Emtricitabine And Tenofovir Disoproxil Fumarate

1 INDICATIONS AND USAGE HIV-1 Treatment ( 1.1 ) Emtricitabine and tenofovir disoproxil fumarate tablet is a two-drug combination of emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), both HIV-1 nucleoside analog reverse transcriptase inhibitors, and is indicated: • in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg. HIV-1 PrEP ( 1.2 ): • Emtricitabine and tenofovir disoproxil fumarate tablet is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test immediately prior to initiating emtricitabine and tenofovir disoproxil fumarate tablet for HIV-1 PrEP. 1.1 Treatment of HIV-1 Infection Emtricitabine and tenofovir disoproxil fumarate tablet is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 17 kg [see Clinical Studies ( 14 )] . 1.2 HIV-1 Pre-Exposure Prophylaxis (PrEP) Emtricitabine and tenofovir disoproxil fumarate tablet is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test immediately prior to initiating emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )].

2 DOSAGE AND ADMINISTRATION • Testing: Prior to or when initiating emtricitabine and tenofovir disoproxil fumarate tablets test for hepatitis B virus infection. Prior to initiation and during use of emtricitabine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus. ( 2.1 ) • HIV-1 Screening: Screen all individuals for HIV-1 infection immediately prior to initiating emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP and at least once every 3 months while taking emtricitabine and tenofovir disoproxil fumarate tablets, and upon diagnosis of any other sexually transmitted infections (STIs). ( 2.2 ) Treatment of HIV-1 Infection • Recommended dosage in adults and pediatric patients weighing at least 35 kg: One emtricitabine and tenofovir disoproxil fumarate tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. ( 2.3 ) • Recommended dosage in pediatric patients weighing at least 17 kg: One emtricitabine and tenofovir disoproxil fumarate low-strength tablet (100 mg/150 mg, 133 mg/200 mg, or 167 mg/250 mg based on body weight) once daily taken orally with or without food. ( 2.4 ) • Recommended dosage in renally impaired HIV-1 infected adult patients: o Creatinine clearance (CrCl) 30 to 49 mL/min: 1 tablet every 48 hours. ( 2.6 ) o CrCl below 30 mL/min or hemodialysis: Emtricitabine and tenofovir disoproxil fumarate tablets are not recommended. ( 2.6 ) HIV-1 Pre-Exposure Prophylaxis (PrEP) • Recommended dosage in HIV-1 uninfected adults and adolescents weighing at least 35 kg: One emtricitabine and tenofovir disoproxil fumarate tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food. ( 2.5 ) • Recommended dosage in renally impaired HIV-uninfected individuals: emtricitabine and tenofovir disoproxil fumarate is not recommended in HIV-uninfected individuals if CrCl is below 60 mL/min. ( 2.6 ) 2.1 Testing Prior to Initiation of Emtricitabine and Tenofovir Disoproxil Fumarate Tablets for Treatment of HIV-1 Infection or for HIV-1 PrEP Prior to or when initiating emtricitabine and tenofovir disoproxil fumarate tablets, test individuals for hepatitis B virus infection [see Warnings and Precautions ( 5.1 )] . Prior to initiation, and during use of emtricitabine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all individuals. In individuals with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions ( 5.3 )] . 2.2 HIV-1 Screening for Individuals Receiving Emtricitabine and Tenofovir Disoproxil Fumarate Tablets for HIV-1 PrEP Screen all individuals for HIV-1 infection immediately prior to initiating emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP and at least once every 3 months while taking emtricitabine and tenofovir disoproxil fumarate tablets, and upon diagnosis of any other sexually transmitted infections (STIs) [see Indications and Usage ( 1.2 ), Contraindications ( 4 ), and Warnings and Precautions ( 5.2 )]. If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute or primary HIV-1 infection [see Warnings and Precautions ( 5.2 ), Use in Specific Populations ( 8.4 ), and Clinical Studies ( 14.3 and 14.4 )]. 