Can hydroxyurea (hydroxycarbamide) cause hyponatremia (low serum sodium)?

Hydroxyurea and Hyponatremia

Hydroxyurea can cause hyponatremia (low serum sodium) in rare cases, as documented in case reports, though this is not listed as a common adverse effect in major guidelines.

Evidence for Hydroxyurea-Induced Hyponatremia

The relationship between hydroxyurea and hyponatremia is supported primarily by case report evidence:

• A documented case of severe hyponatremia with consciousness disturbance in a 79-year-old man with chronic myeloid leukemia taking hydroxyurea (1500 mg/day) 1
• The patient's serum sodium was 119 mEq/L with high urinary sodium excretion
• Symptoms resolved after discontinuation of hydroxyurea, suggesting a causal relationship
• The authors noted this appeared to be the first reported case of hydroxyurea-induced hyponatremia

Mechanism of Action

The proposed mechanism for hydroxyurea-induced hyponatremia appears to be:

• Sodium-losing nephropathy rather than syndrome of inappropriate ADH secretion (SIADH)
• The patient had normal blood ADH levels and sufficient urine volume 1

Risk Assessment and Monitoring

While hyponatremia is not listed among common adverse effects in major guidelines for hydroxyurea use in:

• Sickle cell disease 2
• Myeloproliferative disorders 2
• Thalassemia 3, 4

Prudent monitoring may include:

• Baseline serum electrolytes before initiating therapy
• Periodic monitoring of serum sodium levels, particularly in:
  • Elderly patients
  • Patients with renal impairment
  • Patients on other medications that may cause hyponatremia
  • Patients presenting with neurological symptoms

Common Documented Side Effects of Hydroxyurea

Major guidelines focus on more common adverse effects that require monitoring:

1. Myelosuppression (most common)

   • Regular monitoring of CBC and reticulocyte count every 1-3 months 2
   • Absolute neutrophil count <1.0 × 10^9/L or platelet count <100 × 10^9/L or hemoglobin <10 g/dL are criteria for intolerance 2

2. Mucocutaneous manifestations

   • Leg ulcers
   • Skin pigmentation (observed in 58.6% of patients in one study) 5
   • Oral ulcers

3. Gastrointestinal symptoms 6

4. Temporary impairment of renal tubular function 6

   • May be related to the mechanism of hyponatremia

Management of Hydroxyurea-Induced Hyponatremia

If hyponatremia occurs:

1. Consider discontinuation of hydroxyurea if:

   • Serum sodium falls below 130 mEq/L
   • Patient develops neurological symptoms
   • No other clear cause of hyponatremia is identified

2. Monitor serum sodium levels after discontinuation to confirm improvement

3. Consider alternative disease-modifying therapies based on the underlying condition:

   • For sickle cell disease: L-glutamine, transfusion therapy, or stem cell transplantation 2
   • For myeloproliferative disorders: Interferon-α, ruxolitinib, or other JAK inhibitors 2

Conclusion

While hyponatremia is not a commonly reported adverse effect of hydroxyurea in major guidelines, case report evidence suggests it can occur. Clinicians should be aware of this potential adverse effect, particularly when patients on hydroxyurea present with neurological symptoms or other signs of electrolyte disturbance.