Emtricitabine, Rilpivirine And Tenofovir Disoproxil Fumarate

1 INDICATIONS AND USAGE Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg: • as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy or • to replace a stable antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no treatment failure and no known substitutions associated with resistance to the individual components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets [see Microbiology (12.4) and Clinical Studies (14) ]. Limitations of Use: • More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies (14) ]. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, a combination of two nucleoside analog HIV-1 reverse transcriptase inhibitors (emtricitabine and tenofovir disoproxil fumarate) and one non-nucleoside reverse transcriptase inhibitor (rilpivirine), is indicated for use as a complete regimen for the treatment of HIV-1 infection in patients weighing at least 35 kg (1) as initial therapy in those with no antiretroviral treatment history and with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy, or (2) or to replace a stable antiretroviral regiment in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no treatment failure and no known substitutions associated with resistance to the individual components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. ( 1 , 14 ) Limitations of Use: • More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL. ( 1 , 14 )

2 DOSAGE AND ADMINISTRATION • Testing: Prior to or when initiating emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, test for hepatitis B virus infection. Prior to initiation and during treatment with emtricitabine, rilpivirine 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. ( 2.1 ) • Recommended dosage in adults and pediatric patients weighing at least 35 kg: One tablet taken orally once daily with food. ( 2.2 ) • For pregnant patients who are already on emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet taken once daily may be continued. Lower exposures of rilpivirine were observed during pregnancy; therefore, viral load should be monitored closely. ( 2.3 ) • Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL per minute. ( 2.4 ) • Recommended dosage with rifabutin coadministration: an additional 25 mg tablet of rilpivirine (Edurant) once per day taken concomitantly with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and with a meal for the duration of the rifabutin coadministration. ( 2.5 , 7.6 , 12.3 ) 2.1 Testing Prior to Initiation and During Treatment with Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets Prior to or when initiating emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1) ]. Prior to initiation of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, and during treatment with emtricitabine, rilpivirine 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 (5.5) ]. 2.2 Recommended Dosage Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a three-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets in adult and pediatric patients weighing at least 35 kg is one tablet taken orally once daily with food [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3) ]. 2.3 Recommended Dosage During Pregnancy For pregnant patients who are already on emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets taken once daily may be continued. Lower exposures of rilpivirine, a component of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets, were observed during pregnancy, therefore viral load should be monitored closely [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) ]. 2.4 Not Recommended in Patients with Moderate or Severe Renal Impairment Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL per minute) [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6) ]. 