What are the side effects of hydroxyurea (Hydrea)?

Hydroxyurea Side Effects

Hydroxyurea causes predictable myelosuppression (neutropenia, thrombocytopenia, anemia) as its most common dose-limiting toxicity, along with mucocutaneous complications including leg ulcers, oral/skin ulcers, and hyperpigmentation, while rare but serious effects include pulmonary fibrosis and drug-induced fever. 1, 2

Hematologic Toxicities (Most Common)

Bone marrow suppression is the primary dose-limiting adverse effect:

• Neutropenia (absolute neutrophil count <1.0 × 10⁹/L) occurs commonly and requires monitoring 1, 2
• Thrombocytopenia (platelet count <100 × 10⁹/L) is frequently observed 1, 2
• Anemia (hemoglobin <10 g/dL) develops as a dose-limiting toxicity 1, 2
• Macrocytosis occurs early in treatment, is self-limiting, and resembles pernicious anemia morphologically but is not related to vitamin B12 or folic acid deficiency 2

Critical monitoring point: In sickle cell disease trials, mild to moderate neutropenia occurred in 46.9% of patients on hydroxyurea versus 18.6% on placebo, but severe neutropenia was rare and not complicated by infection 3. Bone marrow suppression resolves within 2 weeks of temporary discontinuation, with therapy resumed at lower doses 3.

Important caveat: Bone marrow suppression can be severely potentiated in patients with chronic kidney disease, leading to prolonged recovery periods even after drug discontinuation 4.

Mucocutaneous Toxicities

Skin and mucous membrane complications are well-recognized:

• Leg ulcers develop after prolonged therapy and are a well-recognized complication requiring drug withdrawal 3, 1, 5
• Oral and skin ulcers occur during treatment 3, 1
• Hyperpigmentation and nail changes (including nail pigmentation) are common dermatologic effects 3, 1, 5
• Stomatitis has been reported 1

In a large cohort study of 152 patients with myeloproliferative disorders, leg ulcers occurred in four patients and required therapy withdrawal 5.

Pulmonary Toxicity (Rare but Potentially Fatal)

Interstitial lung disease represents a serious complication:

• Pulmonary fibrosis, pneumonitis, alveolitis/allergic alveolitis (including fatal cases) have been reported, particularly in myeloproliferative neoplasms 1, 2
• Monitor patients developing pyrexia, cough, dyspnea, or respiratory symptoms frequently 2
• Discontinue hydroxyurea immediately and manage with corticosteroids if pulmonary toxicity is suspected 2

Hepatobiliary Effects

• Elevation of hepatic enzymes occurs in treated patients 1, 2, 6
• Cholestasis and hepatitis have been reported 2

Special warning: Fatal hepatic events were reported most often in HIV patients treated with the combination of hydroxyurea, didanosine, and stavudine—this combination should be avoided 2.

Renal and Metabolic Effects

• Temporary impairment of renal tubular function occurs 1
• Elevations in serum uric acid, BUN, and creatinine are observed 1, 2
• Dysuria has been reported 2

Neurologic Effects

• Headache, dizziness, and drowsiness are common 1, 2
• Disorientation, hallucinations, and convulsions have been reported in postmarketing surveillance 2

Systemic and Constitutional Symptoms

• Drug-induced fever (pyrexia >39°C/102°F) requiring hospitalization occurs, typically within 6 weeks of initiation, and resolves upon discontinuation 1, 2
• Fever, chills, malaise, edema, and asthenia are reported 2

Pattern recognition: Upon re-administration after drug-induced fever, fever typically recurs within 24 hours 2.

Gastrointestinal Effects

• Anorexia, nausea, vomiting occur 6
• Gastric irritation and mucositis are observed, particularly when combined with radiation therapy 2

Malignancy Risk (Controversial)

• Acute myelogenous leukemia has been reported, although causality is difficult to establish 3, 1
• Acute leukemia or myelodysplasia occurred in three patients in a cohort of 152 with myeloproliferative disorders 5

Reassuring data from sickle cell disease: Long-term follow-up studies in sickle cell disease (up to 17 years) have not shown increased risk of neoplasia 3.

Drug Interactions and Laboratory Interference

• Falsely elevated results for uric acid, urea, and lactic acid assays due to interference with enzymes (urease, uricase, lactate dehydrogenase) 2
• Falsely elevated sensor glucose results from certain continuous glucose monitoring (CGM) systems, potentially leading to hypoglycemia if relied upon for insulin dosing 2

Action required: If prescribing hydroxyurea to a patient using CGM, consult with the CGM prescriber about alternative glucose monitoring methods 2.

Reproductive and Teratogenic Effects

• Teratogenic and embryotoxic in animal studies at doses within 1-fold of human doses 2
• Damage to spermatozoa and testicular tissue with possible genetic abnormalities 2
• Azoospermia or oligospermia, sometimes reversible, observed in men 2
• Crosses the placenta and is excreted in human milk 2

Contraception requirements: Females should use effective contraception during and for at least 6 months after therapy; males should use contraception during and for at least 1 year after therapy 2.

Special Populations at Higher Risk

• Elderly patients may be more sensitive to effects and require lower doses, particularly those with decreased renal function 2
• Patients with creatinine clearance <60 mL/min or end-stage renal disease have higher drug exposure and require dose reduction with close hematologic monitoring 2
• Patients with chronic kidney disease are at markedly increased risk of severe, prolonged bone marrow suppression 4

Monitoring Requirements to Prevent Serious Toxicity

Inadequate monitoring is a critical pitfall that can lead to severe myelosuppression:

• CBC with reticulocyte count every 2-4 weeks during dose titration, then every 1-3 months on stable dose 1, 7
• Weekly CBC initially until stable dose achieved 1
• Biannual physical examination focusing on lymph node and skin cancer examination 1

Key Clinical Pitfalls to Avoid

• Inadequate blood count monitoring leading to severe myelosuppression 1, 7
• Failure to recognize mucocutaneous toxicities early, delaying appropriate management 1, 7
• Not adjusting doses in renal impairment, resulting in excessive toxicity 2, 4
• Combining with certain antiretroviral drugs (didanosine, stavudine), causing fatal pancreatitis and hepatotoxicity 2
• Ignoring respiratory symptoms, missing potentially fatal pulmonary toxicity 2