Drug Safety

, Volume 31, Issue 7, pp 609–616

Influence of Regulatory Measures on the Rate of Spontaneous Adverse Drug Reaction Reporting in Italy


    • Department of PharmacologyUniversity of Bologna
  • Antonio Vargiu
    • Department of PharmacologyUniversity of Bologna
  • Roberto Leone
    • Clinical Pharmacology UnitPoliclinico G.B. Rossi
  • Anita Conforti
    • Clinical Pharmacology UnitPoliclinico G.B. Rossi
  • Ugo Moretti
    • Clinical Pharmacology UnitPoliclinico G.B. Rossi
  • Alberto Vaccheri
    • Department of PharmacologyUniversity of Bologna
  • Giampaolo Velo
    • Clinical Pharmacology UnitPoliclinico G.B. Rossi
  • Nicola Montanaro
    • Department of PharmacologyUniversity of Bologna
Original Research Article

DOI: 10.2165/00002018-200831070-00006

Cite this article as:
Motola, D., Vargiu, A., Leone, R. et al. Drug-Safety (2008) 31: 609. doi:10.2165/00002018-200831070-00006


Background: The reporting of adverse drug reactions (ADRs) is the mainstay of post-marketing surveillance systems. Under-reporting and selective reporting are considered the main limitations of a spontaneous reporting-based pharmacovigilance system. However, excessive reporting induced by external events may also impair signal detection by increasing the noise level.

Objective: The aim of this study was to examine the influence of regulatory measures and other external factors on the rate of ADR reporting in Italy, focusing on four situations occurring in the last 10 years: ACE inhibitor-induced cough; HMG-CoA reductase inhibitors (‘statins’) and rhabdomyolysis; nimesulide and hepatic toxicity; and cyclo-oxygenase (COX)-2 selective inhibitors (‘coxibs’) and increase in cardiovascular risk.

Methods: The study was based on data from spontaneous reporting in six Italian regions collected from January 1995 to December 2005. We analysed a 10-year period as a reasonable time interval around the four situations of interest, highlighting the influence of regulatory measures on the rate of ADR reporting (number of reports per million inhabitants). Chi-squared tests were used to assess the statistical significance of any changes in ADR reporting. Drug sales data were also studied to examine possible changes in drug use. Sales data were expressed as daily defined dose per 1000 inhabitants per day.

Results: ACE inhibitors: a 5-fold increase in the reporting rate of ACE inhibitor-induced cough was observed in 1998 and 1999 following a restriction on reimbursement for angiotensin receptor blockers introduced in 1998 and removed at the end of 1999. Statins: after the withdrawal of cerivastatin in 2001, the ADR reporting rate increased more than 4-fold, with musculoskeletal ADRs representing about 60% of all the ADRs reported in that year, and progressively decreased in the following years. Nimesulide: an increase in hepatic ADR reporting was observed after withdrawal of the drug from the Finnish and Spanish markets in 2002. Coxibs: no important changes in the rate of cardiovascular events reporting in the period 2000–4 were observed. In 2005, after the withdrawal of rofecoxib in September 2004, both the ADR reporting rate and sales of the drug decreased drastically.

Conclusion: Our data suggest that spontaneous ADR reporting can be influenced in different ways by external events. Our data emphasize the need for educational initiatives aimed at increasing the doctor’s and patient’s awareness of the usefulness and the limitations of spontaneous reporting in the pharmacovigilance system. Such initiatives should use appropriate risk communication strategies in order to avoid unnecessary alarm, which could cause unjustified interruption of therapies or misplaced confidence in new drugs.

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© Adis Data Information BV 2008