Can Indapamide Cause Hyponatremia?
Yes, indapamide can cause severe hyponatremia, and this is a well-established, dose-related adverse effect that occurs primarily in elderly females and can be life-threatening. 1
FDA-Recognized Risk
The FDA drug label explicitly warns that severe cases of hyponatremia, accompanied by hypokalemia, have been reported with recommended doses of indapamide. 1 This appears to be dose-related, with a large case-controlled pharmacoepidemiology study indicating increased risk at both 2.5 mg and 5 mg doses. 1 The FDA specifically notes that hyponatremia considered possibly clinically significant (<125 mEq/L) has not been observed in clinical trials with the 1.25 mg dosage, leading to the recommendation that patients should be started at 1.25 mg and maintained at the lowest possible dose. 1
Clinical Evidence and Severity
Multiple case reports and case series demonstrate that indapamide-induced hyponatremia can be:
- Severe: Serum sodium levels as low as 100-110 mmol/L have been documented 2, 3, 4
- Rapid in onset: Can occur within 10 days to 6 weeks of initiation 2, 5, 3
- Life-threatening: Associated with seizures, central nervous system symptoms, rhabdomyolysis, and acute kidney injury 2, 5, 4
In a retrospective study of 255 patients admitted with severe hypotonic hyponatremia (serum sodium ≤120 mmol/L), thiazide/indapamide diuretics were the most common etiological factor, accounting for 41% of cases. 6
High-Risk Population
Elderly females are at particularly high risk. 1 A case series of 11 patients with severe indapamide-related hyponatremia found that all patients were female and elderly (mean age 81.7 ± 5.8 years). 4 The mean serum sodium on presentation was 110.9 ± 5.9 mmol/L, and all patients presented predominantly with neurological manifestations, with delirium being most common. 4
Concurrent Electrolyte Disturbances
Indapamide-induced hyponatremia is frequently accompanied by other electrolyte abnormalities:
- Hypokalemia occurs in the majority of cases 2, 4
- Hypomagnesemia was present in 8 of 11 patients in one series 4
- Hypophosphatemia and hypocalcemia have also been reported 5
- Electrocardiographic changes are common, including prolonged QT interval 4
Guideline Recognition
Major cardiovascular guidelines consistently list hyponatremia as a major side effect of indapamide across multiple publications:
- The 2022 AHA/ACC/HFSA guidelines list indapamide among thiazide diuretics used in heart failure management 7
- The 2012 ESC guidelines for heart failure explicitly list hyponatremia as a major side effect of indapamide 7
- The 2005 ESC guidelines similarly identify hyponatremia, along with hypokalaemia and hypomagnesaemia, as major side effects 7
- The 2001 European Heart Journal guidelines list hyponatremia as a major side effect of indapamide 7
Clinical Pitfalls
A critical pitfall is misdiagnosing indapamide-induced hyponatremia as SIADH (syndrome of inappropriate antidiuretic hormone secretion). 2 One case report specifically noted that hyponatremia was initially mistaken for SIADH, delaying appropriate management. 2 The key distinguishing feature is that indapamide-induced hyponatremia resolves with drug discontinuation and electrolyte correction, whereas SIADH requires different management. 7
Monitoring Requirements
The American College of Cardiology recommends monitoring serum potassium and creatinine during indapamide therapy, particularly in high-risk patients, with monitoring at treatment initiation or dose changes. 8 Based on the clinical evidence, serum sodium should also be monitored closely, especially in elderly female patients within the first few weeks of therapy. 1, 4, 6
Management
When severe hyponatremia occurs:
- Immediately discontinue indapamide 2, 3, 4
- Correct electrolyte abnormalities promptly with appropriate replacement therapy 5, 3
- Avoid overly rapid correction (>12 mmol/L in first 24 hours) to prevent osmotic demyelination syndrome 6
- Monitor for concurrent hypokalemia, hypomagnesemia, and other electrolyte disturbances 4
All patients recovered completely after withdrawal of indapamide and correction of electrolyte abnormalities in reported case series. 2, 4