness 8% 7% Upper respiratory tract infections 8% 5% Sinusitis 8% 4% Rash Event c 7% 9% Headache 6% 5% Insomnia 5% 7% Anxiety 5% 4% Nasopharyngitis 5% 3% Vomiting 2% 5% a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC + TDF with EFV. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular. In Study 073, subjects with stable, virologic suppression on antiretroviral therapy and no history of virologic failure were randomized to receive efavirenz, emtricitabine and tenofovir disoproxil fumarate or to stay on their baseline regimen. The adverse reactions observed in Study 073 were generally consistent with those seen in Study 934 and those seen with the individual components of efavirenz, emtricitabine and tenofovir disoproxil fumarate when each was administered in combination with other antiretroviral agents. Efavirenz, Emtricitabine, or TDF In addition to the adverse reactions in Study 934 and Study 073, the following adverse reactions were observed in clinical trials of EFV, FTC, or TDF in combination with other antiretroviral agents. Efavirenz: The most significant adverse reactions observed in subjects treated with EFV were nervous system symptoms [see Warnings and Precautions (5.6) ], psychiatric symptoms [see Warnings and Precautions (5.5) ], and rash [see Warnings and Precautions (5.2) ] . Selected adverse reactions of moderate-to-severe intensity observed in greater than or equal to 2% of EFV-treated subjects in two controlled clinical trials included pain, impaired concentration, abnormal dreams, somnolence, anorexia, dyspepsia, abdominal pain, nervousness, and pruritus. Pancreatitis has also been reported, although a causal relationship with EFV has not been established. Asymptomatic increases in serum amylase levels were observed in a significantly higher number of subjects treated with EFV 600 mg than in control subjects. Skin discoloration has been reported with higher frequency among FTC-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Clinical Trials in Pediatric Subjects Efavirenz: Assessment of adverse reactions is based on three pediatric clinical trials in 182 HIV-1 infected pediatric subjects who received EFV in combination with other antiretroviral agents for a median of 123 weeks. The type and frequency of adverse reactions in the three trials were generally similar to that of adult subjects with the exception of a higher incidence of rash, which was reported in 32% (59/182) of pediatric subjects compared to 26% of adults, and a higher frequency of Grade 3 or 4 rash reported in 3% (6/182) of pediatric subjects compared to 0.9% of adults [see Warnings and Precautions (5.2) ] . Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116). Tenofovir DF: In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with TDF (N=81) were consistent with those observed in clinical trials of TDF in adults [see Warnings and Precautions (5.9) ] . Laboratory Abnormalities Efavirenz, Emtricitabine and Tenofovir DF: Laboratory abnormalities observed in Study 934 were generally consistent with those seen in previous trials (Table 2). Table 2 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Either Treatment Group in Study 934 (0 to 144 Weeks) FTC+TDF+EFV a AZT/3TC+EFV N=257 N=254 Any ≥ Grade 3 Laboratory Abnormality 30% 26% Fasting Cholesterol (>240 mg/dL) 22% 24% Creatine Kinase (M: >990 U/L) (F: >845 U/L) 9% 7% Serum Amylase (>175 U/L) 