What are the long-term side effects of hydroxyurea?

Long-Term Side Effects of Hydroxyurea

The most significant long-term side effects of hydroxyurea include bone marrow suppression, mucocutaneous manifestations, secondary malignancies (particularly leukemia), and potential reproductive toxicity. 1

Hematologic Effects

• Bone marrow depression: The most common and dose-limiting toxicity
  • Leukopenia
  • Anemia
  • Thrombocytopenia 1
• Rapid recovery typically occurs when therapy is interrupted
• More likely in patients with previous radiotherapy or cytotoxic chemotherapy exposure 1
• Megaloblastic erythropoiesis (often self-limiting and occurs early in treatment) 1
• May delay plasma iron clearance and reduce iron utilization by erythrocytes 1

Dermatologic/Mucocutaneous Effects

• Maculopapular rash
• Skin ulceration (particularly leg ulcers)
• Dermatomyositis-like skin changes
• Peripheral and facial erythema 1
• With long-term maintenance therapy:
  • Hyperpigmentation
  • Atrophy of skin and nails
  • Scaling
  • Violet papules 1
• Cutaneous vasculitic toxicities including ulcerations and gangrene (especially in patients with myeloproliferative disorders) 1, 2
• Oral ulcerations can develop rapidly (within days of starting treatment) 3

Malignancy Risk

• Secondary leukemia has been reported in patients receiving long-term hydroxyurea for myeloproliferative disorders 1, 4
• Skin cancer has been reported in patients on long-term therapy 1
• Hydroxyurea is genotoxic in multiple test systems and presumed to be a human carcinogen 1
• Mutagenic in vitro to bacteria, fungi, protozoa, and mammalian cells 1

Gastrointestinal Effects

• Stomatitis
• Anorexia
• Nausea and vomiting
• Diarrhea
• Constipation 1
• GI symptoms may be dose-limiting in some patients

Neurological Effects

• Generally limited to:
  • Headache
  • Dizziness
  • Disorientation
  • Hallucinations
  • Convulsions (rare) 1

Renal Effects

• Temporary impairment of renal tubular function
• Elevations in serum uric acid, BUN, and creatinine levels 1

Reproductive Concerns

• Potential mutagenic agent that may affect DNA synthesis
• Embryotoxic and teratogenic in animal models
• Crosses the placenta
• Can cause fetal harm when administered to pregnant women 1
• Physicians should carefully consider before administering to patients who may contemplate conception 1

Other Effects

• Fever, chills, malaise
• Edema
• Asthenia
• Elevation of hepatic enzymes 1
• Dysuria (rare)
• Alopecia

Special Considerations

In HIV-infected patients:

• Fatal and nonfatal pancreatitis when combined with didanosine
• Hepatotoxicity and hepatic failure (especially with didanosine and stavudine)
• Severe peripheral neuropathy 1

In patients with myeloproliferative disorders:

• Cutaneous vasculitic toxicities (especially with interferon therapy)
• Secondary leukemia risk 2, 1

Monitoring Recommendations

For patients on long-term hydroxyurea therapy, regular monitoring should include:

• Complete blood counts (initially weekly until stable dose, then monthly) 2
• Renal function tests
• Liver function tests
• Skin examinations (particularly for malignancy and ulcerations)
• Assessment for neurological symptoms

When to Consider Discontinuation

Hydroxyurea should be discontinued if:

• Absolute neutrophil count <1.0 × 10^9/L
• Platelet count <100 × 10^9/L
• Hemoglobin <10 g/dL at lowest effective dose 2
• Development of leg ulcers or other unacceptable mucocutaneous manifestations
• Development of cutaneous vasculitic ulcerations 2, 1

While hydroxyurea is generally well-tolerated and effective for conditions like sickle cell disease and myeloproliferative disorders, patients require careful monitoring for these potential long-term complications, with particular attention to bone marrow function, skin integrity, and malignancy risk.