Drug Facts
Composition & Profile
Identifiers & Packaging
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.; PRINCIPAL DISPLAY PANEL - 30 Tablet Bottle Label NDC 61958- 2101 -1 30 tablets Odefsey ® (emtricitabine, rilpivirine, and tenofovir alafenamide) Tablets 200 mg/25 mg/25 mg Note to pharmacist: Do not cover ALERT box with pharmacy label. ALERT: Find out about medicines that should NOT be taken with Odefsey ® odefsey-04.jpg
- 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.
- PRINCIPAL DISPLAY PANEL - 30 Tablet Bottle Label NDC 61958- 2101 -1 30 tablets Odefsey ® (emtricitabine, rilpivirine, and tenofovir alafenamide) Tablets 200 mg/25 mg/25 mg Note to pharmacist: Do not cover ALERT box with pharmacy label. ALERT: Find out about medicines that should NOT be taken with Odefsey ® odefsey-04.jpg
Overview
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
Indications & 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 & 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) ].
Warnings & Precautions
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. ( 5.2 ) 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. ( 5.3 ) 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: 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. ( 5.5 ) 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. ( 5.6 ) Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. ( 5.7 ) Immune reconstitution syndrome: May necessitate further evaluation and treatment. ( 5.8 ) 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 [see Dosage and Administration (2.1) ] . 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. 5.2 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 [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. 5.3 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. 5.4 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. 5.5 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 [see Adverse Reactions (6.1 , 6.2) ] . 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. 5.6 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 [see Contraindications (4) , and Drug Interactions (7) ]: 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 Drug Interactions (7.2) and Clinical Pharmacology (12.2) ] . See Table 3 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 and review concomitant medications during ODEFSEY therapy. 5.7 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). 5.8 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.
Boxed 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 )
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 )
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, −0.25% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1.7% of ODEFSEY participants and 3.0% of FTC/RPV/TDF participants. BMD declines of 7% or greater at the femoral neck were experienced by 0% of ODEFSEY participants and 1.2% of FTC/RPV/TDF participants. In Trial 1160, mean BMD increased in participants who switched to ODEFSEY (1.65% lumbar spine, 1.28% total hip) and decreased slightly in participantswho remained on EFV/FTC/TDF (−0.05% lumbar spine, −0.13% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 2.3% of ODEFSEY participants and 4.9% of EFV/FTC/TDF participants. BMD declines of 7% or greater at the femoral neck were experienced by 1.4% of ODEFSEY participants and 3.3% of EFV/FTC/TDF participants. The long-term clinical significance of these BMD changes is not known. Serum Lipids Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio for Trials 1216 and 1160 are presented in Table 2. Table 2 Lipid Values, Mean Change from Baseline Reported in Participants Receiving ODEFSEY, FTC/RPV/TDF and EFV/FTC/TDF in Trials 1216 and 1160 at 48 Weeks Trial 1216 Trial 1160 ODEFSEY N=316 [n=235] FTC/RPV/TDF N=314 [n=245] ODEFSEY N=438 [n=295] EFV/FTC/TDF N=437 [n=308] Baseline Week 48 Baseline Week 48 Baseline Week 48 Baseline Week 48 mg/dL Change The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values. , Participants who received lipid-lowering agents during the treatment period were excluded. mg/dL Change , mg/dL Change , mg/dL Change , Total Cholesterol (fasted) 176 +17 171 0 193 -7 192 -3 HDL-Cholesterol (fasted) 50 +3 48 0 56 -4 55 -2 LDL-Cholesterol (fasted) 111 +13 108 +1 118 [n=296] for ODEFSEY group in Study 1160 for LDL-Cholesterol (fasted) -1 119 -1 Triglycerides (fasted) 116 +12 119 -9 139 -12 133 +3 Total Cholesterol to HDL Ratio 3.7 +0.2 3.8 +0.1 3.7 +0.2 3.8 0 Adverse Reactions in Clinical Trials of RPV-Containing Regimens in Treatment-Naïve Adult Participants with HIV-1 In pooled 96-week trials of antiretroviral treatment-naïve adult participants with HIV-1, the most common adverse reactions in participantstreated with