2.5 Recommended Dosage with Rifabutin Coadministration If emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with rifabutin, take an additional 25 mg tablet of rilpivirine (Edurant ® ) with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets once daily with a meal for the duration of the rifabutin coadministration [see Drug Interactions (7.6) 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) ]. • Skin and Hypersensitivity Reactions [see Warnings and Precautions (5.2) ]. • Hepatotoxicity [see Warnings and Precautions (5.3) ]. • Depressive Disorders [see Warnings and Precautions (5.4) ]. • New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.5) ]. • Bone Loss and Mineralization Defects [see Warnings and Precautions (5.6) ]. • Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.8) ]. • Immune Reconstitution Syndrome [see Warnings and Precautions (5.9) ]. • Most common adverse reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2 to 4) are depressive disorders, insomnia, and headache. ( 6.1 ) • Most common adverse reactions to emtricitabine and tenofovir disoproxil fumarate (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) 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 Adult Subjects In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History Studies C209 and C215 The safety assessment of RPV, used in combination with other antiretroviral drugs, is based on the Week 96 pooled data from 1,368 subjects in the Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1-infected adult subjects. A total of 686 subjects received RPV in combination with other antiretroviral drugs as background regimen; most (N=550) received FTC/TDF as background regimen. The number of subjects randomized to the control arm EFV was 682, of which 546 received FTC/TDF as background regimen [see Clinical Studies (14) ]. The median duration of exposure for subjects in either treatment arm was 104 weeks. Adverse reactions observed at Week 96 in subjects who received RPV or EFV + FTC/TDF as background regimen are shown in Table 1. No new types of adverse reactions were identified between Week 48 and Week 96. The adverse reactions observed in this subset of subjects were generally consistent with those seen for the overall patient population participating in these studies (refer to the prescribing information for Edurant). The proportion of subjects who discontinued treatment with RPV or EFV + FTC/TDF due to adverse reactions, regardless of severity, was 2% and 5%, respectively. The most common adverse reactions leading to discontinuation were psychiatric disorders: 9 (1.6%) subjects in the RPV + FTC/TDF arm and 12 (2.2%) subjects in the EFV + FTC/TDF arm. Rash led to discontinuation in 1 (0.2%) subject in the RPV + FTC/TDF arm and 10 (1.8%) subjects in the EFV + FTC/TDF arm. Common Adverse Reactions: Clinical adverse reactions to RPV or EFV of at least moderate intensity (≥Grade 2) reported in at least 2% of adult subjects are shown in Table 1. Table 1 Selected Adverse Reactions a (Grades 2 to 4) Reported in ≥2% of Adult Subjects Receiving RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis) a. Frequencies of adverse reactions are based on all Grades 2 to 4 treatment-emergent adverse events assessed to be related to study drug. b. Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. Preferred Term RPV + FTC/TDF EFV + FTC/TDF N=550 N=546 Depressive disorders b Headache Insomnia Abnormal dreams Dizziness Nausea Rash 2% 2% 2% 1% 1% 1% 1% 2% 2% 2% 3% 7% 2% 5% Rilpivirine: Adverse reactions of at least moderate intensity (≥Grade 2) that occurred in less than 2% of subjects treated with RPV plus any of the allowed background regimens (N=686) in clinical studies C209 and C215 include (grouped by Body System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis. In Virologically Suppressed HIV-1-Infected Adult Subjects No new adverse reactions to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets were identified in stable, virologically suppressed subjects switching to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets from a regimen containing a ritonavir-boosted protease inhibitor; however, the frequency of adverse reactions increased by 20% (Study 106) after switching to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Emtricitabine and Tenofovir DF: The most common adverse reactions that occurred in at least 10% of HIV-1-infected treatment-naïve adult subjects in a Phase 3 clinical trial of FTC and TDF in combination with another antiretroviral agent were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving FTC or TDF with other antiretroviral agents in clinical trials included abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis. 