Dosage & Administration
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Odefsey Prescribing Information
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)].
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)].
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)].
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)].
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)].
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)].
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)].
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.
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 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in ODEFSEY. No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of ODEFSEY.
Data
Human Data
Prospective reports from the APR of overall major birth defects in pregnancies exposed to drug components of ODEFSEY are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation.
Emtricitabine (FTC):
Based on prospective reports to the APR of over 5,400 exposures to FTC-containing regimens during pregnancy resulting in live births (including over 3,900 exposed in the first trimester and over 1,500 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.2% to 3.2%) and 2.7% (95% CI: 1.9% to 3.7%) following first and second/third trimester exposure, respectively, to FTC-containing regimens.
Rilpivirine (RPV):
RPV in combination with a background regimen was evaluated in a clinical trial of 19 pregnant participants with HIV-1 during the second and third trimesters and postpartum. Each of the subjects were on an RPV-based regimen at the time of enrollment. Twelve participants completed the trial through the postpartum period (6–12 weeks after delivery) and pregnancy outcomes are missing for six participants. The exposure (C0h and AUC) of total RPV was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of RPV was similar (>99%) during second trimester, third trimester, and postpartum period [see Clinical Pharmacology (12.3)]. One participant discontinued the trial following fetal death at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 participants who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 participants (83.3%) through the third trimester visit and in 9 participants (75%) through the 6–12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two participants who were withdrawn (one participant was nonadherent to the study drug and one participant withdrew consent). Among the 10 infants with HIV test results available, born to 10 pregnant participants with HIV-1, all had test results that were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. RPV was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of RPV in adults with HIV-1.
Based on prospective reports to the APR of over 750 exposures to RPV-containing regimens during pregnancy resulting in live births (including over 550 exposed in the first trimester and over 200 exposed in the second/third trimester), the prevalence of birth defects in live births was 1.4% (95% CI: 0.6% to 2.8%) and 1.5% (95% CI: 0.3% to 4.3%) following first and second/third trimester exposure, respectively, to RPV-containing regimens.
Tenofovir Alafenamide (TAF):
Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2% (95% CI: 2.6% to 6.3%) and 3.0% (95% CI: 0.8% to 7.5%) following first and second/third trimester exposure, respectively, to TAF-containing regimens.
Animal Data
Emtricitabine: FTC was administered orally to pregnant mice (250, 500, or 1000 mg/kg/day) and rabbits (100, 300, or 1000 mg/kg/day) through organogenesis (on gestation days 6 through 15, and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with FTC in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 108 times higher than human exposures at the recommended daily dose. In a pre/postnatal development study with FTC, mice were administered doses up to 1000 mg/kg/day; no significant adverse effects directly related to drug were observed in the offspring exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended daily dose.
Rilpivirine: RPV was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with RPV in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In a pre/postnatal development study with RPV, where rats were administered up to 400 mg/kg/day through lactation, no significant adverse effects directly related to drug were noted in the offspring.
Tenofovir Alafenamide: TAF was administered orally to pregnant rats (25, 100, or 250 mg/kg/day) and rabbits (10, 30, or 100 mg/kg/day) through organogenesis (on gestation days 6 through 17, and 7 through 20, respectively). No adverse embryo-fetal effects were observed in rats and rabbits at TAF exposures similar to (rats) and approximately 53 (rabbits) times higher than the exposure in humans at the recommended daily dose of ODEFSEY. TAF is rapidly converted to tenofovir; the observed tenofovir exposure in rats and rabbits were 59 (rats) and 93 (rabbits) times higher than human tenofovir exposures at the recommended daily doses. Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and mice was observed after TAF administration compared to tenofovir disoproxil fumarate (TDF, another prodrug for tenofovir) administration, a pre/postnatal development study in rats was conducted only with TDF. Doses up to 600 mg/kg/day were administered through lactation, no adverse effects were observed in the offspring on gestation day 7 [and lactation day 20] at tenofovir exposures of approximately 14 [21] times higher than the exposures in humans at the recommended daily dose of ODEFSEY.
