What are the adverse effects of hydroxyurea (Hydrea)?

Hydroxyurea Adverse Effects

Hydroxyurea causes myelosuppression as its most common and dose-limiting toxicity, along with mucocutaneous manifestations including leg ulcers, gastrointestinal symptoms, and less commonly pulmonary toxicity and hepatotoxicity. 1

Hematologic Adverse Effects

Bone marrow suppression is the primary dose-limiting toxicity:

• Neutropenia (absolute neutrophil count <1.0 × 10⁹/L) 2
• Thrombocytopenia (platelet count <100 × 10⁹/L) 2
• Anemia (hemoglobin <10 g/dL) 2
• Hemolytic anemia has been reported in postmarketing surveillance 1
• Macrocytosis occurs early in treatment, is self-limiting, and resembles pernicious anemia morphologically but is not related to vitamin B12 or folate deficiency 1

Mucocutaneous Toxicities

Dermatologic manifestations are particularly problematic in myeloproliferative disorders:

• Leg ulcers are a well-recognized complication, typically developing after prolonged therapy (median 36 months, range 7-96 months), predominantly in lower extremities adjacent to malleoli, suggesting trauma-related etiology 2, 3
• Oral and skin ulcers 2
• Hyperpigmentation and nail changes 2
• Rash and dermatomyositis-like skin changes 2
• Alopecia 2
• Ulcers typically resolve slowly over 1-4 months after hydroxyurea discontinuation 3

Gastrointestinal Effects

• Stomatitis 2
• Anorexia, nausea, vomiting 2, 1
• Diarrhea and constipation 2
• Gastric irritation and mucositis (particularly when combined with radiation therapy) 1

Pulmonary Toxicity

Serious respiratory complications can occur:

• Interstitial lung disease including pulmonary fibrosis (rare but potentially fatal) 2, 1
• Pneumonitis, alveolitis, and allergic alveolitis 1
• Diffuse pulmonary infiltrates, dyspnea, and cough 1
• Monitor patients developing pyrexia, cough, or dyspnea frequently; discontinue hydroxyurea and manage with corticosteroids if pulmonary toxicity occurs 1

Hepatobiliary Effects

• Elevation of hepatic enzymes 2, 1
• Cholestasis and hepatitis 1
• Fatal hepatotoxicity has been reported, particularly in HIV-infected patients receiving hydroxyurea with antiretroviral agents (especially didanosine and stavudine combination) 1

Renal and Metabolic Effects

• Temporary impairment of renal tubular function 2
• Elevations in serum uric acid, BUN, and creatinine 2, 1
• Dysuria (rare) 2, 1

Neurologic Effects

Neurologic disturbances are rare but include:

• Headache, dizziness, drowsiness 2, 1
• Disorientation, hallucinations, and convulsions (rarely seen) 2, 1
• Severe peripheral neuropathy reported in HIV-infected patients receiving hydroxyurea with antiretroviral drugs 1

Systemic and Constitutional Symptoms

• Drug-induced fever (pyrexia >39°C/102°F) requiring hospitalization, typically occurring within 6 weeks of initiation and resolving upon discontinuation; fever recurs within 24 hours upon re-administration 2, 1
• Chills, malaise, edema, and asthenia 2, 1

Serious Complications with Antiretroviral Drugs

Hydroxyurea is NOT indicated for HIV treatment, but when used in HIV-infected patients:

• Fatal and nonfatal pancreatitis (particularly with didanosine, with or without stavudine) 2, 1
• Hepatotoxicity and hepatic failure resulting in death (most often with hydroxyurea, didanosine, and stavudine combination—avoid this combination) 1
• Severe peripheral neuropathy (with didanosine, with or without stavudine) 1

Reproductive and Teratogenic Effects

• Pregnancy Category D: Hydroxyurea is embryotoxic and teratogenic based on animal studies 2, 1
• Male fertility may be compromised: Azoospermia or oligospermia, sometimes reversible 1
• Damage to spermatozoa and testicular tissue with possible genetic abnormalities 1
• Females should use effective contraception during and for at least 6 months after therapy; males for at least 1 year after therapy 1

Malignancy Risk

The leukemogenic potential remains controversial:

• Acute myelogenous leukemia has been reported, though causality is difficult to establish given the underlying myeloproliferative disorder 2, 4
• One case of acute myelogenous leukemia occurred after 5 years of continuous hydroxyurea therapy in a patient who received no other myelosuppressant 4
• The European LeukemiaNet notes that drugs administered after hydroxyurea may enhance the risk of acute leukemia 2

Laboratory Test Interference

• Falsely elevated results for uric acid, urea, and lactic acid assays due to analytical interference with enzymes (urease, uricase, lactate dehydrogenase) 1
• Falsely elevated sensor glucose results from certain continuous glucose monitoring (CGM) systems, potentially leading to hypoglycemia if relied upon for insulin dosing 1

Radiation-Related Toxicity

When combined with radiation therapy:

• Hydroxyurea potentiates adverse reactions usually seen with irradiation alone, particularly gastric distress and mucositis 1
• Almost all patients receiving combined therapy demonstrate concurrent leukopenia 1

Monitoring Requirements to Detect Adverse Effects

• CBC with reticulocyte count every 2-4 weeks during dose titration, then every 1-3 months on stable dose 5
• Weekly CBC until stable dose achieved initially 2
• Biannual physical examination focusing on lymph node and skin cancer examination (particularly squamous cell carcinomas) 2
• Renal function monitoring in elderly patients and those with impaired renal function 1

Important Clinical Pitfalls

Inadequate monitoring of blood counts can lead to severe myelosuppression 5. Failure to recognize mucocutaneous toxicities early delays appropriate management 5. Poor adherence to medication and monitoring schedules compromises treatment efficacy 5. The European LeukemiaNet defines specific criteria for hydroxyurea intolerance that should prompt therapy change, including cytopenias at doses required for clinical response and presence of leg ulcers or other unacceptable toxicities 2.