8% 4% Alkaline Phosphatase (>550 U/L) 1% 0% AST (M: >180 U/L) (F: >170 U/L) 3% 3% ALT (M: >215 U/L) (F: >170 U/L) 2% 3% Hemoglobin (<8.0 mg/dL) 0% 4% Hyperglycemia (>250 mg/dL) 2% 1% Hematuria (>75 RBC/HPF) 3% 2% Glycosuria (≥3+) <1% 1% Neutrophils (<750/mm 3 ) 3% 5% Fasting Triglycerides (>750 mg/dL) 4% 2% a. From Weeks 96 to 144 of the trial, subjects received FTC/TDF administered in combination with EFV in place of FTC + TDF with EFV. Laboratory abnormalities observed in Study 073 were generally consistent with those in Study 934. Hepatic Events: In Study 934, 19 subjects treated with EFV, FTC, and TDF and 20 subjects treated with EFV and fixed-dose zidovudine/lamivudine were hepatitis B surface antigen or hepatitis C antibody positive. Among these coinfected subjects, one subject (1/19) in the EFV, FTC, and TDF arm had elevations in transaminases to greater than five times ULN through 144 weeks. In the fixed-dose zidovudine/lamivudine arm, two subjects (2/20) had elevations in transaminases to greater than five times ULN through 144 weeks. No HBV and/or HCV coinfected subject discontinued from the trial due to hepatobiliary disorders [see Warnings and Precautions (5.3) ] . 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of EFV, FTC, or TDF. 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. Efavirenz : Cardiac Disorders Palpitations Ear and Labyrinth Disorders Tinnitus, vertigo Endocrine Disorders Gynecomastia Eye Disorders Abnormal vision Gastrointestinal Disorders Constipation, malabsorption General Disorders and Administration Site Conditions Asthenia Hepatobiliary Disorders Hepatic enzyme increase, hepatic failure, hepatitis Immune System Disorders Allergic reactions Metabolism and Nutrition Disorders Redistribution/accumulation of body fat [see Warnings and Precautions (5.13) ] , hypercholesterolemia, hypertriglyceridemia Musculoskeletal and Connective Tissue Disorders Arthralgia, myalgia, myopathy Nervous System Disorders Abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor Psychiatric Disorders Aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia Respiratory, Thoracic and Mediastinal Disorders Dyspnea Skin and Subcutaneous Tissue Disorders Flushing, erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome Emtricitabine : No postmarketing adverse reactions have been identified for inclusion in this section. Tenofovir DF : Immune System Disorders Allergic reaction, including angioedema Metabolism and Nutrition Disorders Lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders Dyspnea Gastrointestinal Disorders Pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders Hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT) Skin and Subcutaneous Tissue Disorders Rash Musculoskeletal and Connective Tissue Disorders Rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders Acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions Asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