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. Laboratory Abnormalities in Adult Subjects The percentage of subjects treated with RPV + FTC/TDF or EFV + FTC/TDF in studies C209 and C215 with selected laboratory abnormalities (Grades 1 to 4), representing worst-grade toxicity, is presented in Table 2. Table 2 Selected Laboratory Abnormalities (Grades 1 to 4) Reported in Adult Subjects Who Received RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis) N=number of subjects per treatment group ULN=Upper limit of normal value. Note: Percentages were calculated versus the number of subjects in ITT population with FTC + TDF as background regimen. Laboratory Parameter Abnormality DAIDS Toxicity Range RPV + FTC/TDF EFV + FTC/TDF N=550 N=546 BIOCHEMISTRY Increased Creatinine Grade 1 1.1 to 1.3 x ULN 6% 1% Grade 2 >1.3 to 1.8 x ULN 1% 1% Grade 3 >1.8 to 3.4 x ULN <1% 0 Grade 4 >3.4 x ULN 0 <1% Increased AST Grade 1 1.25 to 2.5 x ULN 16% 19% Grade 2 >2.5 to 5.0 x ULN 4% 7% Grade 3 >5.0 to 10.0 x ULN 2% 3% Grade 4 >10.0 x ULN 1% 1% Increased ALT Grade 1 1.25 to 2.5 x ULN 19% 22% Grade 2 >2.5 to 5.0 x ULN 5% 7% Grade 3 >5.0 to 10.0 x ULN 1% 2% Grade 4 >10.0 x ULN 1% 1% Increased Total Bilirubin Grade 1 1.1 to 1.5 x ULN 6% <1% Grade 2 >1.5 to 2.5 x ULN 3% 1% Grade 3 >2.5 to 5.0 x ULN 1% <1% Increased Total Cholesterol (fasted) Grade 1 200 to 239 mg/dL 14% 31% Grade 2 240 to 300 mg/dL 6% 18% Grade 3 >300 mg/dL <1% 2% Increased LDL Cholesterol (fasted) Grade 1 130 to 159 mg/dL 13% 28% Grade 2 160 to 190 mg/dL 5% 13% Grade 3 >190 mg/dL 1% 4% Increased Triglycerides (fasted) Grade 2 500 to 750 mg/dL 1% 2% Grade 3 751 to 1,200 mg/dL 1% 2% Grade 4 >1,200 mg/dL 0 1% Emtricitabine or Tenofovir DF: The following Grade 3 or 4 laboratory abnormalities have been previously reported in subjects treated with FTC or TDF with other antiretroviral agents in other clinical trials: increased pancreatic amylase (>2.0 x ULN), increased serum amylase (>175 U/L), increased lipase (>3.0 x ULN), increased alkaline phosphatase (>550 U/L), increased or decreased serum glucose (<40 or >250 mg/dL), increased glycosuria (≥3+), increased creatine kinase (M: >990 U/L; F: >845 U/L), decreased neutrophils (<750/mm 3 ), and increased hematuria (>75 RBC/HPF). Adrenal Function: In the pooled Phase 3 trials of C209 and C215, in subjects treated with RPV plus any of the allowed background regimens (N=686), at Week 96 there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the RPV group, and of -0.02 (-0.48, 0.44) micrograms/dL in the EFV group. In the RPV group, 43/588 (7.3%) of subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial compared to 18/561 (3.2%) in the EFV group. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test during the trial, 14 subjects in the RPV group and 9 subjects in the EFV group had an abnormal 250 micrograms ACTH stimulation test at Week 96. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the RPV group is not known. Serum Creatinine: In the pooled Phase 3 trials of C209 and C215 in subjects treated with RPV plus any of the allowed background regimens (N=686), there was a small increase in serum creatinine over 96 weeks of treatment with RPV. Most of this increase occurred within the first 4 weeks of treatment, with a mean change of 0.1 mg/dL (range -0.3 to 0.6 mg/dL) observed through Week 96. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant, and no subject discontinued treatment due to increases in serum creatinine. Creatinine increases were comparable by background N(t)RTIs. Serum Lipids: Changes from baseline in total cholesterol, LDL-cholesterol, and triglycerides are presented in Table 3. Table 3 Lipid Values Reported in Adult Subjects Receiving RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 a N=number of subjects per treatment group a. Excludes subjects who received lipid lowering agents during the treatment period. b. The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values. Pooled Data from the Week 96 Analysis of C209 and C215 Trials RPV + FTC/TDF N=550 EFV + FTC/TDF N=546 N Baseline Week 96 N Baseline Week 96 Mean Mean (mg/dL) Mean (mg/dL) Mean Change b (mg/dL) Mean (mg/dL) Mean (mg/dL) Mean Change b (mg/dL) Total