Off-label use of nicardipine as tocolytic and acute pulmonary oedema: evidence from EudraVigilance

Objectives. Signal detection during the regular monitoring of EudraVigilance (EV) database, that includes all the adverse drug reactions reported worldwide, has been performed by Italian Medicines Agency and Pharmacovigilance Regional Centre of Emilia Romagna, as expected by the new European PharmacoVigilance (PhV) legislation(1). We detected a signal of acute pulmonary oedema (APO) due to nicardipine used off-label as tocolytic in pregnant women. Methods. A periodic Reaction Monitoring Reports file containing aggregate data of drug-reactions pairs and the Proportional Reporting Ratio (PRR) as measure of disproportionality were analyzed. We detected a safety signal and performed a further analysis of the individual cases. Results. Thirty-four spontaneous cases regarding pregnancy women who experienced APO following nicardipine treatment as tocolytic were retrieved. The analysis focused on 10 serious cases (8 with nicardipine as the only suspected drug and 2 other cases where betamethasone was administered as concomitant drug). Most women, aged between 27-39 years, were treated with intravenous nicardipine. Our analysis has strengthened the evidence for causal relationship and a clinical pattern of APO associated with nicardipine was observed. Conclusions. We identified an association between nicardipine used off label as tocolytic and APO. The Pharmacovigilance Risk Assessment Committee (PRAC) confirmed our findings, recommending an update of the summary of the product characteristics for medical products containing nicardipine for both intravenous and oral formulations(2). In particular, it has been reaffirmed that nicardipine use in other indications is no longer recommended. Monitoring of EV database allowed to detect a signal, followed by a regulatory measure, that would have been underestimated if the analysis was limited only to national data.