12.3 Pharmacokinetics Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate : One efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is bioequivalent to one Sustiva tablet (600 mg) plus one EMTRIVA ® capsule (200 mg) plus one VIREAD ® tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45). Efavirenz: In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3 to 5 hours and steady-state plasma concentrations were reached in 6 to 10 days. In 35 HIV-1 infected subjects receiving EFV 600 mg once daily, steady-state C max was 12.9 ± 3.7 µM (mean ± SD), C min was 5.6 ± 3.2 µM, and AUC was 184 ± 73 µM•hr. EFV is highly bound (approximately 99.5 to 99.75%) to human plasma proteins, predominantly albumin. Following administration of 14 C-labeled EFV, 14 to 34% of the dose was recovered in the urine (mostly as metabolites) and 16 to 61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for EFV metabolism. EFV has been shown to induce CYP enzymes, resulting in induction of its own metabolism. EFV has a terminal half-life of 52 to 76 hours after single doses and 40 to 55 hours after multiple doses. Emtricitabine: Following oral administration, FTC is rapidly absorbed, with peak plasma concentrations occurring at 1 to 2 hours postdose. Following multiple dose oral administration of FTC to 20 HIV-1 infected subjects, the steady-state plasma FTC C max was 1.8 ± 0.7 mcg/mL (mean ± SD) and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 mcg•hr/mL. The mean steady-state plasma trough concentration at 24 hours postdose was 0.09 mcg/mL. The mean absolute bioavailability of FTC was 93%. Less than 4% of FTC binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02 to 200 mcg/mL. Following administration of radiolabelled FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. FTC is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 213 ± 89 mL/min (mean ± SD). Following a single oral dose, the plasma FTC half-life is approximately 10 hours. Tenofovir DF: Following oral administration of a single 300 mg dose of TDF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (C max ) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and C max and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng•hr/mL, respectively. The oral bioavailability of tenofovir from TDF in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01 to 25 mcg/mL. Approximately 70 to 80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion, with a renal clearance in adults with normal renal function of 243 ± 33 mL/min (mean ± SD). Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours. Effects of Food on Oral Absorption Efavirenz, emtricitabine and tenofovir disoproxil fumarate has not been evaluated in the presence of food. Administration of EFV tablets with a high-fat meal increased the mean AUC and C max of EFV by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of TDF and FTC in combination with either a high-fat meal or a light meal increased the mean AUC and C max of tenofovir by 35% and 15%, respectively, without affecting FTC exposures [see Dosage and Administration (2.2) and Patient Counseling Information (17) ]. Specific Populations Race Efavirenz: The pharmacokinetics of EFV in HIV-1 infected subjects appear to be similar among the racial groups studied. Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of FTC. Tenofovir DF: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of TDF. Gender Efavirenz, Emtricitabine, and Tenofovir DF: EFV, FTC, and tenofovir pharmacokinetics are similar in male and female subjects. Pediatric Patients Efavirenz: In an open-label trial in NRTI-experienced pediatric subjects (mean age 8 years, range 3 to 16 years), the pharmacokinetics of EFV in pediatric subjects were similar to the pharmacokinetics in adults who received a 600 mg daily dose of EFV. Based on mean