What are the side effects of hydroxyurea (Hydrea)?

Hydroxyurea Side Effects

Hydroxyurea causes a spectrum of adverse effects ranging from common hematologic toxicities to rare but serious organ-specific complications, with myelosuppression being the most frequent dose-limiting toxicity requiring regular monitoring. 1

Hematologic Toxicities (Most Common)

Myelosuppression represents the primary dose-limiting toxicity and includes:

• Neutropenia (absolute neutrophil count <1.0 × 10⁹/L) occurs as a common adverse effect requiring dose adjustment or temporary discontinuation 2, 3
• Thrombocytopenia (platelet count <100 × 10⁹/L) develops frequently and may necessitate treatment modification 2, 3
• Anemia (hemoglobin <10 g/dL) represents a dose-limiting toxicity that can occur at doses required for therapeutic response 2, 3
• Macrocytosis develops early in treatment, is self-limiting, and resembles pernicious anemia morphologically but is not related to vitamin B12 or folic acid deficiency (prophylactic folic acid is recommended) 1
• Hemolytic anemia has been reported in postmarketing surveillance 1

Mucocutaneous Toxicities (Well-Recognized)

Skin and mucous membrane complications are particularly important in long-term therapy:

• Leg ulcers are a well-recognized complication that typically develop after prolonged therapy (median 36 months, range 7-96 months), occur mainly in lower extremities adjacent to malleoli, and constitute grounds for treatment discontinuation 2, 3, 4
• Oral and skin ulcers occur during treatment and may require drug cessation 3, 5
• Hyperpigmentation and nail changes are common dermatologic manifestations 3, 6
• Partial alopecia, scaling, and atrophy of skin and subcutaneous tissues have been documented 6
• Stomatitis occurs in treated patients 3

Gastrointestinal Effects

• Gastric irritation and mucositis occur, particularly when combined with radiation therapy 1
• Anorexia, nausea, and vomiting are recognized side effects 5

Pulmonary Toxicity (Rare but Potentially Fatal)

Respiratory complications require immediate attention:

• Interstitial lung disease including pulmonary fibrosis, pneumonitis, and alveolitis/allergic alveolitis (including fatal cases) have been reported 3, 1
• Monitor patients developing pyrexia, cough, dyspnea, or other respiratory symptoms frequently, investigate promptly, discontinue hydroxyurea, and manage with corticosteroids 1

Hepatobiliary Effects

• Elevation of hepatic enzymes occurs in treated patients 3, 1, 5
• Cholestasis and hepatitis have been reported 1
• Hepatotoxicity and hepatic failure resulting in death have been reported, particularly in HIV patients receiving combination antiretroviral therapy 1

Renal and Metabolic Effects

• Elevations in serum uric acid, BUN, and creatinine occur during treatment 3, 1
• Temporary impairment of renal tubular function has been documented 3
• Dysuria may develop 1

Neurologic Effects

• Headache, dizziness, and drowsiness are common adverse effects 3, 1
• Disorientation, hallucinations, and convulsions have been reported in postmarketing surveillance 1

Systemic and Constitutional Symptoms

• Drug-induced fever (pyrexia >39°C/102°F) requiring hospitalization has been reported, typically occurring within 6 weeks of initiation, resolving upon discontinuation, and recurring within 24 hours upon re-administration 3, 1
• Fever, chills, malaise, edema, and asthenia are recognized general disorders 1

Malignancy Risk (Controversial)

• Acute myelogenous leukemia has been reported in patients taking hydroxyurea, although causality is difficult to establish given the underlying disease 3, 7, 8
• The European LeukemiaNet notes that some drugs administered after hydroxyurea may enhance the risk of acute leukemia 2

Reproductive Toxicity

• Teratogenicity and embryotoxicity occur based on animal studies at doses within 1-fold of human doses 1
• Azoospermia or oligospermia (sometimes reversible) has been observed in men 1, 5
• Females of reproductive potential should use effective contraception during and for at least 6 months after therapy 1
• Males should use effective contraception during and for at least 1 year after therapy 1

Laboratory Test Interference

• Falsely elevated uric acid, urea, and lactic acid results may occur due to analytical interference 1
• Falsely elevated sensor glucose results from certain continuous glucose monitoring systems may lead to hypoglycemia if relied upon for insulin dosing 1

Critical Monitoring Requirements

To detect adverse effects early and prevent severe complications:

• CBC with reticulocyte count every 2-4 weeks during dose titration, then every 1-3 months on stable dose 3, 9
• Weekly CBC until stable dose is achieved initially 3
• Biannual physical examination focusing on lymph node and skin cancer examination 3

Important Clinical Pitfalls to Avoid

• Inadequate monitoring of blood counts can lead to severe myelosuppression 3, 9
• Failure to recognize mucocutaneous toxicities early can delay appropriate management 3, 9
• Discontinuation of hydroxyurea typically leads to slow resolution of leg ulcers over 1-4 months 4
• Patients developing respiratory symptoms require immediate investigation and potential drug discontinuation 1