Hydroxyurea - Drug Monograph

Introduction

Hydroxyurea is an antimetabolite chemotherapeutic agent first synthesized in 1869 and introduced into medical practice in the 1960s. This oral medication represents a cornerstone in the management of several hematologic disorders, particularly sickle cell disease and certain myeloproliferative neoplasms. Its unique mechanism of action and generally favorable safety profile have established hydroxyurea as an essential therapeutic option in hematology practice.

Mechanism of Action

Hydroxyurea exerts its pharmacological effects primarily through inhibition of ribonucleotide reductase, the enzyme responsible for converting ribonucleotides to deoxyribonucleotides. This inhibition depletes intracellular pools of deoxyribonucleotides necessary for DNA synthesis and repair. The resulting impairment of DNA synthesis causes cell cycle arrest at the G1/S phase boundary, preferentially affecting rapidly dividing cells.

In sickle cell disease, hydroxyurea induces fetal hemoglobin (HbF) production through nitric oxide-mediated mechanisms and other pathways. Increased HbF levels reduce sickle hemoglobin polymerization, thereby decreasing hemolysis and vaso-occlusive complications.

Indications

• Sickle cell anemia with recurrent moderate to severe painful crises in adults
• Chronic, resistant, Philadelphia chromosome-negative myeloproliferative disorders (including chronic myelogenous leukemia, polycythemia vera, and essential thrombocythemia)

• HIV infection (as adjunct therapy with antiretrovirals)
• Thrombocytosis secondary to various myeloproliferative disorders
• Certain solid tumors (as part of combination regimens)

Dosage and Administration

• Initial dose: 15 mg/kg orally once daily
• May increase by 5 mg/kg every 12 weeks until maximum tolerated dose (typically 20-35 mg/kg/day)
• Maximum dose: 35 mg/kg/day

• Initial dose: 15-20 mg/kg orally once daily
• Adjust based on hematologic response and toxicity
• Maintenance dose: individualized based on response

• Renal impairment: Reduce dose by 50% for CrCl <60 mL/min
• Hepatic impairment: Use with caution; no specific dosing recommendations
• Elderly: Consider reduced initial doses
• Pediatrics: Safety established for children with sickle cell disease

Pharmacokinetics

Contraindications

• Severe bone marrow suppression (leukocyte count <2,500/mm³, platelet count <100,000/mm³, or hemoglobin <4.0 g/dL)
• History of hypersensitivity to hydroxyurea or its components
• Women who are pregnant or breastfeeding (unless potential benefit justifies potential risk)

Warnings and Precautions

• Myelosuppression: May cause severe bone marrow suppression
• Carcinogenicity: Has demonstrated mutagenic and clastogenic effects; secondary malignancies reported
• Embryo-fetal toxicity: Can cause fetal harm when administered to pregnant women

• Macrocytosis commonly occurs and may mask folate deficiency
• Vasculitic toxicities and gangrene reported in patients with serious cutaneous lesions
• Pancreatitis reported in patients receiving hydroxyurea with antiretroviral medications
• Monitor for pulmonary toxicity including fibrosis and interstitial pneumonitis

Drug Interactions

• Live vaccines: Avoid concurrent administration due to immunosuppression
• Other myelosuppressive agents: Additive bone marrow suppression (e.g., zidovudine, clozapine)
• Interferon alfa: Increased risk of cutaneous vasculitis
• Didanosine: Increased risk of pancreatitis and peripheral neuropathy
• Antiretroviral drugs: Potential additive toxicity

Adverse Effects

• Myelosuppression (anemia, leukopenia, thrombocytopenia)
• Nausea/vomiting
• Dermatologic reactions (rash, skin ulceration)
• Macrocytosis
• Elevated liver enzymes

• Diarrhea or constipation
• Stomatitis
• Alopecia
• Fever
• Discoloration of nails/nail beds

• Severe myelosuppression
• Megaloblastic erythropoiesis
• Acute mucocutaneous toxicity
• Vasculitic ulcerations
• Secondary malignancies
• Pulmonary fibrosis

Monitoring Parameters

• Complete blood count with differential
• Renal and hepatic function tests
• Pregnancy test in women of childbearing potential

• CBC weekly until stable, then every 2-4 weeks
• Liver and renal function every 3-6 months
• Physical examination for skin changes and leg ulcers
• Monitoring for signs of infection
• In sickle cell patients: HbF levels every 3-6 months

• Annual skin examination for secondary malignancies
• Pulmonary function tests if symptoms develop
• Monitoring for signs of vasculitis

Patient Education

• Take exactly as prescribed; do not crush or chew capsules
• Maintain adequate hydration
• Practice reliable contraception during treatment and for at least 6 months after
• Report fever, chills, sore throat, unusual bleeding/bruising, or skin changes promptly
• Avoid contact with people who have infections
• Regular blood tests are essential for safe treatment
• Notify all healthcare providers about hydroxyurea use
• Store at room temperature in original container
• Wash hands after handling medication

References

1. FDA Prescribing Information: Hydroxyurea capsules 2. Yawn BP, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 3. Charache S, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995 4. National Comprehensive Cancer Network (NCCN) Guidelines: Myeloproliferative Neoplasms 5. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008 6. McMullin MF, et al. Guidelines for the diagnosis and management of adult myeloproliferative neoplasms. Br J Haematol. 2011 7. Product Monograph: Hydroxyurea. Various manufacturers 8. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. Hydroxyurea monograph