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Odefsey(rilpivirine/emtricitabine/tenofovir alafenamide)tablets
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ODEFSEY safely and effectively. See full prescribing information for ODEFSEY.
ODEFSEY ® (emtricitabine, rilpivirine, and tenofovir alafenamide) tablets, for oral use
Initial U.S. Approval: 2016
WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
See full prescribing information for complete boxed warning.
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Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs. (5.1)
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ODEFSEY is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), and may occur with ODEFSEY. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.2)
INDICATIONS AND USAGE
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 patients 12 years of age and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of ODEFSEY. (1)
DOSAGE AND ADMINISTRATION
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Testing: prior to initiation of ODEFSEY, patients should be tested for hepatitis B virus infection, and estimated creatinine clearance, urine glucose, and urine protein should be obtained. (2.1)
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Recommended dosage: one tablet taken orally once daily with a meal. (2.2)
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After initiation of ODEFSEY, additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound. (2.3)
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Renal impairment: ODEFSEY is not recommended in patients with estimated creatinine clearance below 30 mL per minute. (2.4)
DOSAGE FORMS AND STRENGTHS
Tablets: 200 mg of FTC, 25 mg of RPV and 25 mg of TAF. (3)
CONTRAINDICATIONS
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)
WARNINGS AND PRECAUTIONS
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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. (5.3)
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Concomitant use of ODEFSEY with other drugs that may reduce the exposure of RPV may lead to loss of therapeutic effect of ODEFSEY and possible development of resistance. (5.4)
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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. (5.5)
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Depressive disorders: Severe depressive disorders have been reported. Immediate medical eva luation is recommended for severe depressive disorders. (5.6)
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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. (5.7)
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Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.8)
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Immune reconstitution syndrome: May necessitate further eva luation and treatment. (5.9)
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New onset or worsening renal impairment: Assess creatinine clearance, urine glucose, and urine protein in all patients before initiating ODEFSEY therapy and monitor during therapy. Monitor serum phosphorus in patients with chronic kidney disease. (5.10)
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Bone loss and mineralization defects: Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.11)
ADVERSE REACTIONS
Rilpivirine: Most common adverse reactions to RPV (incidence greater than or equal to 2%, Grades 2–4) are depressive disorders, insomnia, and headache. (6.1)
Emtricitabine & Tenofovir Alafenamide: Most common adverse reaction (incidence greater than or equal to 10%, all grades) is nausea. (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.
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CYP3A4 inducers or inhibitors: Drugs that induce or inhibit CYP3A4 may affect the plasma concentrations of RPV. (7.1)
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P-glycoprotein (P-gp) inducers or inhibitors: Drugs that strongly affect P-gp activity may lead to changes in TAF absorption. (7.1)
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Drugs that increase gastric pH: Drugs that increase gastric pH may decrease plasma concentrations of RPV. (7.1)
USE IN SPECIFIC POPULATIONS
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Lactation: Women infected with HIV should be instructed not to breastfeed, due to the potential for HIV transmission. (8.2)
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Pediatrics: Not recommended for patients less than 12 years of age or weighing less than 35 kg. (8.4)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 3/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
ODEFSEY is indicated as a complete regimen for the treatment of HIV-1 infection in patients 12 years of age and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least six 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)].
2 DOSAGE AND ADMINISTRATION
2.1 Testing Prior to Initiation of ODEFSEY
Prior to initiation of ODEFSEY, patients should be tested for hepatitis B virus infection [see Warnings and Precautions (5.2)].
Estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating ODEFSEY therapy and should be monitored during therapy in all patients [see Warnings and Precautions (5.10)].
2.2 Recommended Dosage
ODEFSEY is a 3-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 the following patient population: adults and in pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg and a creatinine clearance greater than or equal to 30 mL per minute [see Clinical Pharmacology (12.3)].
2.3 Testing After Initiation of ODEFSEY
In virologically-suppressed patients, additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound [see Clinical Studies (14)].
3 DOSAGE FORMS AND STRENGTHS
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.
4 CONTRAINDICATIONS
ODEFSEY is contraindicated when coadministered with the following drugs, as significant decreases in RPV plasma concentrations may occur due to cytochrome P450 (CYP) 3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to ODEFSEY or to the class of NNRTIs [see Warnings and Precautions (5.4), Drug Interactions (7) and Clinical Pharmacology (12.3)]:
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the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
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the antimycobacterials rifampin and rifapentine
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proton pump inhibitors, such as dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
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the glucocorticoid systemic dexamethasone (more than a single dose)
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St. John's wort (Hypericum perforatum)
5 WARNINGS AND PRECAUTIONS
5.1 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 in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Given that ODEFSEY contains two nucleos(t)ide analogs (i.e., FTC and TAF), ODEFSEY should be discontinued 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).
5.2 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
Patients with HIV-1 should be tested for the presence of hepatitis B virus (HBV) before initiating antiretroviral therapy [see Dosage and Administration (2.1)]. ODEFSEY is not approved for the treatment of chronic HBV infection, and the safety and efficacy of ODEFSEY have not been established in patients coinfected with HIV-1 and HBV.
Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing FTC and/or TDF, and may occur with discontinuation of ODEFSEY. Patients coinfected 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. If appropriate, initiation of antihepatitis 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.
5.3 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 subjects. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions (6.2)].
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.
5.4 Loss of Virologic Response Due to Drug Interactions
The concomitant use of ODEFSEY and other drugs may result in known or 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.
See Table 1 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Contraindications (4) and Drug Interactions (7)]. Consider the potential for drug interactions prior to and during ODEFSEY therapy; review concomitant medications during ODEFSEY therapy; and monitor for the adverse reactions associated with the concomitant drugs.
5.5 Prolongation of QTc Interval with Higher Than Recommended Dosages
In healthy subjects, higher than recommended doses of RPV (75 mg once daily and 300 mg once daily – 3 and 12 times the recommended dosages, respectively) have been shown to prolong the QTc interval of the electrocardiogram [see Drug Interactions (7.2) and Clinical Pharmacology (12.2)]. Consider alternatives to ODEFSEY when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsades de Pointes.
5.6 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 eva luate 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 subjects (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV-treated subjects (n=686) was 9%. Most events were mild or moderate in severity. In RPV-treated subjects, 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 subjects, respectively.
During the Phase 2 trial in RPV-treated pediatric subjects 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 Grade 3 and 4 depressive disorders (regardless of causality) was 6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were r |
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