What is hydroxyurea?

What is Hydroxyurea?

Hydroxyurea is an oral cytoreductive medication that inhibits ribonucleotide reductase, blocking DNA synthesis and arresting cells in S-phase, used primarily as first-line therapy for myeloproliferative neoplasms and sickle cell disease. 1, 2

Mechanism of Action

• Inhibits ribonucleotide diphosphate reductase, the enzyme responsible for converting ribonucleotides to deoxyribonucleotides needed for DNA synthesis 2, 3
• In sickle cell disease specifically, increases fetal hemoglobin (HbF) production, which prevents red blood cell sickling and reduces vaso-occlusive crises 1
• Acts as an S-phase specific agent, making cells more susceptible to damage during DNA replication 2

Primary Clinical Indications

Sickle Cell Disease

• First-line disease-modifying therapy for patients with HbSS or Sβ0-thalassemia, including children as young as 9 months 1, 4
• Reduces painful vaso-occlusive crises, acute chest syndrome episodes, hospitalizations, and transfusion requirements by approximately 50% 1, 5
• Improves health-related quality of life 1

Myeloproliferative Neoplasms

• First-choice cytoreductive agent for polycythemia vera and essential thrombocythemia in high-risk patients 6
• Used in proliferative chronic myelomonocytic leukemia with low blast counts 1
• Controls excessive myeloid proliferation and reduces organomegaly 1
• Should be used with caution in young patients under age 40 years due to potential long-term risks 6

Formulations and Administration

• Available as 500 mg capsules, fast-dissolving tablets, or compounded liquid formulations 1, 4
• Administered once daily orally 1, 4
• Stored at room temperature (20°C to 25°C) in tightly closed containers 2

Key Adverse Effects

Hematologic Toxicity

• Myelosuppression is the primary dose-limiting toxicity, manifesting as neutropenia, thrombocytopenia, and anemia 1, 2
• Typically reversible within 2 weeks of temporary discontinuation 4

Mucocutaneous Toxicity

• Leg ulcers are particularly common in myeloproliferative disorders 6, 1
• Skin atrophy with telangiectases, especially on sun-exposed areas 7
• Hyperpigmentation of skin, mucosa, and nails 7
• Severe stomatitis and glossitis 7
• Acral erythema and dermatomyositis-like changes on hands 7

Serious Long-Term Risks

• Increased risk of secondary malignancies including leukemia and skin cancers (squamous cell carcinomas and keratoacanthomas on sun-exposed sites) 2, 7
• Potential for hepatotoxicity and hepatic failure, particularly when combined with antiretroviral drugs 2
• Carcinogenic potential demonstrated in animal studies 2

Reproductive Toxicity

• Potent teratogen causing fetal malformations and embryotoxicity 2
• Damages spermatozoa and testicular tissue, causing azoospermia or oligospermia (sometimes reversible) 2
• Crosses the placenta 2
• Excreted in breast milk 2

Monitoring Requirements

• Complete blood count with reticulocyte count every 2-4 weeks during dose titration, then every 1-3 months on stable dosing 1, 4
• Verify pregnancy status before initiating therapy in females of reproductive potential 2
• Monitor for mucocutaneous changes throughout treatment 1, 7, 8

Contraception Requirements

• Females must use effective contraception during treatment and for at least 6 months after therapy 2
• Males with female partners of reproductive potential must use effective contraception during treatment and for at least 1 year after therapy 2
• Breastfeeding must be discontinued during treatment 2

Dose Adjustments for Renal Impairment

• Reduce dose in patients with creatinine clearance <60 mL/min or end-stage renal disease, as drug exposure increases by 64% in these populations 2
• Elderly patients are more likely to have decreased renal function and may require lower doses 2

Criteria for Treatment Failure in Myeloproliferative Disorders

Resistance or intolerance is defined by: 6, 1

• Failure to control blood counts after 3 months at ≥2 g/day
• Uncontrolled myeloproliferation (platelets >400×10⁹/L AND WBC >10×10⁹/L) despite adequate dosing
• Cytopenias (ANC <1.0×10⁹/L, platelets <100×10⁹/L, or hemoglobin <10 g/dL) at doses needed for response
• Failure to reduce splenomegaly by >50% or relieve symptoms after 3 months
• Development of leg ulcers or other unacceptable toxicities

Important Drug Interactions and Pitfalls

• Falsely elevates continuous glucose monitoring system readings, potentially leading to hypoglycemia if used to guide insulin dosing 2
• Interferes with laboratory assays for uric acid, urea, and lactic acid, causing falsely elevated results 2
• Fatal hepatic events reported when combined with didanosine and stavudine in HIV patients—avoid this combination 2
• Peripheral neuropathy reported with antiretroviral drug combinations 2

Handling Precautions

• Cytotoxic drug requiring special handling procedures 2
• Caregivers must wear disposable gloves when handling capsules or bottles 2
• Do not open capsules; avoid exposure to crushed or opened capsules 2
• If skin contact occurs with crushed capsules, wash immediately and thoroughly with soap and water 2
• If eye contact occurs, flush for at least 15 minutes with water or isotonic eyewash 2

Historical Context

• Originally developed as an anticancer drug for myeloproliferative syndromes, leukemia, melanoma, and ovarian cancer 5
• First tested in sickle cell disease in 1984 5
• FDA approved for adult use 5
• Listed by the World Health Organization as an "essential drug" 8