What is hydroxycarbamide (hydroxyurea)?

Hydroxycarbamide (Hydroxyurea): Mechanism, Uses, and Monitoring

Hydroxycarbamide (hydroxyurea) is a cytoreductive agent that inhibits DNA synthesis primarily by blocking ribonucleotide reductase, used to treat various myeloproliferative disorders, sickle cell disease, and certain cancers. 1, 2

Mechanism of Action

• Hydroxyurea primarily works by inhibiting ribonucleotide reductase, the enzyme responsible for converting ribonucleotides to deoxyribonucleotides, thereby blocking DNA synthesis and arresting cells in the S-phase of the cell cycle 1, 3
• In sickle cell disease, hydroxyurea increases fetal hemoglobin (HbF) production, which inhibits sickling of red blood cells and reduces painful vaso-occlusive episodes 4, 2
• It also acts as a nitric oxide donor, which contributes to its effectiveness in preventing thrombotic events associated with thrombocytosis in myeloproliferative disorders 5

Clinical Applications

Sickle Cell Disease

• Recommended as first-line disease-modifying therapy for patients with HbSS or Sβ0-thalassemia, including children as young as 9 months of age 4, 6
• Decreases the frequency of painful vaso-occlusive crises, acute chest syndrome episodes, hospitalizations, and need for blood transfusions by approximately 50% 4, 2
• Improves health-related quality of life in patients with sickle cell disease 4

Myeloproliferative Disorders

• First-choice agent for cytoreductive therapy in proliferative chronic myelomonocytic leukemia (MP-CMML) with low blast counts 4
• Used to control excessive proliferation of myelomonocytic cells and reduce organomegaly in myeloproliferative neoplasms 4, 7
• Criteria for resistance/intolerance to hydroxyurea in myeloproliferative disorders include:
  • Failure to reduce splenomegaly or relieve symptoms after 3 months at ≥2g/day 4
  • Uncontrolled myeloproliferation (platelets >400×109/L and WBC >10×109/L) despite adequate dosing 4
  • Cytopenias at doses required for clinical response 4
  • Development of leg ulcers or other unacceptable toxicities 4

Other Uses

• Treatment of various solid tumors and hematologic malignancies 2, 5
• Used in combination with radiation therapy for squamous cell carcinomas of the head and neck 1

Pharmacokinetics

• Oral bioavailability with peak plasma concentrations reached in 1-4 hours 1
• Distributes throughout the body with a volume of distribution approximating total body water 1
• Metabolized through hepatic pathways (up to 60%) and by intestinal bacteria 1
• Approximately 40% of the dose is excreted unchanged in urine 1
• Dose reduction required in patients with renal impairment (CrCl <60 mL/min) or end-stage renal disease 1

Monitoring and Administration

• Available as capsules, fast-dissolving tablets, or compounded liquid formulations for once-daily oral administration 4, 6
• For sickle cell disease, complete blood count (CBC) with reticulocyte count should be monitored every 2-4 weeks during dose titration and every 1-3 months once on stable dose 6
• For myeloproliferative disorders, regular monitoring of blood counts is essential to detect myelosuppression 7
• Temporary discontinuation may be necessary if significant myelosuppression occurs, with resumption at a lower dose once counts recover 6

Adverse Effects

• Myelosuppression (neutropenia, thrombocytopenia, anemia) is the most common dose-limiting toxicity 6, 1
• Mucocutaneous manifestations including leg ulcers, particularly in myeloproliferative disorders 4, 7
• Gastrointestinal symptoms (nausea, vomiting, anorexia) 2
• Hepatotoxicity with elevated liver enzymes 1, 2
• Potential for secondary malignancies, though the risk as a single agent remains controversial 1, 5
• Reproductive toxicity: teratogenic in animal studies, may cause testicular atrophy and decreased spermatogenesis 1

Special Considerations

• Pregnancy: Contraindicated during pregnancy (Category X); females of reproductive potential should use effective contraception during and for at least 6 months after treatment 1
• Males should use contraception during and for at least 1 year after treatment due to potential genetic abnormalities in sperm 1
• May interfere with certain laboratory tests, including uric acid, urea, and lactic acid assays, and continuous glucose monitoring systems 1
• Long-term follow-up studies in sickle cell disease have not shown increased risk of birth defects, infection, stroke, or neoplasia 6

Common Pitfalls

• Inadequate monitoring of blood counts, potentially leading to severe myelosuppression 6, 7
• Failure to recognize and manage mucocutaneous toxicities early 4
• Inappropriate dosing in patients with renal impairment 1
• Poor adherence to medication and monitoring schedule, compromising treatment efficacy 6
• Confusion between different formulations and dosing regimens across various indications 4, 5