Hydroxyurea

Hydroxyurea is an oral ribonucleotide reductase inhibitor used to induce foetal haemoglobin and reduce complications in sickle cell disease, and as cytoreduction in chronic myeloid leukaemia, polycythaemia vera and essential thrombocythaemia.

Classification. Antimetabolite; cytoreductive agent; foetal haemoglobin inducer.

Mechanism. Inhibits ribonucleotide reductase, depleting deoxynucleotides and arresting cells in S phase. In sickle cell disease it raises foetal haemoglobin, lowers neutrophils, reticulocytes and adhesion molecules, and releases nitric oxide.

Pharmacokinetics. Well absorbed orally, with peak levels at 1 to 2 hours. Half-life is 2 to 4 hours. About half is metabolised in the liver and half excreted unchanged in urine. It crosses the placenta and the blood brain barrier.

Sickle cell disease (adults and children from 9 months of age; some labels license from 2 years).

• Starting dose: 15 to 20 mg/kg orally once daily (15 mg/kg in adults, 20 mg/kg in children). In sub-Saharan Africa fixed-dose 20 mg/kg daily has been given safely to children with limited monitoring.
• Titration: increase by 5 mg/kg every 8 to 12 weeks, as tolerated, to the maximum tolerated dose, with neutrophils at 1.0 × 10⁹/L or more (2.0 × 10⁹/L or more where monitoring is full), platelets at 80 × 10⁹/L or more, and haemoglobin at 4.5 g/dL or more (reticulocytes at 80 × 10⁹/L or more if haemoglobin is under 9 g/dL).
• Maximum: 35 mg/kg daily. Loading dose: none. Maintenance: the dose that keeps neutrophils in range and gives clinical benefit, usually 20 to 30 mg/kg daily.
• If counts fall: hold until they recover, then restart 5 mg/kg lower.

Chronic myeloid leukaemia (specialist use). 20 to 40 mg/kg orally daily, adjusted to the white cell count.

Polycythaemia vera and essential thrombocythaemia (specialist use). 15 mg/kg orally daily (usually 500 mg twice daily), adjusted to haematocrit under 45% or platelets under 400 × 10⁹/L.

Adjustments. Kidney: creatinine clearance under 60 mL/min, reduce the starting dose by half (7.5 mg/kg); for dialysis, 7.5 mg/kg given after dialysis. Liver: use with caution; no formal adjustment. Weight: dose by actual weight.

Contraindications. Pregnancy and breastfeeding, severe marrow depression (neutrophils under 1.0 × 10⁹/L or platelets under 80 × 10⁹/L), hypersensitivity.

Boxed-warning-level risk. Myelosuppression and malignancy (leukaemia and skin cancer).

Adverse effects. Neutropenia, thrombocytopenia, anaemia, macrocytosis, nausea, nail and skin pigmentation, dry skin, leg ulcers, alopecia, oligospermia.

Interactions. Additive marrow suppression with zidovudine and other myelosuppressives. Increased risk of pancreatitis, hepatotoxicity and neuropathy with didanosine and stavudine. Live vaccines are avoided. Hydroxyurea may raise uric acid.

Pregnancy and breastfeeding. Avoid. Use effective contraception during therapy and afterwards (6 months for women, 3 to 12 months for men, depending on the label); stop before conception. Do not breastfeed.

Regional points. Malaria-endemic areas: continue with malaria prophylaxis in sickle cell disease. Folic acid supplementation continues.

Common errors. Starting without baseline counts; not escalating to the maximum tolerated dose; unnecessary stopping for mild cytopenia.

Administration. Oral, once daily, with or without food. Carers wear gloves; capsules are not opened; wash hands after handling. Use sun protection.

Baseline. Full blood count with differential and reticulocytes, creatinine, liver function, pregnancy test, and foetal haemoglobin where available.

Monitoring. Full blood count every 4 weeks during titration and every 2 to 3 months once stable; liver and renal function every 6 to 12 months; skin review; foetal haemoglobin if available.

Referral and escalation. Refer for prolonged cytopenia, new leg ulcers, suspected malignancy, or pregnancy.