Odefsey - Drug Monograph

Introduction

Odefsey (emtricitabine/rilpivirine/tenofovir alafenamide) is a fixed-dose combination antiretroviral medication approved by the FDA in 2016 for the treatment of HIV-1 infection. This complete once-daily regimen combines three potent antiretroviral agents into a single tablet, offering improved convenience and a favorable side effect profile compared to earlier antiretroviral regimens.

Mechanism of Action

Odefsey contains three antiretroviral agents with distinct mechanisms of action:

• Emtricitabine: A nucleoside reverse transcriptase inhibitor (NRTI) that competes with deoxycytidine-5'-triphosphate and incorporates into viral DNA, causing chain termination
• Rilpivirine: A non-nucleoside reverse transcriptase inhibitor (NNRTI) that binds to reverse transcriptase, inhibiting both RNA-dependent and DNA-dependent DNA polymerase activities
• Tenofovir alafenamide: A nucleotide reverse transcriptase inhibitor (NtRTI) that is converted to tenofovir diphosphate, which competes with deoxyadenosine triphosphate for incorporation into viral DNA, resulting in chain termination

This triple combination provides synergistic inhibition of HIV-1 replication through complementary mechanisms targeting the reverse transcriptase enzyme.

Indications

Odefsey is indicated for:

• Treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg
• As a complete regimen for antiretroviral-naïve patients with HIV-1 RNA ≤100,000 copies/mL at initiation
• Replacement of current antiretroviral regimen in virologically suppressed (HIV-1 RNA <50 copies/mL) adults with no history of treatment failure and no known substitutions associated with resistance to the individual components

Dosage and Administration

• Must be taken with a meal (approximately 390-500 calories) to ensure adequate rilpivirine absorption
• Should be swallowed whole; not for crushing or chewing

• Renal impairment: Not recommended in patients with CrCl <30 mL/min
• Hepatic impairment: No dosage adjustment needed for mild to moderate impairment; not recommended in severe hepatic impairment
• Pediatric patients: Approved for patients ≥35 kg using adult dosage
• Elderly patients: No dosage adjustment required, but consider age-related renal function changes
• Pregnancy: Category B; use only if potential benefit justifies potential risk

Pharmacokinetics

• Emtricitabine: Tmax ≈1.5 hours, bioavailability 93%
• Rilpivirine: Tmax ≈4 hours, bioavailability increases ~40% with food
• Tenofovir alafenamide: Tmax ≈1 hour, bioavailability increases ~65% with high-fat meal

• Emtricitabine: Vd ≈1.2 L/kg, protein binding <4%
• Rilpivirine: Vd ≈1.7 L/kg, protein binding >99%
• Tenofovir alafenamide: Protein binding ~80%

• Emtricitabine: Minimal metabolism (<13%)
• Rilpivirine: Primarily metabolized by CYP3A4
• Tenofovir alafenamide: Hydrolyzed to tenofovir, then phosphorylated to active form

• Emtricitabine: Renal excretion (86%), half-life ≈10 hours
• Rilpivirine: Fecal excretion (85%), half-life ≈50 hours
• Tenofovir alafenamide: Renal excretion (≥80% as tenofovir), half-life ≈0.5 hours

Contraindications

1. Concomitant use with the following medications due to potential for significant drug interactions: - Strong CYP3A inducers (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, St. John's wort) - Proton pump inhibitors 2. Previous hypersensitivity to any component of Odefsey 3. Patients with severe renal impairment (CrCl <30 mL/min)

Warnings and Precautions

• Depressive disorders: Rilpivirine component associated with depressive symptoms including mood changes, depression, and suicidal ideation
• Hepatotoxicity: Monitor for hepatic toxicity, especially in patients with underlying hepatic disease
• Renal impairment: Monitor renal function in all patients; avoid in those with CrCl <30 mL/min
• Bone effects: Decreases in bone mineral density observed (less pronounced than with tenofovir disoproxil fumarate)
• Immune reconstitution syndrome: May occur during initial treatment
• Lactic acidosis/hepatic steatosis: Rare but serious complication reported with NRTIs

Drug Interactions

• CYP3A4 inducers: Decreased rilpivirine concentrations (avoid concomitant use)
• CYP3A4 inhibitors: Increased rilpivirine concentrations (use with caution)
• Antacids: Separate administration by ≥4 hours
• H2-receptor antagonists: Administer H2 antagonists ≥12 hours before or ≥4 hours after Odefsey
• Divalent cations: Separate administration of supplements containing Ca++, Mg++, Al++, or Fe++ by ≥4 hours
• QT-prolonging drugs: Rilpivirine may prolong QT interval; use caution with other QT-prolonging drugs

Adverse Effects

• Insomnia (4%)
• Headache (3%)
• Depression (2%)
• Rash (2%)
• Nausea (1%)
• Diarrhea (1%)
• Fatigue (1%)

• Severe skin reactions (including Stevens-Johnson syndrome)
• Hepatotoxicity
• Depressive disorders
• Renal impairment
• Lactic acidosis
• Osteomalacia

Monitoring Parameters

• HIV-1 RNA viral load
• CD4+ cell count
• HBV co-infection status
• Renal function (serum creatinine, CrCl, urinalysis)
• Hepatic function
• Bone density (consider in patients with risk factors)
• Pregnancy test (if applicable)

• HIV-1 RNA viral load: At initiation, 2-4 weeks, then every 4-8 weeks until suppressed, then every 3-6 months
• CD4+ cell count: Every 3-6 months
• Renal function: At 3 months, then every 6-12 months
• Hepatic function: Every 3-6 months
• Adherence assessment at every visit
• Screening for depression and mood changes
• Monitoring for signs of immune reconstitution syndrome

Patient Education

• Take exactly as prescribed, one tablet once daily with a meal
• Do not miss doses; maintain consistent timing
• If a dose is missed, take as soon as possible unless it's almost time for the next dose
• Do not stop taking without consulting your healthcare provider
• Report any new symptoms immediately, especially:

- Depression, mood changes, or suicidal thoughts - Skin rash or blistering - Yellowing of skin or eyes - Dark urine - Nausea, vomiting, or abdominal pain

• Use effective contraception; discuss pregnancy plans with your provider
• Inform all healthcare providers about all medications you're taking, including over-the-counter drugs and supplements
• Regular follow-up appointments and laboratory tests are essential
• Odefsey is not a cure for HIV and does not prevent transmission to others

References

1. FDA Prescribing Information: Odefsey (emtricitabine/rilpivirine/tenofovir alafenamide). 2021 2. Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2020 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2020;324(16):1651-1669 3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services 4. Mills A, Crofoot G, McDonald C, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in virologically suppressed adults with HIV: 96-week results from a randomized, double-blind, multicentre, active-controlled, phase 3 non-inferiority study. Lancet HIV. 2019;6(5):e335-e343 5. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naïve patients in the ARTEMIS study. HIV Med. 2013;14(1):49-59 6. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naïve adults with HIV-1 infection: 96 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet Infect Dis. 2013;13(11):927-935