Cholesterol (fasted) 430 162 164 2 401 160 186 26 HDL-cholesterol (fasted) 429 42 45 4 399 40 50 11 LDL-cholesterol (fasted) 427 97 97 -1 397 96 110 14 Triglycerides (fasted) 430 123 109 -14 401 127 133 6 Adult Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus: In adult subjects coinfected with hepatitis B or C virus receiving RPV in studies C209 and C215, the incidence of hepatic enzyme elevation was higher than in subjects receiving RPV who were not coinfected. The same increase was also observed in the EFV arm. The pharmacokinetic exposure of RPV in coinfected subjects was comparable to that in subjects without coinfection. Adverse Reactions from Clinical Trials Experience 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). For additional information, please consult the EMTRIVA ® prescribing information. Rilpivirine: The safety assessment is based on the Week 48 analysis of the single-arm, open-label Phase 2 trial, TMC278-C213, in which 36 antiretroviral treatment-naïve HIV-1-infected subjects 12 to less than 18 years of age and weighing at least 32 kg received RPV (25 mg once daily) in combination with other antiretroviral agents. The median duration of exposure for subjects was 63.5 weeks. No subjects discontinued treatment due to adverse reactions. No new adverse reactions were identified compared to those seen in adults. Adverse reactions were reported in 19 pediatric subjects (52.8%). Most adverse reactions were Grade 1 or 2. The most common adverse reactions reported in at least 2 subjects (regardless of severity) include headache (19.4%), depression (19.4%), somnolence (13.9%), nausea (11.1%), dizziness (8.3%), abdominal pain (8.3%), vomiting (5.6%), and rash (5.6%). Observed laboratory abnormalities were comparable to those in adults. For additional information, please consult the Edurant prescribing information. Adrenal Function In trial TMC278-C213, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 (0.24, 2.93) micrograms/dL. Six of 30 (20%) subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial. Three of these subjects had an abnormal 250 micrograms ACTH stimulation test at Week 48. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the abnormal 250 micrograms ACTH stimulation tests is not known. 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 were consistent with those observed in clinical trials of TDF in adults [see Warnings and Precautions (5.6) ]. For additional information, including information on bone mineral density changes, please consult the VIREAD ® prescribing information. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving RPV- or TDF-containing regimens. 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. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets: Metabolism and Nutrition Disorders weight increased Skin and Subcutaneous Tissue Disorders severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) Rilpivirine: Renal and Urinary Disorders nephrotic 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 Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets: Under fed conditions (total calorie content of the meal was approximately 400 kcal with approximately 13 grams of fat), RPV, FTC, and tenofovir exposures were similar when comparing emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets to EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg) following single-dose administration to healthy subjects (N=34). Single-dose administration of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets to healthy subjects under fasted conditions provided approximately 25% higher exposure of RPV compared to administration of EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg), while exposures of FTC and tenofovir were comparable (N=15). Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic properties of the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are provided in Table 5. The PK parameters of RPV, FTC, and tenofovir are provided in Table 6. Table 5 Pharmacokinetic Properties of the Components of Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets NC=Not Calculated a. Median b. Values refer to % change based on calculated geometric mean ratio [fed/fasted] in AUC. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets light meal = 390 kcal, 12 g fat; Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets standard meal = 540 kcal, 21 g fat. High fat meal not evaluated. Increase = ↑; Decrease = ↓; No Effect= ↔ c. Mean ± SD d. t 1/2 values refer to median terminal plasma half-life. e. Dosing in mass balance studies: FTC (single dose administration of [ 14 C] FTC after multiple dosing of FTC for 10 days); RPV (single dose administration of [ 14 C] RPV); mass balance study not conducted for tenofovir. f. Oral bioavailability of tenofovir from VIREAD. RPV FTC Tenofovir Absorption T max (h) 4 to 5 1 to 2 1 % Fasted oral bioavailability a NC 93 25 f Effect of a light meal (relative to fasting) b ↑9% ↔ ↑28% Effect of a standard meal (relative to fasting) b ↑16% ↔ ↑38% Distribution % Bound to human plasma proteins ~99 <4 <0.7 Source of protein binding data In vitro In vitro In vitro Metabolism Metabolism CYP3A Not significantly metabolized Elimination Major route of elimination Metabolism Glomerular filtration and active tubular secretion CL renal c (mL/min) NC 213±89 243±33 t 1/2 (h) d 50 10 17 % Of dose excreted in urine e 6 86 70 to 80 % Of dose excreted in feces e 85 ~14 NC Table 6 Pharmacokinetic Parameters for RPV, FTC, and Tenofovir in HIV-Infected Adults NA=Not Applicable; SD=Standard Deviation a. Population PK estimates of RPV 25 mg once daily in antiretroviral treatment-naïve HIV-1-infected adult subjects (pooled data from Phase 3 trials through Week 96; n=679) b. Multiple-dose oral administration of FTC 200 mg to HIV-1-infected subjects (n=20) c. Single 300 mg dose of TDF to HIV-1-infected subjects in the fasted state d. Data presented as steady state values e. AUC 0 to 24h Parameter Mean ± SD RPV a FTC b Tenofovir c C max (mcg/mL) NA 1.80±0.72 d 0.30±0.09 AUC tau (mcg · hr/mL) 2.24±0.85 d 10.0±3.12 d 2.29±0.69 e C 0h (mcg/mL) 0.08±0.04 d 0.09±0.07 d NA Specific Populations Geriatric Patients The pharmacokinetics of FTC, RPV, and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations (8.5) ]. Pediatric Patients Pediatric trials have not been conducted using emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Pediatric information is based on trials conducted with the individual components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets [see Use in Specific Populations (8.4) ]. 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 FTC 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. Rilpivirine: The pharmacokinetics of RPV in antiretroviral treatment-naïve HIV-1- infected pediatric subjects 12 to less than 18 years of age receiving RPV 25 mg once daily were comparable to those in treatment-naïve HIV-1-infected adults receiving RPV 25 mg once daily (See Table 7). There was no clinically significant impact of body weight on RPV pharmacokinetics in pediatric subjects in trial C213 (33 to 93 kg). Table 7 Population Pharmacokinetic Estimates of RPV 25 mg once daily in Antiretroviral Treatment-Naïve HIV-1-Infected Pediatric Subjects aged 12 to less than 18 years (Data from Phase 2 Trial through Week 48) Parameter RPV 25 mg once daily N=34 AUC 24h (ng•h/mL) Mean ± Standard Deviation 2,424 ± 1,024 Median (Range) 2,269 (417 to 5,166) C 0h (ng/mL) Mean ± Standard Deviation 85 ± 40 Median (Range) 79 (7 to 202) Tenofovir DF: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1-infected pediatric subjects (12 to less than 18 years). Mean (± SD) C max and AUC tau 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. Gender No clinically relevant pharmacokinetic differences have been observed based on gender for FTC, RPV, and TDF. Race Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of FTC. Rilpivirine: Population pharmacokinetic analysis of RPV in HIV-1-infected subjects indicated that race had no clinically relevant effect on the exposure to RPV. 