ODEFSEY (emtricitabine, rilpivirine, and tenofovir alafenamide) is a fixed-dose combination tablet containing emtricitabine (FTC), rilpivirine (RPV), and tenofovir alafenamide (TAF) for oral administration. FTC, a synthetic nucleoside analog of cytidine, is an HIV-1 nucleoside analog reverse transcriptase inhibitor (HIV-1 NRTI). RPV is an HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI). TAF, an HIV-1 NRTI, is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Each tablet contains 200 mg of FTC, 25 mg of RPV (equivalent to 27.5 of rilpivirine hydrochloride) and 25 mg of TAF (equivalent to 28 mg of tenofovir alafenamide fumarate) and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, and povidone. The tablets are film-coated with a coating material containing iron oxide black, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. Emtricitabine: The chemical name of FTC is 4-amino-5-fluoro-1-(2 R -hydroxymethyl-1,3-oxathiolan-5 S -yl)-(1 H )-pyrimidin-2-one. FTC 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. FTC has a molecular formula of C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24 and 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: The chemical name of rilpivirine hydrochloride drug substance is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C 22 H 18 N 6 ∙ HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula: Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range. Tenofovir Alafenamide: The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N -[( S )-[[(1 R )-2-(6-amino-9 H -purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 1-methylethyl ester, (2 E )-2-butenedioate (2:1). Tenofovir alafenamide fumarate has an empirical formula of C 21 H 29 O 5 N 6 P∙½(C 4 H 4 O 4 ) and a formula weight of 534.50 and has the following structural formula: Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 4.7 mg per mL in water at 20 °C. Chemical Structure Chemical Structure Chemical Structure

ODEFSEY is indicated as a complete regimen for the treatment of HIV-1 infection in adult and pediatric patients weighing at least 25 kg: as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies/mL or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies/mL) for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of ODEFSEY . ODEFSEY is a three-drug combination of emtricitabine (FTC) and tenofovir alafenamide (TAF), both HIV nucleoside analog reverse transcriptase inhibitors (NRTIs), and rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI), and is indicated as a complete regimen for the treatment of HIV-1 infection in adult and pediatric patients weighing at least 25kg: as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies/mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies/mL) for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of ODEFSEY. Limitations of Use : More rilpivirine-treated participants 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 participants with HIV-1 RNA less than or equal to 100,000 copies/mL. ( 14.2 , 14.3 ) Limitations of Use: More rilpivirine-treated participants with no antiretroviral treatment history 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 participants with HIV-1 RNA less than or equal to 100,000 copies/mL .

Each ODEFSEY tablet contains 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV) (equivalent to 27.5 mg of rilpivirine hydrochloride), and 25 mg of tenofovir alafenamide (TAF) (equivalent to 28 mg of tenofovir alafenamide fumarate). The tablets are gray, capsule-shaped, film-coated and debossed with "GSI" on one side and "255" on the other side. Tablets: 200 mg of FTC, 25 mg of RPV and 25 mg of TAF.

Testing: Prior to or when initiating ODEFSEY, test for hepatitis B virus infection. Prior to or when initiating ODEFSEY, and during treatment 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 Recommended dosage: one tablet taken orally once daily with a meal. For pregnant patients who are already on ODEFSEY 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. Renal impairment: ODEFSEY is not recommended in patients with estimated creatinine clearance of 15 to below 30 mL per minute, or below 15 mL per minute who are not receiving chronic hemodialysis

Testing Prior to Initiation and During Treatment with ODEFSEY Prior to or when initiating ODEFSEY, test patients for hepatitis B virus infection . Prior to or when initiating ODEFSEY, and during treatment with ODEFSEY, 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

Recommended Dosage in Adult and Pediatric Patients Weighing at Least 25 kg ODEFSEY is a three-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 25 mg of tenofovir alafenamide (TAF). The recommended dosage of ODEFSEY is one tablet taken orally once daily with a meal in adults and pediatric patients with body weight at least 25 kg and creatinine clearance greater than or equal to 30 mL per minute

Recommended Dosage During Pregnancy For pregnant patients who are already on ODEFSEY prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of ODEFSEY taken once daily may be continued. Lower exposures of rilpivirine, a component of ODEFSEY, were observed during pregnancy, therefore viral load should be monitored closely

Not Recommended in Patients with Severe Renal Impairment ODEFSEY is not recommended in patients with: severe renal impairment (estimated creatinine clearance of 15 to below 30 mL per minute); or end stage renal disease (ESRD; estimated creatinine clearance below 15 mL per minute) who are not receiving chronic hemodialysis .

Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience with RPV-containing regimens, 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. Hepatotoxicity: Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Monitor liver-associated tests before and during treatment with ODEFSEY in patients with underlying hepatic disease or marked elevations in liver-associated tests. Also consider monitoring liver-associated tests in patients without risk factors. Depressive disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. New onset or worsening renal impairment: Assessment of serum creatinine, estimated creatinine clearance, urine glucose, and urine protein when initiating ODEFSEY and during therapy on a clinically appropriate schedule in all patients. Also assess serum phosphorus in patients with chronic kidney disease. Concomitant use of ODEFSEY with drugs with a known risk to prolong the QTc interval of the electrocardiogram may increase the risk of Torsade de Pointes. Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. Immune reconstitution syndrome: May necessitate further evaluation and treatment. 5.1 Severe Acute Exacerbation of Hepatitis B in Patients with HIV-1 and HBV Test patients with HIV-1 for the presence of hepatitis B virus (HBV) before or when initiating antiretroviral therapy . Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients with HIV-1 and HBV who have discontinued products containing FTC and/or TDF, and may occur with discontinuation of ODEFSEY. Patients with HIV-1 and HBV who discontinue ODEFSEY should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with ODEFSEY. If appropriate, anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure

Skin and Hypersensitivity Reactions Severe skin and hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with RPV-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunction, including elevations in hepatic serum biochemistries. During Phase 3 clinical trials of RPV, treatment-related rashes with at least Grade 2 severity were reported in 1% of participants. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy . Discontinue ODEFSEY immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated

Hepatotoxicity Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Patients with underlying hepatitis B or C virus infection, or marked elevations in liver-associated tests prior to treatment, may be at increased risk for worsening or development of liver-associated test elevations with use of ODEFSEY. A few cases of hepatic toxicity have been reported in adult patients receiving an RPV-containing regimen who had no preexisting hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with ODEFSEY is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in liver-associated tests prior to treatment initiation. Liver-associated test monitoring should also be considered for patients without preexisting hepatic dysfunction or other risk factors

Depressive Disorders Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with RPV. Promptly evaluate patients with severe depressive symptoms to assess whether the symptoms are related to ODEFSEY, and to determine whether the risks of continued therapy outweigh the benefits. In Phase 3 trials of RPV in adult participants (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV-treated participants (n=686) was 9%. Most events were mild or moderate in severity. In RPV-treated participants, the incidence of Grades 3 and 4 depressive disorders (regardless of causality) was 1%, the incidence of discontinuation due to depressive disorders was 1%, and suicidal ideation and suicide attempt was reported in 4 and 2 participants, respectively. During the Phase 2 trial in RPV-treated pediatric participants 12 to less than 18 years of age (N=36), the incidence of depressive disorders (regardless of causality, severity) was 19% (7/36) through 48 weeks. Most events were mild or moderate in severity. The incidence of Grades 3 and 4 depressive disorders (regardless of causality) was 6% (2/36). None of the participants discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 participant

New Onset or Worsening Renal Impairment Postmarketing case of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events . ODEFSEY is not recommended in patients with estimated creatinine clearance of 15 to below 30 mL per minute, or in patients with estimated creatinine clearance below 15 mL per minute who are not receiving chronic hemodialysis. Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents, including nonsteroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions. Prior to or when initiating ODEFSEY, and during treatment with ODEFSEY, 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. Discontinue ODEFSEY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of ODEFSEY and other drugs may result in potentially significant drug interactions, some of which may lead to : Loss of therapeutic effect of ODEFSEY and possible development of resistance due to reduced exposure of RPV. In healthy participants, higher than recommended doses of RPV (75 mg once daily and 300 mg once daily – 3 and 12 times the recommended dosages in ODEFSEY, respectively) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to ODEFSEY when coadministered with a drug that is known to have a risk of Torsade de Pointes . See Table 3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations . Consider the potential for drug interactions prior to and during ODEFSEY therapy and review concomitant medications during ODEFSEY therapy

Lactic Acidosis/Severe Hepatomegaly with Steatosis Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of ODEFSEY, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with ODEFSEY should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations)

Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including FTC and RPV, both components of ODEFSEY. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves' disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

ODEFSEY is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Consult the Full Prescribing Information prior to and during treatment for important drug interactions. ( 4 , 5.6 , 7 ) 7.1 Not Recommended with Other Antiretroviral Medications Because ODEFSEY is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended

Drugs Inducing or Inhibiting CYP3A Enzymes RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of RPV . 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 and possible adverse events

Drugs Inducing or Inhibiting P-glycoprotein TAF, a component of ODEFSEY, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp and BCRP activity may lead to changes in TAF absorption . Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of ODEFSEY and development of resistance. Coadministration of ODEFSEY with other drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentration of TAF

Drugs Increasing Gastric pH Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and lead to 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

QT Prolonging Drugs There is limited information available on the potential for a pharmacodynamic interaction between RPV and drugs that prolong the QTc interval. In a study of healthy participants, higher than recommended doses of RPV, 75 mg once daily and 300 mg once daily (3 times and 12 times recommended daily dose in ODEFSEY) prolonged the QTc interval . Consider alternative medications to ODEFSEY in patients taking a drug with a known risk of Torsade de Pointes

Drugs Affecting Renal Function Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of ODEFSEY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs

Significant Drug Interactions Table 4 provides a listing of established or potentially clinically significant drug interactions with recommended steps to prevent or manage the drug interaction (the table is not all inclusive). The drug interactions described are based on studies conducted with either ODEFSEY, the components of ODEFSEY (FTC, RPV and TAF) as individual agents, or are predicted drug interactions that may occur with ODEFSEY . For list of contraindicated drugs, . 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 ODEFSEY. 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. Antimycobacterials: rifabutin ↓ RPV The interaction was evaluated in a clinical study. All other drug interactions shown are predicted. ↓ TAF Coadministration of ODEFSEY with rifabutin is not recommended. 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. The dosing recommendation is applicable to the recommended dose of RPV 25 mg once daily. ↑­ TAF ↓ ketoconazole , No dosage adjustment is required when ODEFSEY is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with ODEFSEY. Glucocorticoid (systemic): dexamethasone (more than a single dose) ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance. 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 ODEFSEY. 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 dosage adjustments are required when initiating coadministration of methadone with ODEFSEY. 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

Drugs Without Clinically Significant Interactions with ODEFSEY Based on drug interaction studies conducted with the fixed dose combination or components of ODEFSEY, no clinically significant drug interactions have been observed when ODEFSEY is combined with the following drugs: acetaminophen, atorvastatin, chlorzoxazone, digoxin, ethinyl estradiol, ledipasvir, metformin, midazolam, norethindrone, norgestimate, sildenafil, simeprevir, sofosbuvir, velpatasvir, and voxilaprevir.