steady-state predicted population pharmacokinetic modeling in pediatric subjects weighing >40 kg receiving the 600 mg dose of EFV, C max was 6.57 mcg/mL, C min was 2.82 mcg/mL, and AUC (0-24) was 254.78 μM•hr. Emtricitabine : The pharmacokinetics of FTC at steady state were determined in 27 HIV-1 infected pediatric subjects 13 to 17 years of age receiving a daily dose of 6 mg/kg up to a maximum dose of 240 mg oral solution or a 200 mg capsule; 26 of 27 subjects in this age group received the 200 mg capsule. Mean ± SD C max and AUC were 2.7 ± 0.9 mcg/mL and 12.6 ± 5.4 mcg•hr/mL, respectively. Exposures achieved in pediatric subjects 12 to less than 18 years of age were similar to those achieved in adults receiving a once daily dose of 200 mg. Tenofovir DF : Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected pediatric subjects (12 to less than 18 years). Mean ± SD Cmax and AUCtau are 0.38 ± 0.13 mcg/mL and 3.39 ± 1.22 mcg•hr/mL, respectively. Tenofovir exposure achieved in these pediatric subjects receiving oral daily doses of TDF 300 mg was similar to exposures achieved in adults receiving once-daily doses of TDF 300 mg. Geriatric Patients Pharmacokinetics of EFV, FTC, and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations (8.5) ]. Patients with Impaired Renal Function Efavirenz: The pharmacokinetics of EFV have not been studied in subjects with renal insufficiency; however, less than 1% of EFV is excreted unchanged in the urine, so the impact of renal impairment on EFV elimination should be minimal. Emtricitabine and Tenofovir DF: The pharmacokinetics of FTC and TDF are altered in subjects with renal impairment. In subjects with creatinine clearance below 50 mL/min, C max and AUC 0-∞ of FTC and tenofovir were increased [see Warnings and Precautions (5.7) ]. Patients with Hepatic Impairment Efavirenz: A multiple-dose trial showed no significant effect on EFV pharmacokinetics in subjects 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 EFV pharmacokinetics [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7 )]. Emtricitabine: The pharmacokinetics of FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited. Tenofovir DF: The pharmacokinetics of tenofovir following a 300 mg dose of TDF have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. Assessment of Drug Interactions The drug interaction trials described were conducted with either efavirenz, emtricitabine and tenofovir disoproxil fumarate or the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate (EFV, FTC, or TDF) as individual agents. Efavirenz: The steady-state pharmacokinetics of EFV and tenofovir were unaffected when EFV and TDF were administered together versus each agent dosed alone. Specific drug interaction trials have not been performed with EFV and NRTIs other than tenofovir, lamivudine, and zidovudine. Clinically significant interactions would not be expected based on NRTIs elimination pathways. 