RPV+FTC/TDF (N=550) (incidence greater than or equal to 2%, Grades 2−4) were headache, depressive disorders, and insomnia. The proportion of participants who discontinued treatment with RPV+FTC/TDF due to adverse reactions, regardless of severity, was 2%. The most common adverse reactions that led to discontinuation in this treatment group were psychiatric disorders (1.6%) and rash (0.2%). Although the safety profile was similar in virologically-suppressed adults with HIV-1 who were switched to RPV and other antiretroviral drugs, the frequency of adverse events increased by 20% (N=317). Adrenal Function In the pooled Phase 3 trials, 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%) of participants 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%) in the EFV group. Of the participants who developed an abnormal 250 micrograms ACTH stimulation test during the trial, 14 participants in the RPV group and 9 participants 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. Adverse Reactions in Clinical Trials of FTC+TAF with EVG+COBI in Treatment-Naïve Adult Participants with HIV-1 In pooled 48-week trials of antiretroviral treatment-naïve adult participants with HIV-1, the most common adverse reaction in participants treated with FTC+TAF with EVG+COBI (N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%). In this treatment group, 0.9% of participants discontinued FTC+TAF with EVG+COBI due to adverse event [see Clinical Studies (14) ] . Antiretroviral treatment-naïve adult participants treated with FTC+TAF with EVG+COBI experienced mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7 mg/dL of HDL cholesterol and 29 mg/dL of triglycerides after 48 weeks of use. Renal Laboratory Tests In two 48-week trials in antiretroviral treatment-naïve adults with HIV-1 treated with FTC+TAF with elvitegravir (EVG) plus cobicistat (COBI) (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. In clinical trials of FTC+TAF with EVG+COBI in treatment-naïve participants and in virologically-suppressed participants switched to FTC+TAF with EVG+COBI with estimated creatinine clearance greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC+TAF with EVG+COBI. In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24. FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) participants. Bone Mineral Density Effects In the pooled analysis of two 48-week trials of antiretroviral treatment-naïve adult participants with HIV-1, bone mineral density (BMD) from baseline to Week 48 was assessed by dual-energy X-ray absorptiometry (DXA). Mean BMD decreased from baseline to Week 48 by -1.30% with FTC+TAF with EVG+COBI at the lumbar spine and -0.66% at the total hip. BMD declines of 5% or greater at the lumbar spine were experienced by 10% of FTC+TAF with EVG+COBI participants. BMD declines of 7% or greater at the femoral neck were experienced by 7% of FTC+TAF with EVG+COBI participants. The long-term clinical significance of these BMD changes is not known. Adverse Reactions in Clinical Trials in Pediatric Participants with HIV-1 In an open-label 48-week trial (TMC278-C213 Cohort 1) of 36 antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years (weighing at least 32 kg) treated with 25 mg per day of RPV and other antiretrovirals, the most common adverse reactions were headache (19%), depression (19%), somnolence (14%), nausea (11%), dizziness (8%), abdominal pain (8%), vomiting (6%) and rash (6%). In an open-label 48-week trial (TMC278-C213 Cohort 2) of 18 antiretroviral treatment-naïve pediatric participants with HIV-1 aged 6 to less than 12 years (weighing at least 17 kg) treated with RPV and other antiretrovirals, the most common adverse reactions were decreased appetite (17%), vomiting (11%), ALT increased (11%), AST increased (11%), and rash (11%). In an open-label 48-week trial (TMC278HTX2002) of 26 virologically suppressed participants with HIV-1 less than 12 years of age (weighing at least 16 kg) treated with RPV and other antiretrovirals, the most commen adverse reactions were vomiting (15%), abdominal pain (12%), nausea (8%), ALT increased (12%), AST increased (8%), and decreased appetite (8%). In a 48-week, open-label trial, 50 antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years and weighing at least 35 kg (Cohort 1) and 52 virologically-suppressed pediatric participants aged 6 to less than 12 years and weighing at least 25 kg (Cohort 2) received FTC+TAF with EVG+COBI. With the exception of a decrease in the mean CD4+ cell count observed in Cohort 2 of this study, the safety profile in pediatric participants who received this combination was similar to that in adults. Bone Mineral Density Effects Among the pediatric participants in Cohort 1 receiving