Hydroxyurea Dosing in Sickle Cell Disease
Start hydroxyurea at 15-20 mg/kg/day orally once daily, then escalate to a maximum tolerated dose (MTD) of 20-35 mg/kg/day based on laboratory monitoring and clinical response. 1, 2
Initial Dosing Strategy
Begin with 15-20 mg/kg/day as a fixed dose for the first 6 months. 2, 3 This starting range has been validated across multiple populations including sub-Saharan Africa where coexisting conditions like malnutrition and malaria are common. 3 The American Academy of Pediatrics recommends offering hydroxyurea to every child with HbSS or Sβ0-thalassemia starting at 9 months of age, even without clinical symptoms. 4, 1
- Hydroxyurea is available as capsules, fast-dissolving tablets, or compounded liquid formulations for ease of administration. 4, 1
- The medication should be taken once daily without interruption unless dose-limiting myelosuppression occurs. 5
Dose Escalation Protocol
After 6 months at the fixed starting dose, escalate by 2.5-5.0 mg/kg increments every 8 weeks to reach MTD of 20-35 mg/kg/day. 2 The target is mild myelosuppression, which indicates optimal dosing without excessive toxicity. 1, 2
- The REACH trial demonstrated that dose escalation to MTD with ongoing optimization significantly improved clinical outcomes compared to fixed dosing, with a 40% reduction in vaso-occlusive episodes (IRR 0.60, p<0.0001) and 79% reduction in acute chest syndrome (IRR 0.21, p<0.0001). 2
- Mean doses achieved in long-term treatment are approximately 28 mg/kg/day. 2
- Some evidence suggests that 15 mg/kg/day may provide adequate clinical benefit with minimal side effects, particularly regarding hemoglobin improvement, though higher doses continue to increase fetal hemoglobin levels. 6
Monitoring Requirements During Dose Titration
Monitor CBC with reticulocyte count every 2-4 weeks during initial dose escalation. 1, 5 Once a stable dose is achieved, monitoring frequency can be reduced to every 1-3 months depending on how long the patient has been on therapy. 4, 1
- The primary dose-limiting toxicity is myelosuppression, which typically resolves within 2 weeks of temporary discontinuation. 1, 5
- If severe bone marrow suppression develops (decreased counts in one or more cell lines), temporarily discontinue hydroxyurea and resume at a lower dose once counts recover. 1, 5
- Dose-limiting toxicity rates remain stable between fixed-dose and MTD phases (approximately 20-24 events per 100 patient-years), indicating that escalation does not increase toxicity risk. 2
Expected Laboratory Responses
Target increases include hemoglobin rising by 0.7-2.0 g/dL, fetal hemoglobin increasing by 1.0-18%, and MCV increasing by 11-28 fL. 2, 6 Expect absolute neutrophil count to decrease as part of the therapeutic effect. 2
- At MTD, mean hemoglobin typically increases from baseline 7.3 g/dL to 8.5 g/dL. 2
- Fetal hemoglobin levels increase from approximately 11% to 23%. 2
- Reticulocyte counts decrease significantly, reflecting reduced hemolysis. 2, 6
Special Populations and Considerations
For patients with chronic kidney disease and worsening anemia, consider combination therapy with erythropoiesis-stimulating agents to allow more aggressive hydroxyurea dosing. 7, 5 However, maintain hemoglobin levels below 10 g/dL (hematocrit <30%) to reduce vaso-occlusive complication risk. 7, 5
- Do not discontinue hydroxyurea when initiating antibiotics like doxycycline for infections. 5
- Adherence to medication and monitoring schedules is critical for achieving optimal outcomes. 1
- Long-term safety data show no increased risk of birth defects, infection, stroke, or neoplasia. 1, 5
Clinical Outcomes with Optimal Dosing
MTD dosing reduces vaso-occlusive pain by 55%, malaria infections by 51%, non-malarial infections by 48%, and mortality by 70% compared to baseline. 2, 3 Transfusion requirements decrease by 67%. 2