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 EFV inhibited CYP isozymes 2C9 and 2C19 with K i values (8.5 to 17 µM) in the range of observed EFV plasma concentrations. In in vitro studies, EFV did not inhibit CYP2E1 and inhibited CYP2D6 and CYP1A2 (K i values 82 to 160 µM) only at concentrations well above those achieved clinically. Coadministration of EFV 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 EFV resulting in lowered plasma concentrations. Drug interaction trials were performed with EFV and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction. There was no clinically significant interaction observed between EFV and zidovudine, lamivudine, azithromycin, fluconazole, lorazepam, cetirizine, or paroxetine. Single doses of famotidine or an aluminum and magnesium antacid with simethicone had no effects on EFV exposures. The effects of coadministration of EFV on C max , AUC, and C min are summarized in Table 4 (effect of other drugs on EFV) and Table 5 (effect of EFV on other drugs) [see Drug Interactions (7) ]. Table 4 Drug Interactions: Changes in Pharmacokinetic Parameters for EFV in the Presence of the Coadministered Drug NA = not available a. Increase = ↑; Decrease = ↓; No Effect = ↔ b. Parallel-group design; N for EFV + lopinavir/ritonavir, N for EFV alone. c. 95% CI d. 90% CI not available e. Relative to steady-state administration of EFV (600 mg once daily for 9 days). Mean % Change of EFV Pharmacokinetic Parameters a (90% CI) Coadministered Drug Dose of Coadministered Drug (mg) EFV Dose (mg) N C max AUC C min Lopinavir/ ritonavir 400/100 mg q12h x 9 days 600 mg qd x 9 days 11, 12 b ↔ ↓ 16 (↓ 38 to ↑ 15) ↓ 16 (↓ 42 to ↑ 20) Nelfinavir 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↓ 12 (↓ 32 to ↑ 13) c ↓ 12 (↓ 35 to ↑ 18) c ↓ 21 (↓ 53 to ↑ 33) Ritonavir 500 mg q12h x 8 days 600 mg qd x 10 days 9 ↑ 14 (↑ 4 to ↑ 26) ↑ 21 (↑ 10 to ↑ 34) ↑ 25 (↑ 7 to ↑ 46) c Boceprevir 800 mg tid x 6 days 600 mg qd x 16 days NA ↑11 (↑ 2 to ↑ 20) ↑ 20 (↑ 15 to ↑ 26) NA Rifabutin 300 mg qd x 14 days 600 mg qd x 14 days 11 ↔ ↔ ↓ 12 (↓ 24 to ↑ 1) Rifampin 600 mg x 7 days 600 mg qd x 7 days 12 ↓ 20 (↓ 11 to ↓ 28) ↓ 26 (↓ 15 to ↓ 36) ↓ 32 (↓ 15 to ↓ 46) Artemether/ lumefantrine Artemether 20 mg/ lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) 600 mg qd × 26 days 12 ↔ ↓17 NA Simvastatin 40 mg qd × 4 days 600 mg qd x 15 days 14 ↓ 12 (↓ 28 to ↑ 8) ↔ ↓ 12 (↓ 25 to ↑ 3) 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 to ↓ 26) ↓ 36 (↓ 32 to ↓ 40) ↓ 47 (↓ 41 to ↓ 53) Diltiazem 240 mg x 14 days 600 mg qd x 28 days 12 ↑ 16 (↑ 6 to ↑ 26) ↑ 11 (↑ 5 to ↑ 18) ↑ 13 (↑ 1 to ↑ 26) Voriconazole 400 mg po q12h x 1 day then 200 mg po q12h x 8 days 400 mg qd x 9 days NA ↑ 38 d ↑ 44 d NA 300 mg po q12h days 2 to 7 300 mg qd x 7 days NA ↓ 14 e (↓ 7 to ↓ 21) ↔ e NA 400 mg po q12h days 2 to 7 300 mg qd x 7 days NA ↔ e ↑ 17 e (↑ 6 to ↑ 29) NA No effect on the pharmacokinetic parameters of EFV was observed with the following coadministered drugs: indinavir, saquinavir soft gelatin capsule, simeprevir, ledipasvir/sofosbuvir, sofosbuvir, clarithromycin, itraconazole, atorvastatin, pravastatin, or sertraline. Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of EFV NA = not available a. Increase = ↑; Decrease = ↓; No Effect = ↔ b. Compared with atazanavir 400 mg qd alone. c. Comparator dose of indinavir was 800 mg q8h × 10 days. d. Parallel-group design; N for EFV + lopinavir/ritonavir, N for lopinavir/ritonavir alone. e. Values are for lopinavir. The pharmacokinetics of ritonavir 100 mg q12h are unaffected by concurrent EFV. f. 95% CI g. Soft Gelatin Capsule h. Not available because of insufficient data. i. 90% CI not available. j. Relative to steady-state administration of voriconazole (400 mg for 1 day, then 200 mg po q12h for 2 days). k. Study conducted with efavirenz, emtricitabine and tenofovir