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. Patients with Renal Impairment 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 per minute or with end stage renal disease requiring dialysis, C max and AUC of FTC and tenofovir were increased [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6) ]. Rilpivirine: Population pharmacokinetic analysis indicated that RPV exposure was similar in HIV-1-infected subjects with mild renal impairment relative to HIV-1-infected subjects with normal renal function. There is limited or no information regarding the pharmacokinetics of RPV in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and RPV concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction [see Use in Specific Populations (8.6) ]. Patients with Hepatic Impairment 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. Rilpivirine: RPV is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of RPV was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. RPV has not been studied in subjects with severe hepatic impairment (Child-Pugh score C) [see Use in Specific Populations (8.7) ]. 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. Hepatitis B and/or Hepatitis C Virus Coinfection The pharmacokinetics of FTC and TDF have not been fully evaluated in hepatitis B and/or C virus-coinfected patients. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure to RPV. Pregnancy and Postpartum The exposure (C 0h and AUC 24h ) to total RPV after intake of RPV 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 8). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials of RPV-containing regimens. Based on the exposure-response relationship for RPV, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of RPV was similar (>99%) during the second trimester, third trimester, and postpartum. Table 8: Pharmacokinetic Results of Total RPV After Administration of RPV 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2 nd Trimester of Pregnancy, the 3 rd Trimester of Pregnancy and Postpartum Pharmacokinetics of total RPV (mean ±SD, t max : median [range]) Postpartum (6 to 1 2 Weeks) (n=11) 2 nd Trimester of pregnancy (n=15) 3 rd Trimester of pregnancy (n=13) C 0h , ng/mL 111 ± 69.2 65.0 ± 23.9 63.5 ± 26.2 C min , ng/mL 84.0 ± 58.8 54.3 ± 25.8 52.9 ± 24.4 C max , ng/mL 167 ± 101 121 ± 45.9 123 ± 47.5 t max , h 4.00 (2.03 to 25.08) 4.00 (1.00 to 9.00) 4.00 (2.00 to 24.93) AUC 24h , ng•h/mL 2,714 ± 1,535 1,792 ± 711 1,762 ± 662 Drug Interaction Studies Rilpivirine: RPV is primarily metabolized by cytochrome CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. Coadministration of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance. Coadministration of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV. Coadministration of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with drugs that increase gastric pH may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV and to the class of NNRTIs. RPV at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Emtricitabine and Tenofovir DF: 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. FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of FTC and TDF with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug [see Drug Interactions (7.4 , 7.6 )]. Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir. The drug interaction studies described in Tables 9 to 14 were conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (RPV/FTC/TDF) or the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (RPV, FTC, or TDF) administered individually. The effects of coadministration of other drugs on the AUC, C max , and C min values of RPV, FTC, and TDF are summarized in Tables 9, 10, and 11, respectively. The effect of coadministration of RPV, FTC, and TDF on the AUC, C max , and C min values of other drugs are summarized in Tables 12, 13, and 14, respectively. For information regarding clinical recommendations, see Drug Interactions (7) . Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for RPV in the Presence of the Coadministered Drugs NA=not available a. N=maximum number of subjects for C max , AUC, or C min b. Increase = ↑; Decrease = ↓; No Effect = ↔ c. The interaction study has been performed with a dose higher than the recommended dose for RPV (25 mg once daily) assessing the maximal effect on the coadministered drug. d. Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (RPV/FTC/TDF) coadministered with HARVONI (ledipasvir/sofosbuvir). e. Comparison based on historic controls. f. Reference arm for comparison was 25 mg q.d. RPV administered alone. g. Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets coadministered with EPCLUSA (sofosbuvir/velpatasvir). h. Study conducted with ODEFSEY ® (FTC/RPV/tenofovir alafenamide). i. Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. Coadministered Drug Dose of Coadministered Drug (mg) RPV Dose (mg) N a Mean % Change of RPV Pharmacokinetic Parameters b (90% CI) C max AUC C min Acetaminophen 500 single dose 150 once daily c 16 ↑9 (↑1 to ↑18) ↑16 (↑10 to ↑22) ↑26 (↑16 to ↑38) Atorvastatin 40 once daily 150 once daily c 16 ↓9 (↓21 to ↑6) ↓10 (↓19 to ↓1) ↓10 (↓16 to ↓4) Chlorzoxazone 500 single dose taken 2 hours after RPV 150 once daily c 16 ↑17 (↑8 to ↑27) ↑25 (↑16 to ↑35) ↑18 (↑9 to ↑28) Ethinyl Estradiol/ Norethindrone 0.035 once daily/1 once daily 25 once daily 16 ↔ d ↔ d ↔ d Famotidine 40 single dose taken 12 hours before RPV 150 single dose c 24 ↓1 (↓16 to ↑16) ↓9 (↓22 to ↑7) NA 40 single dose taken 2 hours before RPV 150 single dose c 23 ↓85 (↓88 to ↓81) ↓76 (↓80 to ↓72) NA 40 single dose taken 4 hours after RPV 150 single dose c 24 ↑21 (↑6 to ↑39) ↑13 (↑1 to ↑27) NA Ketoconazole 400 once daily 150 once daily c 15 ↑30 (↑13 to ↑48) ↑49 (↑31 to ↑70) ↑76 (↑57 to ↑97) Ledipasvir/ Sofosbuvir 90/400 once daily 25 once daily d 14 ↓3 (↓12 to ↑7) ↑2 (↓6 to ↑11) ↑12 (↑3 to ↑21) Methadone 60 to 100 once daily individualized dose 25 once daily 12 ↔ e ↔ e ↔ e Omeprazole 20 once daily 150 once daily c 16 ↓40 (↓52 to ↓27) ↓40 (↓49 to ↓29) ↓33 (↓42 to ↓22) Rifabutin 300 once daily 25 once daily 18 ↓31 (↓38 to ↓24) ↓42 (↓48 to ↓35) ↓48 (↓54 to ↓41) 300 once daily 50 once daily 18 ↑43 (↑30 to ↑56) f ↑16 (↑6 to ↑26) f ↓7 (↓15 to ↑1) f Rifampin 600 once daily 150 once daily c 16 ↓69 (↓73 to ↓64) ↓80 (↓82 to ↓77) ↓89 (↓90 to ↓87) Simeprevir 25 once daily 150 once daily 23 ↑ 4 (↓ 5 to ↑ 13) ↑ 12 (↑ 5 to ↑ 19) ↑ 25 (↑ 16 to ↑ 35) Sildenafil 50 single dose 75 once daily 16 ↓8 (↓15 to ↓1) ↓2 (↓8 to ↑5) ↑4 (↓2 to ↑9) Sofosbuvir/ Velpatasvir 400/100 once daily 25 once daily g 24 ↓7 (↓12 to ↓2) ↓5 (↓10 to 0) ↓4 (↓10 to ↑3) Sofosbuvir/ Velpatasvir/ Voxilaprevir h 400/100/100 + 100 voxilaprevir i once daily 25 once daily 30 ↓21 (↓26 to ↓16) ↓20 (↓24 to ↓15) ↓18 (↓23 to ↓13) TDF 300 once daily 150 once daily c 16 ↓4 (↓19 to ↑13) ↑1 (↓13 to ↑18) ↓1 (↓17 to ↑16) Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Drugs NA=not available a. N=maximum number of subjects for C max , AUC, or C min b. Increase = ↑; Decrease = ↓; No Effect = ↔ c. Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets coadministered with HARVONI. d. Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets coadministered with EPCLUSA. e. Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. f. Study conducted with ODEFSEY (FTC/RPV/tenofovir alafenamide). Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) N a Mean % Change of FTC Pharmacokinetic Parameters b (90% CI) C max AUC C min Famciclovir 500 x 1 200 x 1 12 ↔ ↔ NA Ledipasvir/ Sofosbuvir 90/400 once daily 200 once daily c 15 ↑2 (↓2 to ↑6) ↑5 (↑2 to ↑8) ↑6 (↓3 to ↑15) Sofosbuvir/ Velpatasvir 400/100 once daily 200 once daily d 24 ↓5 (↓10 to 0) ↓1 (↓3 to ↑2) ↑5 (↓1 to ↑11) Sofosbuvir/ Velpatasvir/ Voxilaprevir 400/100/100 + Voxilaprevir e 100 once daily 200 once daily f 30 ↓12 (↓17 to ↓7) ↓7 (↓10 to ↓4) ↑7 (↑1 to ↑14) TDF 300 once daily x 7 days 200 once daily x 7 days 17 ↔ ↔ ↑ 20 (↑ 12 to ↑ 29) Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drugs NA=not available a. Subjects received VIREAD 300 mg daily. b. N=maximum number of subjects for C max , AUC, or Cmin c. Increase = ↑ ; Decrease =↓ ; No Effect = ↔ d. Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets coadministered with HARVONI. e. Study conducted with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets coadministered with EPCLUSA. Coadministered Drug Dose of Coadministered Drug (mg) TDF Dose (mg) a N b Mean % Change of Tenofovir Pharmacokinetic Parameters c (90% CI) C max AUC C min Entecavir 1 once daily x 10 days 300 once daily ↔ ↔ ↔ Emtricitabine 200 once daily x 7 days 300 once daily x 7 days 17 ↔ ↔ ↔ Ledipasvir/ Sofosbuvir 90/400 once daily x 10 days 300 once daily d 14 ↑ 32 (↑ 25 to ↑ 39) ↑ 40 (↑ 31 to ↑ 50) ↑ 91 (↑ 74 to ↑ 110) Sofosbuvir/ Velpatasvir 400/100 once daily 300 once daily 24 ↑ 44 (↑ 33 to ↑ 55) ↑ 40 (↑ 34 to ↑46) ↑ 84 (↑ 76 to ↑ 92) Tacrolimus 0.05 mg/kg twice daily x 7 days 300 once