2.3 Recommended Dosage for Treatment of HIV-1 Infection in Adults and Pediatric Patients Weighing at Least 35 kg Emtricitabine and tenofovir disoproxil fumarate tablet is a two-drug fixed dose combination product containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The recommended dosage of emtricitabine and tenofovir disoproxil fumarate tablets in adults and in pediatric patients weighing at least 35 kg is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food [see Clinical Pharmacology ( 12.3 )] . 2.4 Recommended Dosage for Treatment of HIV-1 Infection in Pediatric Patients Weighing at Least 17 kg and Able to Swallow a Tablet The recommended oral dosage of emtricitabine and tenofovir disoproxil fumarate tablets for pediatric patients weighing at least 17 kg and who can swallow a tablet is presented in Table 1. Tablets should be taken once daily with or without food. Weight should be monitored periodically and the emtricitabine and tenofovir disoproxil fumarate tablets dose adjusted accordingly. Table 1 Dosing for Treatment of HIV-1 Infection in Pediatric Patients Weighing 17 kg to less than 35 kg Body Weight (kg) Dosing ofEmtricitabine and Tenofovir Disoproxil Fumarate Tablets (FTC/TDF) 17 to less than 22 one 100 mg /150 mg tablet once daily 22 to less than 28 one 133 mg /200 mg tablet once daily 28 to less than 35 one 167 mg /250 mg tablet once daily 2.5 Recommended Dosage for HIV-1 PrEP in Adults and Adolescents Weighing at Least 35 kg The dosage of emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP is one tablet (containing 200 mg of FTC and 300 mg of TDF) once daily taken orally with or without food in HIV-1 uninfected adults and adolescents weighing at least 35 kg [see Clinical Pharmacology ( 12.3 )] . 2.6 Dosage Adjustment in Individuals with Renal Impairment Treatment of HIV-1 Infection Table 2 provides dosage interval adjustment for patients with renal impairment. No dosage adjustment is necessary for HIV-1 infected patients with mild renal impairment (creatinine clearance 50 to 80 mL/min). The safety and effectiveness of the dosing interval adjustment recommendations in patients with moderate renal impairment (creatinine clearance 30 to 49 mL/min) have not been clinically evaluated; therefore, clinical response to treatment and renal function should be closely monitored in these patients [see Warnings and Precautions ( 5.3 )] . No data are available to make dosage recommendations in pediatric patients with renal impairment. Table 2 Dosage Interval Adjustment for HIV-1 Infected Adult Patients with Altered Creatinine Clearance Creatinine Clearance (mL/min) a ≥50 30 to 49 <30 (Including Patients Requiring Hemodialysis) Recommended Dosing Interval Every 24 hours Every 48 hours Emtricitabine and Tenofovir disoproxil fumarate tablets are not recommended. a. Calculated using ideal (lean) body weight HIV-1 PrEP Emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP are not recommended in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min [see Warnings and Precautions ( 5.3 )]. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [see Warnings and Precautions ( 5.3 )] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: • Severe Acute Exacerbations of Hepatitis B in Patients with HBV Infection [see Warnings and Precautions ( 5.1 )] . • New Onset or Worsening Renal Impairment [see Warnings and Precautions ( 5.3 )] . • Immune Reconstitution Syndrome [see Warnings and Precautions ( 5.4 )] . • Bone Loss and Mineralization Defects [see Warnings and Precautions ( 5.5 )]. • Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions ( 5.6 )] . • In HIV-1 infected patients, the most common adverse reactions (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6.1 ) • In HIV-1 uninfected adults in PrEP trials, adverse reactions that were reported by more than 2% of emtricitabine and tenofovir disoproxil fumarate participants and more frequently than by placebo participants were headache, abdominal pain, and weight decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 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. Adverse Reactions from Clinical Trials Experience in HIV-1 Infected Subjects Clinical Trials in Adult Subjects In Study 934, 511 antiretroviral-naïve subjects received efavirenz (EFV) administered in combination with either FTC+TDF (N=257) or zidovudine (AZT)/lamivudine (3TC) (N=254) for 144 weeks. The most common adverse reactions (incidence greater than or equal to 10%, all grades) included diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Table 3 provides the treatment-emergent adverse reactions (Grades 2 to 4) occurring in greater than or equal to 5% of subjects treated in any treatment group. Skin discoloration, manifested by hyperpigmentation, occurred in 3% of subjects taking FTC+TDF, and was generally mild and asymptomatic. The mechanism and clinical significance are unknown. Table 3 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥5% in Any Treatment Group in Study 934 (0 to 144 Weeks) FTC+TDF+EFV b AZT/3TC+EFV N=257 N=254 Fatigue Depression Nausea Diarrhea Dizziness Upper respiratory tract infections Sinusitis Rash event c Headache Insomnia Nasopharyngitis Vomiting 9% 9% 9% 9% 8% 8% 8% 7% 6% 5% 5% 2% 8% 7% 7% 5% 7% 5% 4% 9% 5% 7% 3% 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 emtricitabine and tenofovir disoproxil fumarate with efavirenz in place of FTC+TDF with efavirenz. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and rash vesicular. Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in other trials of TDF and/or FTC (Table 4). Table 4 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in Any 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 emtricitabine and tenofovir disoproxil fumarate with efavirenz in place of FTC+TDF with efavirenz. Clinical Trials in Pediatric Subjects Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116). Tenofovir Disoproxil Fumarate: In pediatric clinical trials (Studies 352 and 321) conducted in 184 HIV-1 infected subjects 2 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with TDF were consistent with those observed in clinical trials of TDF in adults. In Study 352 (2 to less than 12 years of age), 89 pediatric subjects received TDF for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and had decreases in total body or spine BMD Z-score [see Warnings and Precautions ( 5.5 )] . Total body BMD gain at Week 48 was less in the TDF group compared to the stavudine (d4T) or zidovudine (AZT) treatment groups. The mean rate of BMD gain in lumbar spine was similar between treatment groups. One TDF-treated subject and none of the d4T- or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z-scores were −0.012 for lumbar spine and −0.338 for total body in the 64 subjects who were treated with TDF for 96 weeks. In Study 321 (12 to less than 18 years of age), the mean rate of BMD gain at Week 48 was less in the TDF compared to the placebo treatment group. Six TDF-treated subjects and one placebo-treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were −0.341 for lumbar spine and −0.458 for total body in the 28 subjects who were treated with TDF for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected. Adverse Reactions from Clinical Trial Experience in Uninfected Subjects Taking Emtricitabine and Tenofovir Disoproxil Fumarate for HIV-1 PrEP Clinical Trials in Adult Subjects The safety profile of emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP was comparable to that observed in clinical trials of HIV-infected subjects based on two