disoproxil fumarate coadministered with HARVONI. l. The predominant circulating nucleoside metabolite of sofosbuvir. m. Study conducted with efavirenz, emtricitabine and tenofovir disoproxil fumarate coadministered with SOVALDI ® (sofosbuvir). n. Study conducted with efavirenz, emtricitabine and tenofovir disoproxil fumarate coadministered with EPCLUSA. Mean % Change of Coadministered Drug Pharmacokinetic Parameters a (90% CI) Coadministered Drug Dose of Coadministered Drug (mg) EFV Dose (mg) N C max AUC C min Atazanavir 400 mg qd with a light meal d 1 to 20 600 mg qd with a light meal d 7 to 20 27 ↓ 59 (↓ 49 to ↓ 67) ↓ 74 (↓ 68 to ↓ 78) ↓ 93 (↓ 90 to ↓ 95) 400 mg qd d 1 to 6, then 300 mg qd d 7 to 20 with ritonavir 100 mg qd and a light meal 600 mg qd 2 h after atazanavir and ritonavir d 7 to 20 13 ↑ 14 b (↓ 17 to ↑ 58) ↑ 39 b (↑ 2 to ↑ 88) ↑ 48 b (↑ 24 to ↑ 76) 300 mg qd/ritonavir 100 mg qd d 1 to 10 (pm), then 400 mg qd/ritonavir 100 mg qd d 11 to 24 (pm) (simultaneous with EFV) 600 mg qd with a light snack d 11 to 24 (pm) 14 ↑ 17 (↑ 8 to ↑ 27) ↔ ↓ 42 (↓ 31 to ↓ 51) Indinavir 1000 mg q8h × 10 days 600 mg qd × 10 days 20 After morning dose ↔ c ↓ 33 c (↓ 26 to ↓ 39) ↓ 39 c (↓ 24 to ↓ 51) After afternoon dose ↔ c ↓ 37 c (↓ 26 to ↓ 46) ↓ 52 c (↓ 47 to ↓ 57) After evening dose ↓ 29 c (↓ 11 to ↓ 43) ↓ 46 c (↓ 37 to ↓ 54) ↓ 57 c (↓ 50 to ↓ 63) Lopinavir/ ritonavir 400/100 mg q12h x 9 days 600 mg qd x 9 days 11, 7 d ↔ e ↓ 19 e (↓ 36 to ↑ 3) ↓ 39 e (↓ 3 to ↓ 62) Nelfinavir Metabolite AG-1402 750 mg q8h x 7 days 600 mg qd x 7 days 10 ↑ 21 (↑ 10 to ↑ 33) ↓ 40 (↓ 30 to ↓ 48) ↑ 20 (↑ 8 to ↑ 34) ↓ 37 (↓ 25 to ↓ 48) ↔ ↓ 43 (↓ 21 to ↓ 59) Ritonavir 500 mg q12h x 8 days 600 mg qd x 10 days 11 After AM dose ↑ 24 (↑ 12 to ↑ 38) ↑ 18 (↑ 6 to ↑ 33) ↑ 42 (↑ 9 to ↑ 86) f After PM dose ↔ ↔ ↑ 24 (↑ 3 to ↑ 50) f Saquinavir SGC g 1200 mg q8h x 10 days 600 mg qd x 10 days 12 ↓ 50 (↓ 28 to ↓ 66) ↓ 62 (↓ 45 to ↓ 74) ↓ 56 (↓ 16 to ↓ 77) f Maraviroc 100 mg bid 600 mg qd 12 ↓ 51 (↓ 37 to ↓ 62) ↓ 45 (↓ 38 to ↓ 51) ↓ 45 (↓ 28 to ↓ 57) Raltegravir 400 mg single dose 600 mg qd 9 ↓ 36 (↓ 2 to ↓ 59) ↓ 36 (↓ 20 to ↓ 48) ↓ 21 (↓ 51 to ↑ 28) Boceprevir 800 mg tid x 6 days 600 mg qd x 16 days NA ↓ 8 (↓ 22 to ↑ 8) ↓ 19 (↓ 11 to ↓ 25) ↓ 44 (↓ 26 to ↓ 58) Simeprevir 150 mg qd × 14 days 600 mg qd × 14 days 23 ↓ 51 (↓ 46 to ↓ 56) ↓ 71 (↓ 67 to ↓ 74) ↓ 91 (↓ 88 to ↓ 92) Ledipasvir/ sofosbuvir k Ledipasvir Sofosbuvir GS-331007 l 90/400 mg qd x 14 days 600 mg qd x 14 days 15 ↓ 34 (↓ 25 to ↓ 41) ↔ ↔ ↓ 34 (↓ 25 to ↓ 41) ↔ ↔ ↓ 34 (↓ 24 to ↓ 43) NA ↔ Sofosbuvir m GS-331007 l 400 mg qd single dose 600 mg qd x 14 days 16 ↓ 19 (↓ 40 to ↑ 10) ↓ 23 (↓ 16 to ↓ 30) ↔ ↓ 16 (↓ 24 to ↓ 8) NA NA Sofosbuvir/ velpatasvir n Sofosbuvir GS-331007 l Velpatasvir 400/100 mg qd × 14 days 600 mg qd × 14 days 14 ↑ 38 (↑ 14 to ↑ 67) ↓ 14 (↓ 20 to ↓ 7) ↓ 47 (↓ 57 to ↓ 36) ↔ ↔ ↓ 53 (↓ 61 to ↓ 43) NA ↔ ↓ 57 (↓ 64 to ↓ 48) Clarithromycin 14-OH metabolite 500 mg q12h x 7 days 400 mg qd x 7 days 11 ↓ 26 (↓ 15 to ↓ 35) ↑ 49 (↑ 32 to ↑ 69) ↓ 39 (↓ 30 to ↓ 46) ↑ 34 (↑ 18 to ↑ 53) ↓ 53 (↓ 42 to ↓ 63) ↑ 26 (↑ 9 to ↑ 45) Itraconazole Hydroxy-itraconazole 200 mg q12h x 28 days 600 mg qd x 14 days 18 ↓ 37 (↓ 20 to ↓ 51) ↓ 35 (↓ 12 to ↓ 52) ↓ 39 (↓ 21 to ↓ 53) ↓ 37 (↓ 14 to ↓ 55) ↓ 44 (↓ 27 to ↓ 58) ↓ 43 (↓ 18 to ↓ 60) Posaconazole 400 mg (oral suspension) bid × 10 and 20 days 400 mg qd × 10 and 20 days 11 ↓ 45 (↓ 34 to ↓ 53) ↓ 50 (↓ 