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Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Alafenamide

FDA Drug Information • Also known as: Odefsey

Brand Names
Odefsey
Drug Class
Human Immunodeficiency Virus Nucleoside Analog Reverse Transcriptase Inhibitor [EPC]
Route
ORAL
Dosage Form
TABLET
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B Severe acute exacerbations of hepatitis B have been reported in patients with HIV-1 and HBV who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of ODEFSEY. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients with HIV-1 and HBV who discontinue ODEFSEY. If appropriate, anti-hepatitis B therapy may be warranted [see Warnings and Precautions (5.1) ] . WARNING: POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. Severe acute exacerbations of hepatitis B have been reported in patients with HIV-1 and HBV who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with discontinuation of ODEFSEY. Hepatic function should be monitored closely in these patients. If appropriate, anti-hepatitis B therapy may be warranted. ( 5.1 )

Description

11 DESCRIPTION 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...

What Is Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Alafenamide Used For?

1 INDICATIONS AND USAGE 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 [see Microbiology (12.4) and Clinical Studies (14) ]. 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. ( 1 ) 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 [see Clinical Studies (14.2 , 14.3) ].

Dosage and Administration

2 DOSAGE AND ADMINISTRATION 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 ( 2.1 ) Recommended dosage: one tablet taken orally once daily with a meal. ( 2.2 ) 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. ( 2.3 ) 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. ( 2.4 ) 2.1 Testing Prior to Initiation and During Treatment with ODEFSEY Prior to or when initiating ODEFSEY, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1) ] . 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 [see Warnings and Precautions (5.5) ]. 2.2 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]. 2.3 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 [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) ] . 2.4 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 [see Dosage and Administration (2.2) , Warnings and Precautions (5.5) , and Use in Specific Populations (8.6) ].

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B [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) ] Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Warnings and Precautions (5.7) ] Immune Reconstitution Syndrome [see Warnings and Precautions (5.8) ] Most common adverse reactions (incidence greater than or equal to 2%, all grades) are headache and sleep disturbances. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 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 (or a drug given in various combinations with other concomitant therapy) cannot be directly compared to rates in the clinical trials of another drug (or drug given in the same or different combination therapy) and may not reflect the rates observed in practice. Adverse Reactions in Clinical Trials of ODEFSEY in Virologically-Suppressed Adult Participants with HIV-1 The safety of ODEFSEY in virologically-suppressed adults is based on Week 48 data from two randomized, double-blinded, active-controlled clinical trials, 1160 and 1216, that enrolled 1505 adult participants with HIV-1 who were virologically-suppressed for at least 6 months. Both trials were designed to compare switching to ODEFSEY to maintaining efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) or emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) in Trials 1160 and 1216, respectively. A total of 754 participants received one tablet of ODEFSEY daily [see Clinical Studies (14.1) ]. The most common adverse reactions (all Grades) reported in at least 2% of participants in the ODEFSEY group across Trials 1216 and 1160 were headache and sleep disturbances (Table 1). Over 98% of the adverse reactions in the ODEFSEY group were of mild to moderate intensity. The proportion of participants who discontinued treatment with ODEFSEY due to adverse events, regardless of severity, was 2% compared to 1% for FTC/RPV/TDF and 2% for EFV/FTC/TDF. Table 1 Adverse Reactions Frequencies of adverse reactions are based on all adverse events attributed to study drugs by the investigator. (All Grades) Reported in ≥1% of Virologically-Suppressed Adults with HIV-1 in Trial 1160 or Trial 1216 (Week 48 analysis) Adverse Reaction Trial 1160 Trial 1216 ODEFSEY (N=438) EFV/FTC/TDF (N=437) Data from Trials 1160 and 1216 do not provide an adequate basis for comparison of adverse reaction incidences between ODEFSEY and the FTC/RPV/TDF and EFV/FTC/TDF groups. ODEFSEY (N=316) FTC/RPV/TDF (N=313) Headache 2% 1% 0 1% Sleep Disturbances 2% 1% 0 <1% Flatulence 1% <1% <1% 1% Abnormal Dreams 1% 1% 0 2% Diarrhea 1% 3% 1% 2% Nausea 1% 1% 1% 1% Renal Laboratory Tests In Trial 1216, the median baseline eGFR was 104 mL per minute for participants who switched to ODEFSEY from FTC/RPV/TDF (N=316) and the mean serum creatinine decreased by 0.02 mg per dL from baseline to Week 48. In Trial 1160, the median baseline eGFR was 110 mL per minute for participants who switched to ODEFSEY from EFV/FTC/TDF (N=438), and the mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. Bone Mineral Density Effects Changes in BMD from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA) in Trials 1216 and 1160. In Trial 1216, mean bone mineral density (BMD) increased in participants who switched to ODEFSEY (1.61% lumbar spine, 1.04% total hip) and remained stable or decreased in participants who remained on FTC/RPV/TDF (0.08% lumbar spine,...

Drug Interactions

7 DRUG INTERACTIONS 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. ( 7.1 ) 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. 7.2 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 [see 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 [see Contraindications (4) , Warnings and Precautions (5.6) , and Table 4 ] . Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV and possible adverse events. 7.3 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 (see Table 4 ) . 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. 7.4 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 [see Contraindications (4) and Table 4 ]. 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. 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 [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.2) ] . Consider alternative medications to ODEFSEY in patients taking a drug with a known risk of Torsade de Pointes. 7.6 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...

Contraindications

4 CONTRAINDICATIONS ODEFSEY is contraindicated when coadministered with the following drugs; coadministration may result in loss of virologic response and possible resistance to ODEFSEY or to the class of NNRTIs [see Warnings and Precautions (5.6) , 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 ODEFSEY is contraindicated when coadministered with drugs where significant decreases in RPV plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to ODEFSEY 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 statistically significant difference in the overall risk of major birth defects for emtricitabine (FTC), rilpivirine (RPV) or tenofovir alafenamide (TAF) compared with the background rate for major birth defects of 2.7% in a US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data ) . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15–20%. Based on the experience of pregnant individuals with HIV-1 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 compared to the postpartum period. 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 ODEFSEY were administered separately during the period of organogenesis at exposures up to 60 and 108 times (mice and rabbits, respectively; FTC), 15 and 70 times (rats and rabbits, respectively; RPV) and equal to and 53 times (rats and rabbits, respectively; TAF) the exposure at the recommended daily dose of these components in ODEFSEY (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...

Overdosage

10 OVERDOSAGE Limited data are available on overdose of the components of ODEFSEY in patients. If overdose occurs, monitor the patient for evidence of toxicity. Treatment of overdose with ODEFSEY consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. Emtricitabine (FTC): Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis. Rilpivirine (RPV): Human experience of overdose with RPV is limited. There is no specific antidote for overdose with RPV. Since RPV is highly bound to plasma protein, dialysis is unlikely to result in significant removal of RPV. Tenofovir Alafenamide (TAF): Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING ODEFSEY tablets are gray, capsule-shaped, and film coated with "GSI" debossed on one side and "255" on the other side. Each bottle contains 30 tablets (NDC 61958-2101-1), a silica gel desiccant, and a polyester coil, and is closed with a child-resistant closure. Store below 30°C (86°F). Keep container tightly closed. Dispense only in original container.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.