randomized placebo-controlled clinical trials (iPrEx, Partners PrEP) in which 2,830 HIV-1 uninfected adults received emtricitabine and tenofovir disoproxil fumarate once daily for HIV-1 PrEP. Subjects were followed for a median of 71 weeks and 87 weeks, respectively. Table 5 provides a list of selected adverse events that occurred in 2% or more of subjects in any treatment group in the iPrEx trial, with an incidence greater than placebo. Table 5 Selected Adverse Events (All Grades) Reported in ≥2% in Any Treatment Group in the iPrEx Trial and Greater than Placebo FTC/TDF Placebo (N=1251) (N=1248) Headache 7% 6% Abdominal pain 4% 2% Weight decreased 3% 2% In the Partners PrEP trial, the frequency of adverse events in the emtricitabine and tenofovir disoproxil fumarate treatment group was generally either less than or the same as in the placebo group. Laboratory Abnormalities: Table 6 provides a list of Grade 2 to 4 laboratory abnormalities observed in the iPrEx and Partners PrEP trials. Six subjects in the TDF-containing arms of the Partners PrEP trial discontinued from the trial due to an increase in serum creatinine compared with no discontinuations in the placebo group. One subject in the emtricitabine and tenofovir disoproxil fumarate arm of the iPrEx trial discontinued from the trial due to an increase in serum creatinine and another subject discontinued due to low serum phosphorus. Grades 2 to 3 proteinuria (2 to 4+) and/or glycosuria (3+) occurred in less than 1% of subjects treated with emtricitabine and tenofovir disoproxil fumarate in the iPrEx trial and Partners PrEP trial. Table 6 Laboratory Abnormalities (Highest Toxicity Grade Reported for Each Subject) in the iPrEx Trial and Partners PrEP Trial Grade 2 to 4 a iPrEx Trial Partners PrEP Trial FTC/TDF (N=1251) Placebo (N=1248) FTC/TDF (N=1579) Placebo (N=1584) Creatinine (>1.4 x ULN) <1% <1% <1% <1% Phosphorus (<2.0 mg/dL) 10% 8% 9% 9% AST (>2.6 x ULN) 5% 5% <1% <1% ALT (>2.6 x ULN) 7% 7% <1% <1% Hemoglobin (<9.4 mg/dL) 1% 2% 2% 2% Neutrophils (<750/mm 3 ) <1% <1% 5% 3% a. Grading is per DAIDS criteria. Changes in Bone Mineral Density: In clinical trials of HIV-1 uninfected individuals, decreases in BMD were observed. In the iPrEx trial, a substudy of 503 subjects found mean changes from baseline in BMD ranging from -0.4% to -1.0% across total hip, spine, femoral neck, and trochanter in the emtricitabine and tenofovir disoproxil fumarate group compared with the placebo group, which returned toward baseline after discontinuation of treatment. Thirteen percent of emtricitabine and tenofovir disoproxil fumarate-treated subjects versus 6% of placebo-treated subjects lost at least 5% of BMD at the spine during treatment. Bone fractures were reported in 1.7% of the emtricitabine and tenofovir disoproxil fumarate group compared with 1.4% in the placebo group. No correlation between BMD and fractures was noted [see Clinical Studies ( 14.3 )]. The Partners PrEP trial found similar fracture rates between the treatment and placebo groups (0.8% and 0.6%, respectively); no BMD evaluations were performed in this trial [see Clinical Studies ( 14.4 )] . Clinical Trials in Adolescent Subjects In a single-arm, open-label clinical trial (ATN113), in which 67 HIV-1 uninfected adolescent (15 to 18 years of age) men who have sex with men received emtricitabine and tenofovir disoproxil fumarate once daily for HIV-1 PrEP, the safety profile of emtricitabine and tenofovir disoproxil fumarate was similar to that observed in adults. Median duration to exposure of emtricitabine and tenofovir disoproxil fumarate was 47 weeks [see Use in Specific Populations ( 8.4 )] . In the ATN113 trial, median BMD increased from baseline to Week 48, +2.58% for lumbar spine and +0.72% for total body. One subject had significant (greater than or equal to 4%) total body BMD loss at Week 24. Median changes from baseline BMD Z-scores were 0.0 for lumbar spine and −0.2 for total body at Week 48. Three subjects showed a worsening (change from > −2 to ≤ −2) from baseline in their lumbar spine or total body BMD Z-scores at Week 24 or 48. Interpretation of these data, however, may be limited by the low rate of adherence to emtricitabine and tenofovir disoproxil fumarate by Week 48. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TDF. No additional adverse reactions have been identified during postapproval use of FTC. 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. 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 Emtricitabine and Tenofovir Disoproxil Fumarate: One emtricitabine and tenofovir disoproxil fumarate tablet was comparable to one FTC capsule (200 mg) plus one TDF tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39). Emtricitabine: The pharmacokinetic properties of FTC are summarized in Table 8. Following oral administration of FTC, FTC is rapidly absorbed with peak plasma concentrations occurring at 1 to 2 hours postdose. 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. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of FTC, the plasma FTC half-life is approximately 10 hours. Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of TDF are summarized in Table 8. Following oral administration of TDF, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. 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. Following a single oral dose of TDF, the terminal elimination half-life of tenofovir is approximately 17 hours. Table 8 Single Dose Pharmacokinetic Parameters for FTC and Tenofovir in Adults a FTC Tenofovir Fasted Oral Bioavailability b (%) 92 (83.1–106.4) 25 (NC–45.0) Plasma Terminal Elimination Half-Life b (hr) 10 (7.4–18.0) 17 (12.0–25.7) C max c (mcg/mL) 1.8 ± 0.72 d 0.30±0.09 AUC c (mcg·hr/mL) 10.0 ± 3.12 d 2.29±0.69 CL/F c (mL/min) 302 ± 94 1043±115 CL renal c (mL/min) 213 ± 89 243±33 a. NC = Not calculated b. Median (range) c. Mean (± SD) d. Data presented as steady state values Effects of Food on Oral Absorption Emtricitabine and tenofovir disoproxil fumarate may be administered with or without food. Administration of emtricitabine and tenofovir disoproxil fumarate following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir C max by approximately 0.75 hour. The mean increases in tenofovir AUC and C max were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, TDF (tenofovir) was taken under fed conditions. FTC systemic exposures (AUC and C max ) were unaffected when emtricitabine and tenofovir disoproxil fumarate was administered with either a high fat or a light meal. Specific Populations Race Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of FTC. Tenofovir Disoproxil Fumarate: 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 Emtricitabine and Tenofovir Disoproxil Fumarate: FTC and tenofovir pharmacokinetics are similar in male and female subjects. Pediatric Patients Treatment of HIV-1 Infection: The pharmacokinetic data for tenofovir and FTC following administration of emtricitabine and tenofovir disoproxil fumarate in pediatric subjects weighing 17 kg and above are not available. The dosage recommendations of FTC and TDF in this population are based on the dosage recommendations of emtricitabine and tenofovir disoproxil fumarate in this population. Refer to the EMTRIVA and VIREAD prescribing information for pharmacokinetic information on the individual products in pediatric patients. HIV-1 PrEP: The pharmacokinetic data for tenofovir and FTC following administration of emtricitabine and tenofovir disoproxil fumarate in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP in this population are based on safety and adherence data from the ATN113 trial [see Use in Specific Populations ( 8.4 )] and known pharmacokinetic information in HIV-infected adolescents taking TDF and FTC for treatment. Geriatric