What are the considerations and instructions for initiating hydroxyurea in a patient with sickle cell disease?

Initiating Hydroxyurea in Sickle Cell Disease: Considerations and Instructions

Hydroxyurea should be offered to all patients with HbSS or HbSβ0-thalassemia genotypes starting at 9 months of age, regardless of clinical symptoms, to reduce morbidity and mortality associated with sickle cell disease. 1

Patient Selection and Indications

Hydroxyurea therapy is indicated for:

• All children with HbSS or HbSβ0-thalassemia starting at 9 months of age, even without clinical symptoms 1
• Adults with SCD who have:
  • Three or more vaso-occlusive crises (VOC) per year 2
  • History of acute chest syndrome 2
  • Severe symptomatic anemia 1
  • Pulmonary hypertension or increased risk of mortality (TRV >2.5 m/s or NT-pro-BNP >160 pg/ml) 1
  • Recurrent priapism 3
  • Frequent pain requiring healthcare interventions 1

Pre-Initiation Assessment

Before starting hydroxyurea:

1. Laboratory testing:

   • Complete blood count with differential and reticulocyte count
   • Comprehensive metabolic panel (liver and renal function)
   • Pregnancy test for women of childbearing potential (hydroxyurea is teratogenic)

2. Patient education regarding:

   • Expected benefits: reduced pain crises, hospitalizations, acute chest syndrome, and mortality
   • Potential side effects: myelosuppression, gastrointestinal symptoms
   • Importance of adherence and regular monitoring
   • Need for contraception (both men and women)

Dosing Protocol

1. Initial dosing:

   • Start at 15-20 mg/kg/day orally once daily 4, 5
   • For patients with renal impairment, reduce initial dose as hydroxyurea is excreted through the kidneys 4

2. Dose escalation:

   • Monitor blood counts every 2-4 weeks during dose adjustment
   • If blood counts remain acceptable, increase by 5 mg/kg/day every 8-12 weeks
   • Target maximum tolerated dose (MTD) up to 35 mg/kg/day 2
   • For priapism prevention, higher doses (25-35 mg/kg/day) may be required 3

3. Maintenance phase:

   • Once stable dose is achieved, monitor CBC every 1-3 months 1
   • Adjust dose based on laboratory parameters and clinical response

Laboratory Monitoring

• Frequency: Every 2-4 weeks during dose adjustment; every 1-3 months during maintenance
• Parameters to monitor:
  • Complete blood count with differential and reticulocyte count
  • Renal and liver function tests
  • Fetal hemoglobin levels (HbF) periodically to assess response

Dose Adjustments

• Hold hydroxyurea if:

  • Absolute neutrophil count (ANC) <2,500/mm³
  • Platelet count <100,000/mm³
  • Hemoglobin <4.5 g/dL
  • Reticulocyte count <80,000/mm³ (if hemoglobin <9 g/dL)

• Resume at reduced dose when counts recover, then gradually increase as tolerated

Expected Benefits

Patients should be informed that hydroxyurea therapy typically results in:

• Increased hemoglobin levels (8.3 g/dL to 9.0 g/dL) 5
• Increased fetal hemoglobin (2.6% to 19.8%) 5
• Increased MCV (89 fl to 105 fl) 5
• Decreased leukocyte count (10,050/µl to 5,700/µl) 5
• Reduced painful crises (median 4.5 to 2.5 per year) 2
• Reduced acute chest syndrome episodes (51 to 25 cases) 2
• Reduced hospitalizations (1.63 to 0.53 per year) 5
• Reduced transfusions (1.23 to 0.1 per year) 5

Important Caveats and Pitfalls

1. Delayed effect: Therapeutic benefits may not be evident for 3-6 months after initiation; patients should be encouraged to continue therapy even if immediate improvement is not seen 2

2. Adherence challenges: Regular monitoring and education are crucial to maintain adherence, as interruption of therapy can lead to recurrence of symptoms 3

3. Pregnancy considerations: Hydroxyurea is teratogenic and should be discontinued at least 3 months before planned conception; effective contraception is essential during therapy 4

4. Renal impairment: Dose reduction is necessary in patients with renal dysfunction as hydroxyurea is primarily excreted by the kidneys 4

5. Combination therapy: For patients with SCD and chronic kidney disease with worsening anemia, combination therapy with erythropoiesis-stimulating agents may be considered 1

6. Maximum hemoglobin threshold: When treating with hydroxyurea (especially in combination with erythropoiesis-stimulating agents), hemoglobin should not exceed 10 g/dL to reduce the risk of vaso-occlusive complications, stroke, and venous thromboembolism 1

Hydroxyurea remains the cornerstone of SCD management, with demonstrated benefits in reducing morbidity and mortality when used appropriately with careful monitoring.