Introduction
Voydeya (danicopan) is a first-in-class oral complement factor D inhibitor developed by AstraZeneca. It represents a novel therapeutic approach for managing paroxysmal nocturnal hemoglobinuria (PNH), particularly addressing the challenging complication of extravascular hemolysis (EVH) that may persist despite standard C5 inhibitor therapy.
Mechanism of Action
Voydeya selectively inhibits complement factor D, a key serine protease in the alternative pathway of the complement system. By blocking factor D, danicopan prevents the formation of the C3 convertase enzyme complex (C3bBb), thereby inhibiting downstream complement activation. This mechanism specifically targets C3-mediated extravascular hemolysis while preserving the terminal complement pathway activity controlled by C5 inhibitors, providing a targeted approach to managing breakthrough hemolysis in PNH.
Indications
Voydeya is indicated for the treatment of extravascular hemolysis in adults with paroxysmal nocturnal hemoglobinuria who are being treated with a C5 inhibitor (eculizumab or ravulizumab).
Dosage and Administration
Initial dose: 100 mg orally three times daily Maintenance dose: May be increased to 150 mg three times daily based on clinical response Administration: Can be taken with or without food Dosage adjustment: Required for patients with severe hepatic impairment (Child-Pugh Class C)Pharmacokinetics
Absorption: Rapid absorption with median Tmax of 2 hours Distribution: Apparent volume of distribution ~92 L; protein binding approximately 99% Metabolism: Primarily metabolized by CYP3A4 with minor contributions from CYP2C8 and CYP2C9 Elimination: Terminal half-life approximately 4-6 hours; primarily excreted in feces (77%) with minimal renal excretion Special populations: Exposure increased in hepatic impairment; no significant differences based on age, sex, or renal functionContraindications
- History of serious hypersensitivity reaction to danicopan or any component of the formulation
- Concomitant use with strong CYP3A4 inhibitors in patients with moderate to severe hepatic impairment
Warnings and Precautions
Hepatic Toxicity: Elevations in liver enzymes observed; monitor liver function tests regularly Infections: Increased susceptibility to encapsulated bacterial infections due to complement inhibition; ensure current vaccinations against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae type B Pregnancy: Based on animal data, may cause fetal harm; use only if potential benefit justifies potential risk Lactation: No data on presence in human milk; consider developmental and health benefits versus potential risk Pediatric Use: Safety and effectiveness not establishedDrug Interactions
Strong CYP3A4 Inhibitors: Contraindicated with moderate to severe hepatic impairment; in normal hepatic function, consider dose reduction Moderate CYP3A4 Inhibitors: May increase danicopan exposure; monitor for adverse effects CYP3A4 Inducers: May decrease danicopan exposure; consider alternative agents or dose adjustment Sensitive CYP3A4 Substrates: Danicopan may increase exposure of these medicationsAdverse Effects
Most common (≥10%): Headache, nasopharyngitis, diarrhea, nausea, abdominal pain Serious adverse effects: Hepatic enzyme elevations, serious infections including meningitis Laboratory abnormalities: Increased bilirubin, increased lactate dehydrogenaseMonitoring Parameters
- Complete blood count with reticulocytes
- Lactate dehydrogenase levels
- Haptoglobin levels
- Liver function tests (baseline and periodically)
- Signs and symptoms of infection
- Hemoglobin stability and transfusion requirements
- Direct antiglobulin test (Coombs test) monitoring
Patient Education
- Take Voydeya exactly as prescribed, typically three times daily
- Report any signs of infection (fever, chills, persistent sore throat) immediately
- Be aware of potential liver problems and report symptoms such as jaundice, dark urine, or abdominal pain
- Maintain current vaccinations, particularly against meningococcal infections
- Inform all healthcare providers about Voydeya use before starting any new medications
- Use effective contraception during treatment if of reproductive potential
- Do not stop C5 inhibitor therapy unless instructed by healthcare provider
References
1. FDA Approval Package: Voydeya (danicopan). U.S. Food and Drug Administration. 2024. 2. Risitano AM, et al. Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria. Haematologica. 2021;106(12):3188-3197. 3. Kulasekararaj AG, et al. Danicopan as add-on therapy to C5 inhibition in paroxysmal nocturnal hemoglobinuria: phase 2 study results. Blood. 2023;141(10):1135-1146. 4. Voydeya [package insert]. Wilmington, DE: AstraZeneca; 2024. 5. Schrezenmeier H, et al. Complement inhibition in paroxysmal nocturnal hemoglobinuria: a targeted approach. Lancet Haematol. 2023;10(5):e350-e361. 6. ClinicalTrials.gov: NCT04469465 (ALPHA Study) 7. European Medicines Agency Assessment Report: Voydeya. 2024.