What is the prescribed dose of hydroxyurea (hydroxycarbamide) for sickle cell disease?

Hydroxyurea Dosing for Sickle Cell Disease

Start hydroxyurea at 15-20 mg/kg/day as a single daily oral dose, then titrate to a maximum tolerated dose of 20-35 mg/kg/day based on hematologic response and tolerance. 1

Initial Dosing Strategy

Begin with 15-20 mg/kg/day orally once daily for all patients with HbSS or Sβ0-thalassemia, including children as young as 9 months of age, even without clinical symptoms. 2, 1

• Hydroxyurea is available as capsules, fast-dissolving tablets, or compounded liquid formulations to facilitate administration across age groups 2, 3
• The FDA label confirms this medication is taken once daily by mouth 4

Dose Escalation Protocol

Titrate upward to achieve maximum tolerated dose (MTD) of 20-35 mg/kg/day based on hematologic parameters and clinical tolerance. 1

• Research suggests that 15 mg/kg/day produces significant clinical benefit with minimal side effects, showing improved hemoglobin (0.7-2.0 g/dL increase) and fetal hemoglobin (1.0-18.1% increase) 5
• When escalating from 15 to 20 mg/kg/day, hemoglobin levels plateau but fetal hemoglobin continues to increase, though at the cost of greater myelosuppression 5
• Pediatric studies using average doses of 20 mg/kg/day (range 14-30 mg/kg/day) demonstrated sustained clinical improvement with good tolerability 6

Monitoring Requirements During Titration

Check CBC with reticulocyte count every 2-4 weeks during initial dose escalation, then every 1-3 months once stable dose is achieved. 3

• More frequent monitoring (every 1-3 months) is needed for patients who have been on therapy for shorter durations or have not yet reached dose stability 2, 3
• Watch for dose-limiting myelosuppression, which occurs in approximately 5% of patients but typically resolves within 2 weeks of temporary discontinuation 2, 1

Dose Modifications for Renal Impairment

Reduce the dose for patients with creatinine clearance <60 mL/min or end-stage renal disease (ESRD) on hemodialysis, as drug exposure increases by 64% in these populations. 4

• The FDA label specifically mandates dose reduction in renal impairment based on pharmacokinetic data showing significantly increased drug exposure 4
• For ESRD patients, administer hydroxyurea following hemodialysis sessions 4

Special High-Dose Situations

In hyperleukocytosis emergencies (leukocytes >100 × 10⁹/L), hydroxyurea can be used at 50-60 mg/kg/day until leukocytes decrease to <10-20 × 10⁹/L. 1

• This represents a distinct emergency indication separate from standard sickle cell disease management 1

Managing Toxicity

If myelosuppression occurs (decrease in one or more cell lines), temporarily suspend hydroxyurea for approximately 2 weeks, then resume at a lower dose once counts recover. 2, 1

• Bone marrow suppression is the primary dose-limiting toxicity but is manageable and reversible 2
• Severe neutropenia (absolute neutrophil count <500/mm³) is rare and has not been complicated by infection in clinical trials 2
• Long-term safety data show no increased risk of birth defects, infection, stroke, or neoplasia 2, 1

Critical Pitfalls to Avoid

Do not suspend hydroxyurea when initiating antibiotics like doxycycline, as this is unnecessary and interrupts disease-modifying therapy. 1

• However, hydroxyurea should be suspended ≥72 hours before CAR-T cell infusion in transplant protocols 1
• Caregivers must wear disposable gloves when handling capsules and should never open or crush them due to cytotoxic risk 4
• Adherence to both medication and monitoring schedules is critical for achieving optimal outcomes 3

Expected Clinical Response

Hydroxyurea reduces vaso-occlusive pain crises, acute chest syndrome episodes, hospitalizations, and transfusion requirements by approximately 50%. 2, 7

• In sub-Saharan African children, hydroxyurea reduced vaso-occlusive pain from 98.3 to 44.6 events per 100 patient-years (incidence rate ratio 0.45) and decreased mortality from 3.6 to 1.1 deaths per 100 patient-years (incidence rate ratio 0.30) 8
• Laboratory improvements include increased hemoglobin, increased fetal hemoglobin, increased MCV, and decreased reticulocyte, neutrophil, and platelet counts 2, 5, 6
• Prolonged therapy (≥5 years) is necessary to achieve mortality benefit, with 17-year data showing 30.4% vs 51.1% mortality in those receiving ≥5 years of therapy versus <5 years (RR 0.60) 2