Risk factors for clazosentan-induced fluid retention in subarachnoid hemorrhage from the Japanese adverse event database

BACKGROUND: Clazosentan, a selective endothelin receptor antagonist, is used to prevent cerebral vasospasm. We investigated patient characteristics and concomitant medications associated with an increased risk of clazosentan-induced fluid retention, the risk factors of which remain unknown. METHODS: We retrospectively reviewed cases of clazosentan-induced adverse drug reactions from the Japanese Adverse Drug Event Report (JADER) database, published by the Pharmaceuticals and Medical Devices Agency. We investigated the time course of fluid retention onset following clazosentan administration before analyzing whether specific patient characteristics and concomitant medications were associated with an increased risk of clazosentan-induced fluid retention. RESULTS: Among 241 cases of clazosentan use identified, fluid retention occurred in 114 (47.3 %). The median time interval from clazosentan initiation to onset of fluid retention was 3 days, and 88.7 % of fluid retention cases were reported within 1 week of initiation. Patients with fluid retention were older than those without; patients >70 years old accounted for 63.16 % of the cohort with fluid retention vs 44.1 % of the cohort without fluid retention. Fluid retention occurred more frequently in patients with concomitant use of fasudil hydrochloride, a conventional vasospasm drug in Japan, than in those without. Multivariate logistic regression analysis revealed that older age (>70 years) and concomitant use of fasudil hydrochloride remained independent risk factors for fluid retention. CONCLUSIONS: Clazosentan-induced fluid retention occurred more frequently in older adult patients. Clazosentan combined with fasudil hydrochloride increased the incidence of fluid retention. These findings can guide pharmacological treatment of cerebral vasospasm in patients with subarachnoid hemorrhage.