40 to ↓ 57) NA Rifabutin 300 mg qd x 14 days 600 mg qd x 14 days 9 ↓ 32 (↓ 15 to ↓ 46) ↓ 38 (↓ 28 to ↓ 47) ↓ 45 (↓ 31 to ↓ 56) Artemether/ lumefantrine Artemether dihydroartemisinin lumefantrine Artemether 20 mg/lumefantrine 120 mg tablets (6 4-tablet doses over 3 days) 600 mg qd × 26 days 12 ↓ 21 ↓ 38 ↔ ↓ 51 ↓ 46 ↓ 21 NA NA NA Atorvastatin Total active (including metabolites) 10 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 14 (↓ 1 to ↓ 26) ↓ 15 (↓ 2 to ↓ 26) ↓ 43 (↓ 34 to ↓ 50) ↓ 32 (↓ 21 to ↓ 41) ↓ 69 (↓ 49 to ↓ 81) ↓ 48 (↓ 23 to ↓ 64) Pravastatin 40 mg qd x 4 days 600 mg qd x 15 days 13 ↓ 32 (↓ 59 to ↑ 12) ↓ 44 (↓ 26 to ↓ 57) ↓ 19 (↓ 0 to ↓ 35) Simvastatin Total active (including metabolites) 40 mg qd x 4 days 600 mg qd x 15 days 14 ↓ 72 (↓ 63 to ↓ 79) ↓ 68 (↓ 55 to ↓ 78) ↓ 68 (↓ 62 to ↓ 73) ↓ 60 (↓ 52 to ↓ 68) ↓ 45 (↓ 20 to ↓ 62) NA h Carbamazepine Epoxide metabolite 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 to ↓ 24) ↔ ↓ 27 (↓ 20 to ↓ 33) ↔ ↓ 35 (↓ 24 to ↓ 44) ↓ 13 (↓ 30 to ↑ 7) Diltiazem Desacetyl diltiazem N-monodesmethyl diltiazem 240 mg x 21 days 600 mg qd x 14 days 13 ↓ 60 (↓ 50 to ↓ 68) ↓ 64 (↓ 57 to ↓ 69) ↓ 28 (↓ 7 to ↓ 44) ↓ 69 (↓ 55 to ↓ 79) ↓ 75 (↓ 59 to ↓ 84) ↓ 37 (↓ 17 to ↓ 52) ↓ 63 (↓ 44 to ↓ 75) ↓ 62 (↓ 44 to ↓ 75) ↓ 37 (↓ 17 to ↓ 52) Ethinyl estradiol/ norgestimate Ethinyl estradiol Norelgestromin Levonorgestrel 0.035 mg/0.25 mg x 14 days 600 mg qd x 14 days 21 ↔ ↔ ↔ 21 ↓ 46 (↓ 39 to ↓ 52) ↓ 64 (↓ 62 to ↓ 67) ↓ 82 (↓ 79 to ↓ 85) 6 ↓ 80 (↓ 77 to ↓ 83) ↓ 83 (↓ 79 to ↓ 87) ↓ 86 (↓ 80 to ↓ 90) Methadone Stable maintenance 35 to 100 mg daily 600 mg qd x 14 to 21 days 11 ↓ 45 (↓ 25 to ↓ 59) ↓ 52 (↓ 33 to ↓ 66) NA Bupropion Hydroxybupropion 150 mg single dose (sustained- release) 600 mg qd × 14 days 13 ↓ 34 (↓ 21 to ↓ 47) ↑ 50 (↑ 20 to ↑ 80) ↓ 55 (↓ 48 to ↓ 62) ↔ NA NA Sertraline 50 mg qd x 14 days 600 mg qd x 14 days 13 ↓ 29 (↓ 15 to ↓ 40) ↓ 39 (↓ 27 to ↓ 50) ↓ 46 (↓ 31 to ↓ 58) Voriconazole 400 mg po q12h x 1 day then 200 mg po q12h x 8 days 400 mg qd x 9 days NA ↓ 61 i ↓ 77 i NA 300 mg po q12h days 2 to 7 300 mg qd x 7 days NA ↓ 36 j (↓ 21 to ↓ 49) ↓ 55 j (↓ 45 to ↓ 62) NA 400 mg po q12h days 2 to 7 300 mg qd x 7 days NA ↑ 23 j (↓ 1 to ↑ 53) ↓ 7 j (↓ 23 to ↑ 13) NA Emtricitabine and Tenofovir DF: The steady-state pharmacokinetics of FTC and tenofovir were unaffected when FTC and TDF were administered together versus each agent dosed alone. In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP mediated interactions involving FTC and tenofovir with other medicinal products is low. TDF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When TDF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed. No clinically significant drug interactions have been observed between FTC and famciclovir, indinavir, sofosbuvir/velpatasvir, stavudine, TDF, and zidovudine. Similarly, no clinically significant drug interactions have been observed between TDF and abacavir, EFV, FTC, entecavir, indinavir, lamivudine, lopinavir/ritonavir, methadone, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir, sofosbuvir, or tacrolimus in trials conducted in healthy volunteers. Following multiple dosing to HIV-negative subjects receiving either chronic methadone maintenance therapy, oral contraceptives, or single doses of ribavirin, steady-state tenofovir pharmacokinetics were similar to those observed in previous trials, indicating a