Indapamide-Induced Rhabdomyolysis: An Evaluation of Case Reports in VigiBase Using the Bradford Hill Criteria

BACKGROUND: Indapamide can cause hypokalaemia and hyponatraemia. Rhabdomyolysis associated with these electrolyte abnormalities has been reported. OBJECTIVE: The aim of this study was to assess causal association between the use of indapamide and the occurrence of rhabdomyolysis using the Bradford Hill criteria. METHODS: Variables in the rhabdomyolysis case reports and literature were reviewed. Bradford Hill criteria were used in the assessment of causal association. RESULTS: Up to 11 November 2020, there were 28 unique cases in VigiBase from 13 countries reporting indapamide-associated rhabdomyolysis. In 18 of these cases, hypokalaemia (n = 14) or hyponatremia (n = 8) was a co-reported event, including four cases where both of these events were reported. Indapamide was the only suspected drug in nine of these 18 cases and positive dechallenge was mentioned in 13 of them. In addition, there were risk factors such as falls, concomitant drugs with risk of hypokalaemia, or muscle injury. In two cases, liquorice (containing glycyrrhizin) was concomitantly used with indapamide before hypokalaemia and rhabdomyolysis occurred. Thiazide diuretics, known to cause hypokalaemia, showed similar disproportionality patterns as indapamide regarding rhabdomyolysis and myopathy, while calcium channel blockers (not causing hypokalaemia), had lower disproportionality values than indapamide. CONCLUSIONS: Based on the review of case series and causality assessment using Bradford Hill criteria, indapamide may cause rhabdomyolysis due to hypokalaemia or hyponatremia. Considering the seriousness of the reported cases, health care professionals should be aware of this potential risk following indapamide intake, particularly when there are risk factors for hypokalaemia and hyponatremia such as excessive liquorice consumption. A similar risk of muscle injuries may apply to thiazide diuretics as well.