EMTRICITABINE, RILPIVIRINE, TENOFOVIR DISOPROXIL FUMARATE

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are fixed-dose combination tablets containing FTC, rilpivirine hydrochloride, and TDF. Emtricitabine (FTC) is a synthetic nucleoside analog of cytidine. Rilpivirine (RPV) is a non-nucleoside reverse transcriptase inhibitor. Tenofovir disoproxil fumarate (TDF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are for oral administration. Each tablet contains 200 mg of FTC, 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of RPV), and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: corn starch, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, red iron oxide, talc, titanium dioxide, triacetin and yellow iron oxide. Emtricitabine: The chemical name of FTC is 4-Amino-5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-2(1H)-pyrimidinone. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position. It has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.25. It has the following structural formula: FTC is a white to off-white powder with a solubility of approximately 112 mg per mL in water at 25°C. Rilpivirine : RPV is available as the hydrochloride salt. The chemical name for rilpivirine hydrochloride is 4-{[4-({4-[(E)-2-Cyanoethenyl]-2, 6-dimethylphenyl} amino) pyrimidin-2-yl] amino}benzonitrile. Hydrochloride. Its molecular formula is C 22 H 18 N 6 • HCl and its molecular weight is 402.9. Rilpivirine hydrochloride has the following structural formula: Rilpivirine hydrochloride is an off-white to yellow colored powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range. Tenofovir DF: TDF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of TDF is 9-[2-(R)-[[bis[[(isopropoxy carbonyl) oxy] methoxy]phosphinoyl]methoxy]propyl]-adenine fumaric acid (1:1). It has a molecular formula of C 19 H 3 0N 5 O 10 P • C 4 H 4 O 4 and a molecular weight of 635.51. It has the following structural formula: TDF is a white to off-white powder with a solubility of 13.4 mg per mL in water at 25°C. All dosages are expressed in terms of TDF except where otherwise noted. Emtricitabine Structural Formula Rilpivirine hydrochloride structural formula TDF structural formula

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), are 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 )

• 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 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) ] .

Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are contraindicated when coadministered with the following drugs; coadministration may result in loss of virologic response and possible resistance to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets or to the class of NNRTIs [see Warnings and Precautions (5.7) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ] : • Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin • Antimycobacterials: rifampin, rifapentine • Glucocorticoid (systemic): dexamethasone (more than a single-dose) • Herbal Products: St John’s wort ( Hypericum perforatum ) • Proton Pump Inhibitors: e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are contraindicated when coadministered with drugs which may result in loss of virologic response and possible resistance to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. ( 4 )

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 2–4) 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 1368 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 Frequencies of adverse reactions are based on all Grades 2–4 treatment-emergent adverse events assessed to be related to study drug. (Grades 2–4) Reported in ≥ 2% of Adult Subjects Receiving RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis) Preferred Term RPV + FTC/TDF EFV + FTC/TDF N=550 N=546 Depressive disorders Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. 2% 2% Headache 2% 2% Insomnia 2% 2% Abnormal dreams 1% 3% Dizziness 1% 7% Nausea 1% 2% Rash 1% 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 1–4), representing worst-grade toxicity, is presented in Table 2. Table 2 Selected Laboratory Abnormalities (Grades 1–4) 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 1.1–1.3 × ULN 6% 1% Grade 2 >1.3–1.8 × ULN 1% 1% Grade 3 >1.8–3.4 × ULN <1% 0 Grade 4 >3.4 × ULN 0 <1% Increased AST Grade 1 1.25–2.5 × ULN 16% 19% Grade 2 >2.5–5.0 × ULN 4% 7% Grade 3 >5.0–10.0 × ULN 2% 3% Grade 4 >10.0 × ULN 1% 1% Increased ALT Grade 1 1.25–2.5 × ULN 19% 22% Grade 2 >2.5–5.0 × ULN 5% 7% Grade 3 >5.0–10.0 × ULN 1% 2% Grade 4 >10.0 × ULN 1% 1% Increased Total Bilirubin Grade 1 1.1–1.5 × ULN 6% <1% Grade 2 >1.5–2.5 × ULN 3% 1% Grade 3 >2.5–5.0 × ULN 1% <1% Increased Total Cholesterol (fasted) Grade 1 200–239 mg/dL 14% 31% Grade 2 240–300 mg/dL 6% 18% Grade 3 >300 mg/dL < 1% 2% Increased LDL Cholesterol (fasted) Grade 1 130–159 mg/dL 13% 28% Grade 2 160–190 mg/dL 5% 13% Grade 3 >190 mg/dL 1% 4% Increased Triglycerides (fasted) Grade 2 500–750 mg/dL 1% 2% Grade 3 751–1200 mg/dL 1% 2% Grade 4 >1200 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 × ULN), increased serum amylase (>175 U/L), increased lipase (>3.0 × 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 Excludes subjects who received lipid lowering agents during the treatment period. N = number of subjects per treatment group 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 The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values. (mg/dL) Mean (mg/dL) Mean (mg/dL) Mean Change (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: I mmune 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.

• Emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. ( 7.1 ) • Consult the Full Prescribing Information prior to and during treatment for important drug interactions. ( 4 , 5.7 , 7 ) 7.1 Not Recommended with Other Antiretroviral Medications Because emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Comprehensive information regarding potential drug-drug interactions with other antiretroviral medications is not provided. This section describes clinically relevant drug interactions with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Drug interaction studies were conducted with the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets (FTC, RPV, and TDF as single agents) or with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets as a combination product [see Dosage and Administration (2) , Contraindications (4) , and Clinical Pharmacology (12.3) ] . 7.2 Drugs Inducing or Inhibiting CYP3A Enzymes Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV [see Contraindications (4) , Warnings and Precautions (5.7) , and Clinical Pharmacology (12.3) ] . Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV. 7.3 Drugs Increasing Gastric pH Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Use of RPV with proton pump inhibitors is contraindicated and use of RPV with H2-receptor antagonists requires staggered administration [see Contraindications (4) and Clinical Pharmacology (12.3) ] . 7.4 Drugs Affecting Renal Function Because FTC and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion, coadministration of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of FTC, tenofovir, and/or other renally eliminated drugs. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.5) ] . 7.5 QT Prolonging Drugs There is limited information available on the potential for a pharmacodynamic interaction between RPV and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, 75 mg once daily and 300 mg once daily doses of RPV (3 times and 12 times the dose in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets) have been shown to prolong the QTc interval of the electrocardiogram [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.2) ] . Consider alternatives to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets when coadministered with a drug with a known risk of Torsade de Pointes. 7.6 Significant Drug Interactions Important drug interaction information for emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets is summarized in Table 4. The drug interactions described are based on studies conducted with FTC, RPV, or TDF as individual medications or with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets as a combination product, or are potential drug interactions [see Clinical Pharmacology (12.3) , Tables 9–14] . For list of contraindicated drugs, [see Contraindications (4) ] . Table 4 Significant This table is not all inclusive. Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration Increase = ↑; Decrease = ↓; No Effect = ↔ Clinical Comment Antacids: antacids (e.g., aluminum, magnesium hydroxide, or calcium carbonate) ↔ RPV (antacids taken at least 2 hours before or at least 4 hours after RPV) ↓ RPV (concomitant intake) Administer antacids at least 2 hours before or at least 4 hours after emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. Antimycobacterials: rifampin rifapentine ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. rifabutin ↓ RPV The interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. If emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with rifabutin, an additional 25 mg tablet of RPV (Edurant) once per day is recommended to be taken concomitantly with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and with a meal for the duration of rifabutin coadministration. Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole ↑ RPV , This interaction study has been performed with a dose higher than the recommended dose for RPV assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended dose of RPV 25 mg once daily. ↓ ketoconazole , No dose adjustment is required when emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment) ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir sofosbuvir/velpatasvir/ voxilaprevir ↑ tenofovir Patients receiving emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets concomitantly with HARVONI ® (ledipasvir/sofosbuvir), EPCLUSA ® (sofosbuvir/velpatasvir), or VOSEVI ® (sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with TDF. H 2 -Receptor Antagonists: cimetidine famotidine nizatidine ranitidine ↔ RPV , (famotidine taken 12 hours before RPV or 4 hours after RPV) ↓ RPV , (famotidine taken 2 hours before RPV) Administer H 2 -receptor antagonists at least 12 hours before or at least 4 hours after emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Herbal Products: St John’s wort ( Hypericum perforatum ) ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin ↑ RPV ↔ clarithromycin ↔ erythromycin ↔ telithromycin Where possible, alternatives such as azithromycin should be considered. Narcotic Analgesics: methadone ↓ R(−) methadone ↓ S(+) methadone ↔ RPV ↔ methadone (when used with tenofovir) No dose adjustments are required when initiating coadministration of methadone with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. Proton Pump Inhibitors: e.g., dexlansoprazole esomeprazole lansoprazole omeprazole pantoprazole rabeprazole ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. 7.7 Drugs with No Observed Interactions with Emtricitabine, Rilpivirine and Tenofovir Disoproxil Fumarate Tablets No clinically significant drug interactions have been observed between FTC and the following medications: famciclovir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF. No clinically significant drug interactions have been observed between TDF and the following medications: entecavir, methadone, oral contraceptives, ribavirin, sofosbuvir, or tacrolimus in studies conducted in healthy subjects. No clinically significant drug interactions have been observed between RPV and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinyl estradiol, ledipasvir/sofosbuvir, norethindrone, sildenafil, simeprevir, sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF. RPV did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.