daily e 21 ↑ 13 (↑ 1 to ↑ 27) ↔ ↔ Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of RPV NA = not available a. N=maximum number of subjects for C max , AUC, or C min b. Increase = ↑; Decrease = ↓; No Effect = ↔ c. The Interaction study has been performed with a dose higher than the recommended dose for RPV (25 mg once daily). d. The predominant circulating nucleoside metabolite of sofosbuvir. e. Study conducted with ODEFSEY. Coadministered Drug Dose of Coadministered Drug (mg) RPV Dose (mg) N a Mean % Change of Coadministered Drug Pharmacokinetic Parameters b (90% CI) C max AUC C min Acetaminophen 500 single dose 150 once daily c 16 ↓ 3 (↓ 14 to ↑ 10) ↓ 8 (↓ 15 to ↓ 1) NA Atorvastatin 40 once daily 150 once daily c 16 ↑ 35 (↑ 8 to ↑ 68) ↑ 4 (↓ 3 to ↑ 12) ↓ 15 (↓ 31 to ↑ 3) 2-hydroxy- atorvastatin 16 ↑ 58 (↑ 33 to ↑ 87) ↑ 39 (↑ 29 to ↑ 50) ↑ 32 (↑ 10 to ↑ 58) 4-hydroxy- atorvastatin 16 ↑ 28 (↑ 15 to ↑ 43) ↑ 23 (↑ 13 to ↑ 33) NA Chlorzoxazone 500 single dose taken 2 hours after RPV 150 once daily c 16 ↓ 2 (↓ 15 to ↑ 13) ↑ 3 (↓ 5 to ↑ 13) NA Digoxin 0.5 single dose 25 once daily 22 ↑ 6 (↓ 3 to ↑ 17) ↓ 2 (↓ 7 to ↑ 4) NA Ethinyl estradiol 0.035 once daily 25 once daily 17 ↑ 17 (↑ 6 to ↑ 30) ↑ 14 (↑ 10 to ↑ 19) ↑ 9 (↑ 3 to ↑ 16) Norethindrone 1 mg once daily ↓ 6 (↓ 17 to ↑ 6) ↓ 11 (↓ 16 to ↓ 6) ↓ 1 (↓ 10 to ↑ 8) Ketoconazole 400 once daily 150 once daily c 14 ↓ 15 (↓ 20 to ↓ 10) ↓ 24 (↓ 30 to ↓ 18) ↓ 66 (↓ 75 to ↓ 54) Ledipasvir 90 once daily 25 once daily 41 ↑ 1 (↓ 3 to ↑ 5) ↑ 2 (↓ 3 to ↑ 6) ↑ 2 (↓ 2 to ↑ 7) R(-) methadone 60 to 100 once daily individualized dose 25 once daily 13 ↓ 14 (↓ 22 to ↓ 5) ↓ 16 (↓ 26 to ↓ 5) ↓ 22 (↓ 33 to ↓ 9) S(+) methadone 13 ↓ 13 (↓ 22 to ↓ 3) ↓ 16 (↓ 26 to ↓ 4) ↓ 21 (↓ 33 to ↓ 8) Metformin 850 single dose 25 once daily 20 ↑ 2 (↓ 5 to ↑ 10) ↓ 3 (↓ 10 to ↑ 6) NA Omeprazole 20 once daily 150 once daily c 15 ↓ 14 (↓ 32 to ↑ 9) ↓ 14 (↓ 24 to ↓ 3) NA Rifampin 600 once daily 150 once daily c 16 ↑ 2 (↓ 7 to ↑ 12) ↓ 1 (↓ 8 to ↑ 7) NA 25- desacetylrifampin 16 ↔ (↓ 13 to ↑ 15) ↓ 9 (↓ 23 to ↑ 7) NA Simeprevir 150 once daily 25 once daily 21 ↑ 10 (↓ 3 to ↑ 26) ↑ 6 (↓ 6 to ↑ 19) ↓ 4 (↓ 17 to ↑ 11) Sildenafil N -desmethyl-sildenafil 50 single dose 75 once daily c 16 ↓ 7 (↓ 20 to ↑ 8) ↓ 10 (↓ 20 to ↑ 2) ↓ 3 (↓ 13 to ↑ 8) ↓ 8 (↓ 15 to ↓ 1) NA NA Sofosbuvir GS-331007 d 400 once daily 25 once daily 24 ↑ 9 (↓ 5 to ↑ 25) ↓ 4 (↓ 10 to ↑ 1) ↑ 16 (↑ 10 to ↑ 24) ↑ 4 (0 to ↑ 7) NA ↑ 12 (↑ 7 to ↑ 17) Velpatasvir 100 once daily 25 once daily 24 ↓ 4 (↓ 15 to ↑ 10) ↓ 1 (↓ 12 to ↑ 11) ↑ 2 (↓ 9 to ↑ 15) Sofosbuvir GS-331007 d 400 once daily 25 once daily e 30 ↓ 5 (↓ 14 to ↑ 5) ↑ 2 (↓ 2 to ↑ 6) ↑ 1 (↓ 3 to ↑ 6) ↑ 4 (↑ 1 to ↑ 6) NA NA Velpatasvir 100 once daily 25 once daily e 30 ↑ 5 (↓ 4 to ↑ 16) ↑ 1 (↓ 6 to ↑ 7) ↑ 1 (↓ 5 to ↑ 9) Voxilaprevir 100 + 100 once daily 25 once daily e 30 ↓ 4 (↓ 16 to ↑ 11) ↓ 6 (↓ 16 to ↑ 5) ↑ 2 (↓ 8 to ↑ 12) TDF 300 once daily 150 once daily c 16 ↑ 19 (↑ 6 to ↑ 34) ↑ 23 (↑ 16 to ↑ 31) ↑ 24 (↑ 10 to ↑ 38) Table 13 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of FTC NA=not available a. All interaction trials conducted in healthy volunteers b. No Effect = ↔ Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) N a Mean % Change of Coadministered Drug Pharmacokinetic Parameters b (90% CI) C max AUC C min Famciclovir 500 x 1 200 x 1 12 ↔ ↔ NA TDF 300 once daily x 7 days 200 once daily x 7 days 17 ↔ ↔ ↔ No clinically significant drug interactions have been observed between FTC and indinavir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, stavudine, and zidovudine. Table 14 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of TDF NA=not available a. All interaction trials conducted in healthy volunteers b. Increase = ↑; No Effect = ↔ Coadministered Drug Dose of Coadministered Drug (mg) TDF Dose (mg) N a Mean % Change of Coadministered Drug Pharmacokinetic Parameters b (90% CI) C max AUC C min Emtricitabine 200 once daily x 7 days 300 once daily x 7 days 17 ↔ ↔ ↑20 (↑12 to ↑29) Entecavir 1 once daily x 10 days 300 once daily 28 ↔ ↑ 13 (↑ 11 to ↑ 15) ↔ Tacrolimus 0.05 mg/kg twice daily x 7 days 300 once daily 21 ↔ ↔ ↔ No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TDF: methadone, oral contraceptives (ethinyl estradiol/norgestimate), or ribavirin.