Patients Pharmacokinetics of FTC and tenofovir have not been fully evaluated in the elderly (65 years of age and older). Patients with Renal Impairment The pharmacokinetics of FTC and tenofovir are altered in subjects with renal impairment [see Warnings and Precautions ( 5.3 )] . In adult subjects with creatinine clearance below 50 mL/min, C max and AUC 0 to ∞ of FTC and tenofovir were increased. No data are available to make dosage recommendations in pediatric patients with renal impairment. Patients with Hepatic Impairment 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. The pharmacokinetics of emtricitabine and tenofovir disoproxil fumarate or 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. Assessment of Drug Interactions The steady state pharmacokinetics of FTC and tenofovir were unaffected when FTC and TDF were administered together versus each agent dosed alone. In vitro studies and clinical pharmacokinetic drug-drug interaction trials 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, stavudine, TDF, and zidovudine (Tables 9 and 10). Similarly, no clinically significant drug interactions have been observed between TDF and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir in trials conducted in healthy volunteers (Tables 11 and 12). Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Drug a Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) N % Change of FTC Pharmacokinetic Parameters b (90% CI) C max AUC C min TDF 300 once daily x 7 days 200 once daily x 7 days 17 ⇔ ⇔ ↑ 20 (↑ 12 to ↑ 29) Zidovudine 300 twice daily x 7 days 200 once daily x 7 days 27 ⇔ ⇔ ⇔ Indinavir 800 x 1 200 x 1 12 ⇔ ⇔ NA Famciclovir 500 x 1 200 x 1 12 ⇔ ⇔ NA Stavudine 40 x 1 200 x 1 6 ⇔ ⇔ NA a. All interaction trials conducted in healthy volunteers b. ↑ = Increase; ⇔ = No Effect; NA = Not Applicable Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of FTC a Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters b (90% CI) C max AUC C min TDF 300 once daily x 7 days 200 once daily x 7 days 17 ⇔ ⇔ ⇔ Zidovudine 300 twice daily x 7 days 200 once daily x 7 days 27 ↑ 17 (↑ 0 to ↑ 38) ↑ 13 (↑ 5 to ↑ 20) ⇔ Indinavir 800 x 1 200 x 1 12 ⇔ ⇔ NA Famciclovir 500 x 1 200 x 1 12 ⇔ ⇔ NA Stavudine 40 x 1 200 x 1 6 ⇔ ⇔ NA a. All interaction trials conducted in healthy volunteers b. ↑ = Increase; ⇔ = No Effect; NA = Not Applicable Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir a in the Presence of the Coadministered Drug Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic Parameters b (90% CI) C max AUC C min Atazanavir c 400 once daily × 14 days 33 ↑ 14 (↑ 8 to ↑ 20) ↑ 24 (↑ 21 to ↑ 28) ↑ 22 (↑ 15 to ↑ 30) Atazanavir/ Ritonavir c 300/100 once daily 12 ↑ 34 (↑ 20 to ↑ 51) ↑ 37 (↑ 30 to ↑ 45) ↑ 29 (↑ 21 to ↑ 36) Darunavir/ Ritonavir d 300/100 twice daily 12 ↑ 24 (↑ 8 to ↑ 42) ↑ 22 (↑ 10 to ↑ 35) ↑ 37 (↑ 19 to ↑ 57) Indinavir 800 three times daily × 7 days 13 ↑ 14 (↓ 3 to ↑ 33) ⇔ ⇔ Ledipasvir/ Sofosbuvir e,f 90/400 once daily x 10 days 24 ↑ 47 (↑ 37 to ↑ 58) ↑ 35 (↑ 29 to ↑ 42) ↑ 47 (↑ 38 to ↑ 57) Ledipasvir/ Sofosbuvir e,g 23 ↑ 64 (↑ 54 to ↑ 74) ↑ 50 (↑ 42 to ↑ 59) ↑ 59 (↑ 49 to ↑ 70) Ledipasvir/ Sofosbuvir h 90/400 once daily x 14 days 15 ↑ 79 (↑ 56 to ↑ 104) ↑ 98 (↑ 77 to ↑ 123) ↑ 163 (↑ 132 to ↑ 197) Ledipasvir/ Sofosbuvir i 90/400 once daily x 10 days 14 ↑ 32 (↑ 25 to ↑ 39) ↑ 40 (↑ 31 to ↑ 50) ↑ 91 (↑ 74 to ↑ 110) Ledipasvir/ Sofosbuvir j 90/400 once daily × 10 days 29 ↑ 61 (↑ 51 to ↑ 72) ↑ 65 (↑ 59 to ↑ 71) ↑ 115 (↑ 105 to ↑ 126) Lopinavir/ Ritonavir 400/100 twice daily × 14 days 24 ⇔ ↑ 32 (↑ 25 to ↑ 38) ↑ 51 (↑ 37 to ↑ 66) Saquinavir/ Ritonavir 1000/100 twice daily × 14 days 35 ⇔ ⇔ ↑ 23 (↑ 16 to ↑ 30) Sofosbuvir k 400 single dose 16 ↑ 25 (↑ 8 to ↑ 45) ⇔ ⇔ Sofosbuvir/ Velpatasvir l 400/100 once daily 24 ↑ 44 (↑ 33 to ↑ 55) ↑ 40 (↑ 34 to ↑ 46) ↑ 84 (↑ 76 to ↑ 92) Sofosbuvir/ Velpatasvir m 400/100 once daily 30 ↑ 46 (↑ 39 to ↑ 