Voxelotor

• Sickle Cell Disease
• Sickle Cell Anemia
• Hemolytic Anemia

Voxelotor is a hemoglobin S (HbS) polymerization inhibitor used to treat sickle cell disease (SCD) in adults and pediatric patients 4 years of age and older. It works by increasing hemoglobin's affinity for oxygen, preventing the sickling of red blood cells that causes the vaso-occlusive crises and hemolytic anemia characteristic of sickle cell disease.

Mechanism of Action

Voxelotor works through a unique mechanism targeting hemoglobin:

• Hemoglobin S polymerization inhibitor: Binds reversibly to hemoglobin with high affinity
• Increases oxygen affinity: Stabilizes the oxygenated state of hemoglobin
• Prevents sickling: Oxygenated HbS cannot polymerize into the rigid fibers that deform red blood cells
• Reduces hemolysis: Decreases destruction of sickled cells, improving anemia
• Improves blood flow: May reduce vaso-occlusion by maintaining normal RBC shape

By keeping hemoglobin in its oxygenated form, voxelotor addresses a fundamental aspect of sickle cell pathophysiology.

Available Formulations

Voxelotor is available as:

• 500 mg film-coated tablets (Oxbryta)
• 300 mg film-coated tablets for pediatric dosing
• Powder for oral suspension (300 mg/5 mL after reconstitution)

Medical Uses

FDA-Approved Indication:

• Treatment of sickle cell disease in adults and pediatric patients 4 years of age and older

Voxelotor can be used as monotherapy or in combination with hydroxyurea.

Dosing Guidelines

Adults and Pediatric Patients ≥12 years:

• 1500 mg (three 500 mg tablets) orally once daily

Pediatric Patients 4 to <12 years:

• Weight-based dosing:
  • <20 kg: 600 mg once daily
  • 20 to <40 kg: 900 mg once daily
  • ≥40 kg: 1500 mg once daily

Administration:

• Take with or without food
• Swallow tablets whole; do not cut, crush, or chew
• Oral suspension available for patients who cannot swallow tablets
• Can be given with or without hydroxyurea

Important Safety Information

Warnings and Precautions:

• Laboratory interference: May interfere with measurement of HbS percentage on certain hemoglobin electrophoresis methods; results may be falsely low
• Hypersensitivity reactions: Serious reactions including rash and urticaria reported; discontinue if severe reaction occurs

Drug Interactions

• Strong CYP3A4 inhibitors (itraconazole, clarithromycin, ritonavir): Increase voxelotor exposure; consider dose reduction to 1000 mg daily
• Moderate CYP3A4 inhibitors (fluconazole, verapamil): May increase voxelotor levels; monitor for adverse reactions
• Strong CYP3A4 inducers (rifampin, phenytoin, carbamazepine, St. John's Wort): Avoid concurrent use; decrease voxelotor efficacy
• Sensitive CYP3A4 substrates (certain hormonal contraceptives, midazolam): Voxelotor may decrease their levels; consider alternative contraception
• P-glycoprotein substrates (digoxin): May increase substrate exposure; monitor digoxin levels
• Hydroxyurea: Can be used concomitantly; no dose adjustment needed

Special Populations

• Hepatic Impairment: Reduce to 1000 mg daily in severe impairment (Child-Pugh C); no adjustment for mild-moderate
• Renal Impairment: No dose adjustment for eGFR ≥15 mL/min; limited data in ESRD
• Pregnancy: Limited human data; animal studies showed fetal harm at high doses; counsel on risks and benefits
• Lactation: Unknown if excreted in breast milk; consider developmental benefits of breastfeeding
• Pediatric: Approved for ages 4+; safety and efficacy established in clinical trials
• Geriatric: Limited data in patients ≥65 years; use with caution

Monitoring

• Hemoglobin levels (typically increases 1-2 g/dL)
• Signs of hemolysis improvement
• Note that HbS percentage may appear falsely low on certain assays