Lactation
Risk Summary
Data from the published literature report the presence of FTC, TAF, and TFV (tenofovir) in human milk; it is unknown if RPV is present in human milk. RPV is present in rat milk (see Data). Data from the published literature have not reported adverse effects of FTC or TAF on a breastfed child; it is not known if RPV has effects on the breastfed child. It is not known if the components of ODEFSEY affect milk production.
Potential risks of breastfeeding include: (1) HIV-1 transmission to infants without HIV-1, (2) developing viral resistance in infants with HIV-1, and (3) adverse reactions in a breastfed infant similar to those seen in adults.
Data
Rilpivirine: In animals, no studies have been conducted to assess the excretion of RPV directly; however, RPV was measured in rat pups which were exposed through the milk of treated dams (dosed up to 400 mg/kg/day).
Pediatric Use
The efficacy and safety of ODEFSEY as a complete regimen for the treatment of HIV-1 was established in pediatric patients 6 years of age and older with body weight greater than or equal to 25 kg [see Dosage and Administration (2.2)]. No pediatric clinical trials were conducted with ODEFSEY. Use of ODEFSEY in this age group is supported by adequate and well-controlled studies of RPV+FTC+TDF in adults with HIV-1 infection, adequate and well-controlled studies of FTC+TAF with EVG+COBI in adults with HIV-1, and by the following pediatric studies conducted using the components of ODEFSEY [see Clinical Studies (14)]:
- 48-week open-label trials of antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years and weighing at least 32 kg (N=36) and aged 6 to less than 12 years weighing at least 17 kg (N=18) treated with RPV and other antiretrovirals. The safety and efficacy of RPV administered with other antiretrovirals were similar to that in antiretroviral treatment-naïve adults with HIV-1 on this regimen [see Adverse Reactions (6.1) and Clinical Studies (14)].
- 48-week open-label trial of 26 virologically-suppressed pediatric participants with HIV-1 aged less than 12 years old and weighing at least 16 kg (N=26) treated with RPV and other antiretrovirals. The safety and efficacy of RPV administered with other antiretrovirals were similar to that in virologically-suppressed adults with HIV-1 on this regimen [see Adverse Reactions (6.1)]
- 48-week open-label trials of antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years and weighing at least 35 kg (N=50) and virologically-suppressed pediatric participants between the ages of 6 to less than 12 years weighing at least 25 kg (N=52) treated with FTC+TAF with EVG+COBI. The safety and efficacy of FTC+TAF with EVG+COBI were similar to that in adults with HIV-1 on this regimen, with the exception of a decrease from baseline in CD4+ cell counts in participants 6 to less than 12 years of age weighing at least 25 kg [see Adverse Reactions (6.1) and Clinical Studies (14)].
Because it is a fixed-dose combination tablet, the dose of ODEFSEY cannot be adjusted for patients of lower age and weight. The safety and efficacy of ODEFSEY have not been established in pediatric patients weighing less than 25 kg [see Clinical Pharmacology (12.3) and Clinical Studies (14)].
Geriatric Use
In clinical trials, 80 of the 97 participants enrolled aged 65 years and over received FTC+TAF with EVG+COBI. No differences in safety or efficacy have been observed between elderly participants and those between 12 and less than 65 years of age. Clinical trials of RPV did not include sufficient numbers of participants aged 65 years and over to determine whether they respond differently from younger participants [see Clinical Pharmacology (12.3)].
Renal Impairment
No dosage adjustment of ODEFSEY is recommended in patients with estimated creatinine clearance greater than or equal to 30 mL per minute. ODEFSEY should be used with caution in adults patients with ESRD (estimated creatinine clearance below 15mL per minute) who are receiving chronic hemodialysis and increased monitoring is recommended for RPV-related adverse effects in patients with ESRD, as RPV concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. On days of hemodialysis, administer the daily dose of ODEFSEY after completion of hemodialysis treatment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
ODEFSEY is not recommended in patients with severe renal impairment (estimated creatinine clearance of 15 to below 30 mL per minute), or in patients with ESRD who are not receiving chronic hemodialysis, as the safety of ODEFSEY has not been established in these populations [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].
Hepatic Impairment
No dosage adjustment of ODEFSEY is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. ODEFSEY has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [see Clinical Pharmacology (12.3)].
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