lack of clinically significant drug interactions between these agents and TDF. The effects of coadministered drugs on the C max , AUC, and C min of tenofovir are shown in Table 6. The effects of coadministration of TDF on C max , AUC, and C min of coadministered drugs are shown in Table 7. Table 6 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drug a,b a. All interaction trials conducted in healthy volunteers. b. Subjects received TDF 300 mg once daily. c. Increase = ↑; Decrease = ↓; No Effect = ↔ d. Reyataz Prescribing Information. e. Prezista Prescribing Information. f. Subjects received didanosine buffered tablets. g. Aptivus Prescribing Information. Coadministered Drug Dose of Coadministered Drug (mg) N Mean % Change of Tenofovir Pharmacokinetic Parameters c (90% CI) C max AUC C min Atazanavir d 400 once daily x 14 days 33 ↑ 14 (↑ 8 to ↑ 20) ↑ 24 (↑ 21 to ↑ 28) ↑ 22 (↑ 15 to ↑ 30) Atazanavir/ ritonavir d 300/100 once daily 12 ↑ 34 (↑ 20 to ↑ 51) ↑ 37 (↑ 30 to ↑ 45) ↑ 29 (↑ 21 to ↑ 36) Darunavir/ ritonavir e 300/100 twice daily 12 ↑ 24 (↑ 8 to ↑ 42) ↑ 22 (↑ 10 to ↑ 35) ↑ 37 (↑ 19 to ↑ 57) Didanosine f 250 or 400 once daily × 7 days 14 ↔ ↔ ↔ Ledipasvir/ sofosbuvir 90/400 once daily 15 ↑ 79 (↑ 56 to ↑ 104) ↑ 98 (↑ 77 to ↑ 123) ↑ 163 (↑ 132 to ↑ 197) Lopinavir/ ritonavir 400/100 twice daily × 14 days 24 ↔ ↑ 32 (↑ 25 to ↑ 38) ↑ 51 (↑ 37 to ↑ 66) Sofosbuvir 400 once daily 16 ↑ 25 (↑ 8 to ↑ 45) ↔ ↔ Sofosbuvir/ velpatasvir 400/100 once daily 15 ↑ 77 (↑ 53 to ↑ 104) ↑ 81 (↑ 68 to ↑ 94) ↑ 121 (↑ 100 to ↑ 143) Tipranavir/ ritonavir g 500/100 twice daily 22 ↓ 23 (↓ 32 to ↓ 13) ↓ 2 (↓ 9 to ↑ 5) ↑ 7 (↓ 2 to ↑ 17) 750/200 twice daily (23 doses) 20 ↓ 38 (↓ 46 to ↓ 29) ↑ 2 (↓ 6 to ↑ 10) ↑ 14 (↑ 1 to ↑ 27) Table 7 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of TDF a,b a. All interaction trials conducted in healthy volunteers. b. Subjects received TDF 300 mg once daily. c. Increase = ↑; Decrease = ↓; No Effect = ↔ d. Reyataz Prescribing Information. e. In HIV-infected patients, addition of TDF to atazanavir 300 mg plus ritonavir 100 mg, resulted in AUC and C min values of atazanavir that were 2.3- and 4-fold higher than the respective values observed for atazanavir 400 mg when given alone. f. Prezista Prescribing Information. g. Videx EC Prescribing Information. Subjects received didanosine enteric-coated capsules. h. 373 kcal, 8.2 g fat. i. Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions. j. Aptivus Prescribing Information. Coadministered Drug Dose of Coadministered Drug (mg) N Mean % Change of Coadministered Drug Pharmacokinetic Parameters c (90% CI) C max AUC C min Atazanavir d 400 once daily x 14 days 34 ↓ 21 (↓ 27 to ↓ 14) ↓ 25 (↓ 30 to ↓ 19) ↓ 40 (↓ 48 to ↓ 32) Atazanavir/ritonavir 300/100 once daily x 42 days 10 ↓ 28 (↓ 50 to ↑ 5) ↓ 25 e (↓ 42 to ↓ 3) ↓ 23 e (↓ 46 to ↑ 10) Darunavir f Darunavir/ritonavir 300/100 once daily 12 ↑ 16 (↓ 6 to ↑ 42) ↑ 21 (↓ 5 to ↑ 54) ↑ 24 (↓ 10 to ↑ 69) Didanosine g 250 once, simultaneously with TDF and a light meal h 33 ↓ 20 i (↓ 32 to ↓ 7) ↔ i NA Lopinavir Ritonavir Lopinavir/ritonavir 400/100 twice daily x 14 days 24 ↔ ↔ ↔ Lopinavir/ritonavir 400/100 twice daily x 14 days 24 ↔ ↔ ↔ Tipranavir j Tipranavir/ritonavir 500/100 twice daily 22 ↓ 17 (↓ 26 to ↓ 6) ↓ 18 (↓ 25 to ↓ 9) ↓ 21 (↓ 30 to ↓ 10) Tipranavir/ritonavir 750/200 twice daily (23 doses) 20 ↓ 11 (↓ 16 to ↓ 4) ↓ 9 (↓ 15 to ↓ 3) ↓ 12 (↓ 22 to 0)