54) ↑ 40 (↑ 34 to ↑ 45) ↑ 70 (↑ 61 to ↑ 79) Sofosbuvir/ Velpatasvir/ Voxilaprevir n 400/100/100+ Voxilaprevir o 100 once daily 29 ↑ 48 (↑ 36 to ↑ 61) ↑ 39 (↑ 32 to ↑ 46) ↑ 47 (↑ 38 to ↑ 56) Tacrolimus 0.05 mg/kg twice daily x 7 days 21 ↑ 13 (↑ 1 to ↑ 27) ⇔ ⇔ Tipranavir/ Ritonavir p 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) a. Subjects received tenofovir disoproxil fumarate 300 mg once daily. b. Increase = ↑; Decrease = ↓; No Effect = ⇔ c. Reyataz Prescribing Information. d. Prezista Prescribing Information. e. Data generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provided similar results. f. Comparison based on exposures when administered as atazanavir/ritonavir + FTC/TDF. g. Comparison based on exposures when administered as darunavir/ritonavir + FTC/TDF. h. Study conducted with ATRIPLA (efavirenz/FTC/TDF) coadministered with HARVONI. i. Study conducted with COMPLERA (FTC/rilpivirine/TDF) coadministered with HARVONI. j. Study conducted with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) + dolutegravir coadministered with HARVONI. k. Study conducted with ATRIPLA coadministered with SOVALDI ® (sofosbuvir). l. Study conducted with COMPLERA coadministered with EPCLUSA; coadministration with EPCLUSA also results in comparable increases in tenofovir exposures when TDF is administered as ATRIPLA, STRIBILD, emtricitabine and tenofovir disoproxil fumarate + atazanavir/ritonavir, or emtricitabine and tenofovir disoproxil fumarate + darunavir/ritonavir. m. Administered as raltegravir + FTC/TDF. n. Comparison based on exposures when administered as darunavir + ritonavir + FTC/TDF. o. Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients p. Aptivus Prescribing Information. No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with emtricitabine and tenofovir disoproxil fumarate: abacavir, didanosine (buffered tablets), FTC, entecavir, and lamivudine. Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters a (90% CI) C max AUC C min Abacavir 300 once 8 ↑ 12 (↓ 1 to ↑ 26) ⇔ NA Atazanavir b 400 once daily x 14 days 34 ↓ 21 (↓ 27 to ↓ 14) ↓ 25 (↓ 30 to ↓ 19) ↓ 40 (↓ 48 to ↓ 32) Atazanavir b Atazanavir/Ritonavir 300/100 once daily x 42 days 10 ↓ 28 (↓ 50 to ↑ 5) ↓ 25 c (↓ 42 to ↓ 3) ↓ 23 c (↓ 46 to ↑ 10) Darunavir d Darunavir/Ritonavir 300/100 once daily 12 16 (↓ 6 to ↑ 42) ↑ 21 (↓ 5 to ↑ 54) ↑ 24 (↓ 10 to ↑ 69) Didanosine e 250 once, simultaneously with TDF and a light meal f 33 ↓ 20 g (↓ 32 to ↓ 7) ⇔ g NA Emtricitabine 200 once daily x 7 days 17 ⇔ ⇔ ↑ 20 (↑ 12 to ↑ 29) Indinavir 800 three times daily x 7 days 12 ↓ 11 (↓ 30 to ↑ 12) ⇔ ⇔ Entecavir 1 once daily x 10 days 28 ⇔ ↑ 13 (↑ 11 to ↑ 15) ⇔ Lamivudine 150 twice daily x 7 days 15 ↓ 24 (↓ 34 to ↓ 12) ⇔ ⇔ Lopinavir Ritonavir Lopinavir/Ritonavir 400/100 twice daily x 14 days 24 ⇔ ⇔ ⇔ ⇔ ⇔ ⇔ Saquinavir Ritonavir Saquinavir/Ritonavir 1000/100 twice daily x 14 days 32 ↑ 22 (↑ 6 to ↑41) ⇔ ↑ 29h (↑ 12 to ↑48) ⇔ ↑ 47h (↑ 23 to ↑ 76) ↑ 23 (↑ 3 to ↑ 46) Tacrolimus 0.05 mg/kg twice daily x 7 days 21 ⇔ ⇔ ⇔ Tipranavir i 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) a. Increase = ↑; Decrease = ↓; No Effect = ⇔; NA = Not Applicable b. Reyataz Prescribing Information. c. In HIV-infected subjects, 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. d. Prezista Prescribing Information. e. Videx EC Prescribing Information. Subjects received didanosine enteric-coated capsules. When didanosine 250 mg enteric-coated capsules were administered with TDF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric-coated capsules alone under fasted conditions. f. 373 kcal, 8.2 g fat g. Compared with didanosine (enteric-coated) 400 mg administered alone under fasting conditions. h. Increases in AUC and C min are not expected to be clinically relevant; hence, no dose adjustments are required when TDF and ritonavir-boosted saquinavir are coadministered. i. Aptivus Prescribing Information.