FTC+TAF with EVG+COBI, mean BMD increased from baseline to Week 48, +4.2% at the lumbar spine and +1.3% for the total body less head (TBLH). Mean changes from baseline BMD Z-scores were -0.07 for lumbar spine and -0.20 for TBLH at Week 48. In cohort 1, one participant had significant (at least 4%) lumbar spine BMD loss at Week 48. Among the pediatric participants in Cohort 2 receiving FTC+TAF with EVG+COBI, mean BMD increased from baseline to Week 48, +3.9% at the lumbar spine and +4.2% for TBLH. Mean changes from baseline BMD Z-scores were -0.24 for lumbar spine and -0.19 for TBLH at Week 48. In Cohort 2, six participants had significant (at least 4%) lumbar spine BMD loss at Week 48; 2 participants also had at least 4% TBLH BMD loss at Week 48. Change from Baseline in CD4+ Cell Counts Although all participants in Cohort 2 receiving FTC+TAF with EVG+COBI had HIV-1 RNA < 50 copies/mL, there was a decrease from baseline in CD4+ cell count at Weeks 24 and 48. The mean baseline and mean change from baseline in CD4+ cell count and in CD4% from Week 2 to Week 48 are presented in Table 3. All participants maintained their CD4+ cell counts above 400 cells/mm 3 [see Use in Specific Populations (8.4) and Clinical Studies (14.3) ]. Table 3 Mean Change in CD4+ Count and CD4 Percentage from Baseline to Week 48 in Virologically-Suppressed Pediatric Patients from 6 to <12 Years Who Switched to FTC+TAF with EVG+COBI Mean Change from Baseline Baseline Week 2 Week 4 Week 12 Week 24 Week 32 Week 48 CD4+ Cell Count (cells/mm 3 ) 961 (275.5) Mean (SD) -117 -114 -112 -118 -62 -66 CD4% 38 (6.4) +0.3% -0.1% -0.8% -0.8% -1.0% -0.6% Adrenal Function in Clinical Trials of RPV in Pediatric Participants In trial TMC278-C213 Cohort 1, 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%) participants 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 participants 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. In trial TMC278-C213 Cohort 2, basal cortisol at baseline was normal (≥9 μg/dL) for 4/18 participants, low for 13/18 participants, and missing for 1/18 participants. Among the 4 participants with normal basal cortisol at baseline, 3 participants had either normal basal cortisol levels (≥9 μg/dL) or normal cortisol levels 1 hour after ACTH stimulation (≥18.1 μg/dL) throughout the trial and/or at the last available visit (Week 24 and Week 72), and 1 participant had low basal cortisol at the last available assessment (Week 48) and no ACTH stimulation test was performed. Among the 13 participants with low basal cortisol pre-dose at baseline, 2 participants had low basal and ACTH stimulated cortisol values throughout the trial, including ACTH stimulated cortisol at baseline before starting treatment with RPV. For both participants, no adverse events suggestive for adrenal insufficiency were reported. The remaining 11 participants had normal serum cortisol values after ACTH stimulation at baseline and/or during treatment. In trial TMC278HTX2002, 15/26 participants had either normal basal cortisol (≥9 μg/dL) or normal cortisol 1 hour after ACTH stimulation (≥18.1 μg/dL), 9 had low basal cortisol on Day 1, and in 2 participants the baseline value was missing. From the 19 participants with low basal cortisol at Week 48, in 15 participants, the Week 48 serum cortisol levels returned to normal (≥248 nmol/L) after repeat serum basal cortisol testing or was normal after ACTH stimulation testing (≥500 nmol/L). In 4 participants, the serum cortisol levels remained low after repeat serum basal cortisol testing or after ACTH stimulation testing. At Week 48, 6 participants had normal (basal) cortisol (≥9 ug/dL) and the Week 48 result was not available for 1 participant. 6.2 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving RPV or TAF-containing regimens. Because these 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. Rilpivirine: 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) Renal and Urinary Disorders Nephrotic syndrome Tenofovir alafenamide: Skin and Subcutaneous Tissue Disorders Angioedema, urticaria, and rash Renal and Urinary Disorders Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome
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 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 [see Warnings and Precautions (5.5) ] . 7.7 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 [see Clinical Pharmacology (12.3) , Tables 9–12]. 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 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. 7.8 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.
Storage & Handling
Store below 30°C (86°F). Keep container tightly closed. Dispense only in original container.
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