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 ta…

5 WARNINGS AND PRECAUTIONS • Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develops and closely monitor clinical status, including hepatic serum biochemistries. ( 5.2 ) • Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Monitor liver-associated tests before and during treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets in patients with underlying hepatic disease or marked elevations in liver-associated tests. Also consider monitoring liver-associated tests in patients without risk factors. ( 5.3 ) • Depressive disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. ( 5.4 ) • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with concurrent or recent use of nephrotoxic drugs. ( 5.5 ) • Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. ( 5.6 ) • Concomitant use of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets with drugs with a known risk to prolong the QTc interval of the electrocardiogram may increase the risk of Torsade de Pointes. ( 5.7 ) • Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.8 ) • Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.9 ) 5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV Test all patients with HIV-1 for the presence of chronic hepatitis B virus (HBV) before or when initiating antiretroviral therapy [see Dosage and Administration (2.1) ]. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing FTC and/or TDF, two of the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Patients coinfected with HIV-1 and HBV who discontinue emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure. 5.2 Skin and Hypersensitivity Reactions Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with RPV-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials, treatment-related rashes with at least Grade 2 severity were reported in 1% of subjects receiving RPV plus FTC/TDF. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions (6.1 and 6.2 )]. Discontinue emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets immediately if signs or symptoms of severe skin or hyper…

4 CONTRAINDICATIONS 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 )

7 DRUG INTERACTIONS • 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 H 2 -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 are summarized in Table 4. The drug interactions described are based on studies conducted with FTC, RPV, or TDF as indiv…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no increase in the overall risk of major birth defects with first trimester exposure for emtricitabine (FTC), rilpivirine (RPV), or tenofovir (TDF) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data) . In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period [see Clinical Pharmacology (12.3) ]. The rate of miscarriage for individual drugs is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15 to 20%. Based on the experience of HIV-1-infected pregnant individuals who completed a clinical trial through the postpartum period with an RPV-based regimen, no dose adjustments are required for pregnant patients who are already on a stable RPV-containing regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of RPV were observed during pregnancy, therefore viral load should be monitored closely [see Data and Clinical Pharmacology (12.3) ]. In animal studies, no adverse developmental effects were observed when the components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets were administered separately during the period of organogenesis at exposures up to 60 and 120 times (mice and rabbits, respectively, FTC) and 15 and 70 times (rats and rabbits, respectively; RPV) the exposure of these components in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets and at 14 and 19 times (rats and rabbits, respectively) the human dose of TDF based on body surface area comparisons (see Data). Likewise, no adverse developmental effects were seen when FTC was administered to mice and RPV was administered to rats through lactation at exposures up to approximately 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. No adverse effects were observed in the offspring of rats when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets. Data Human Data Prospective reports from the APR of overall major birth defects in pregnancies exposed to drug components of emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease. Emtricitabine: Based on prospective reports to the APR of exposures to FTC-containing regimens during pregnancy resulting in live births (including over 2,750 exposed in the first trimester and over 1,200 exposed in the second/third trimester), there was no increase in overall major birth defects with FTC compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with the second/third trimester exposure to FTC-containing regimens. Rilpivirine: RPV in combination with a background regimen was eva…

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…