Hydroxyurea

• Sickle Cell Disease
• Essential Thrombocythemia
• Polycythemia Vera
• Chronic Myeloid Leukemia

Hydroxyurea (hydroxycarbamide) is an antineoplastic agent and disease-modifying therapy used in the treatment of various conditions including sickle cell disease, certain cancers, and myeloproliferative disorders. This oral medication works by inhibiting DNA synthesis and has become a cornerstone of sickle cell disease management.

Mechanism of Action

Hydroxyurea primarily inhibits ribonucleotide reductase, an enzyme essential for converting ribonucleotides to deoxyribonucleotides required for DNA synthesis. This inhibition causes cells to arrest in the S phase of the cell cycle. In sickle cell disease, hydroxyurea has multiple beneficial mechanisms: it increases fetal hemoglobin (HbF) production, which does not polymerize with sickle hemoglobin (HbS); reduces neutrophil and reticulocyte counts; decreases adhesion of red blood cells to vascular endothelium; and increases nitric oxide production, promoting vasodilation. These effects reduce the frequency of vaso-occlusive crises and acute chest syndrome.

Available Formulations

Hydroxyurea is available as oral capsules (200 mg, 300 mg, 400 mg, 500 mg) and tablets (100 mg, 1000 mg). A specific formulation (Siklos) is approved for sickle cell disease in pediatric patients. The capsules and tablets should be handled with care; pregnant women should not handle hydroxyurea due to teratogenicity concerns.

Medical Uses

Hydroxyurea is FDA-approved to reduce the frequency of painful crises and the need for blood transfusions in adults with sickle cell anemia with recurrent moderate to severe painful crises; for resistant chronic myeloid leukemia; and for locally advanced squamous cell carcinomas of the head and neck (except lip) in combination with radiation. It is widely used off-label for essential thrombocythemia, polycythemia vera, and other myeloproliferative disorders.

Dosing Guidelines

For sickle cell disease in adults, the initial dose is typically 15 mg/kg once daily, with dose escalation every 12 weeks (by 5 mg/kg) until maximum tolerated dose (up to 35 mg/kg/day) or adequate response. Pediatric dosing starts at 20 mg/kg/day. For myeloproliferative disorders, doses range from 500-2000 mg daily. Complete blood counts must be monitored closely during dose titration. Doses should be reduced for renal impairment.

Important Safety Information

Hydroxyurea is a myelosuppressive agent that causes bone marrow suppression; blood counts must be monitored regularly. The medication is carcinogenic and mutagenic. Secondary leukemias have been reported in patients receiving long-term hydroxyurea for myeloproliferative disorders. Severe anemia requiring transfusion may occur in patients with sickle cell disease. Cutaneous vasculitic toxicities, including ulcerations and gangrene, have been reported. The medication can cause fetal harm and should not be used during pregnancy.

Drug Interactions

Live vaccines should be avoided due to immunosuppression. Concurrent use with other myelosuppressive agents or radiation therapy may increase bone marrow toxicity. Hydroxyurea may increase the effects of antiretroviral nucleoside analogs (didanosine, stavudine), potentially increasing the risk of pancreatitis and hepatotoxicity; this combination requires caution. No significant CYP450 interactions are expected.

Special Populations

Hydroxyurea is contraindicated during pregnancy due to demonstrated teratogenicity. Effective contraception should be used during treatment and for at least 6 months (females) or 1 year (males) after stopping. Breastfeeding is contraindicated as hydroxyurea is excreted in breast milk. Safety and efficacy have been established in pediatric patients with sickle cell anemia (2 years and older for some formulations). Elderly patients should have renal function monitored. Dose reduction is required in renal impairment; some recommend 50% dose reduction when CrCl is less than 60 mL/min. Use with caution in hepatic impairment.