Drug Safety

, Volume 31, Issue 7, pp 609–616

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

  • Domenico Motola
  • Antonio Vargiu
  • Roberto Leone
  • Anita Conforti
  • Ugo Moretti
  • Alberto Vaccheri
  • Giampaolo Velo
  • Nicola Montanaro
Original Research Article


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.


  1. 1.
    Cosentino M, Leoni O, Michielotto D, et al. Increased reporting of adverse reactions to ACE inhibitors associated with limitations to drug reimbursement for angiotensin-II receptor antagonists. Eur J Clin Pharmacol 2001; 57: 509–12PubMedCrossRefGoogle Scholar
  2. 2.
    Hartneil NR, Wilson JP. Replication of the Weber effect using postmarketing adverse event reports voluntarily submitted to the United States Food and Drug Administration. Pharmacotherapy 2004; 24: 743–9CrossRefGoogle Scholar
  3. 3.
    de Graaf L, Fabius MA, Diemont WL, et al. The Weber-curve pitfall: effects of a forced introduction on reporting rates and reported adverse reaction profiles. Pharm World Sci 2003; 25: 260–3PubMedCrossRefGoogle Scholar
  4. 4.
    Stephenson WP, Hauben M. Data mining for signals in spontaneous reporting databases: proceed with caution. Pharmacoepidemiol Drug Saf 2007; 16: 359–65PubMedCrossRefGoogle Scholar
  5. 5.
    Moore N, Hall G, Sturkenboom M, et al. Biases affecting the proportional reporting ratio (PPR) in spontaneous reports pharmacovigilance databases: the example of sertindole. Pharmacoepidemiol Drug Saf 2003; 12: 271–81PubMedCrossRefGoogle Scholar
  6. 6.
    Leone R, Conforti A, Venegoni M, et al. Drug-induced anaphylaxis: case/non-case study based on an Italian pharmacovigilance database. Drug Saf 2005; 28: 547–56PubMedCrossRefGoogle Scholar
  7. 7.
    Gruppo Interegionale di Farmcovigilanza [online]. Available from URL: http://www.gruppogif.org [Accessed 2007 Sep 28]
  8. 8.
    Leone R, Venegoni M, Motola D, et al. Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three Italian regions. Drug Saf 2003; 26: 109–20PubMedCrossRefGoogle Scholar
  9. 9.
    Motola D, Vargiu A, Leone R, et al. Hepatic adverse drug reactions: a case/non-case study in Italy. Eur J Clin Pharmacol 2007; 63: 73–9PubMedCrossRefGoogle Scholar
  10. 10.
    Rocchi F, Addis A, Martini N. Current national initiatives about drug policies and cost control in Europe: the Italy example. J Ambul Care Manage 2004; 27: 127–31PubMedGoogle Scholar
  11. 11.
    European Medicines Agency (EMEA). Committee for Proprietary Medicinal Products (CPMP): opinion following an article 36 referral Cerivastatin CPMP/3962/02 [online]. Available from URL: http://www.emea.europa.eu/pdfs/human/referral/Cerivastatin/396202en.pdf [Accessed 2008 May 19]
  12. 12.
    US FDA. Bayer voluntarily withdraws Baycol. FDA Talk Papers 2001 Aug 8 [online]. Available from URL: http://www.f-da.gov/bbs/topics/ANSWERS/2001/ANS01095.html [Accessed 2008 May 14]
  13. 13.
    Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343: 1520–8PubMedCrossRefGoogle Scholar
  14. 14.
    Bresalier RS, Sandier RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352: 1092–102PubMedCrossRefGoogle Scholar
  15. 15.
    Roth-Cline MD. Clinical trials in the wake of Vioxx: requiring statistically extreme evidence of benefit to ensure the safety of new drugs. Circulation 2006; 113: 2253–9PubMedCrossRefGoogle Scholar
  16. 16.
    Avorn J. Evaluating drug effects in the post-Vioxx world: there must be a better way. Circulation 2006; 113: 2173–6PubMedCrossRefGoogle Scholar
  17. 17.
    Fontanarosa PB, Rennie D, DeAngelis CD. Postmarketing surveillance: lack of vigilance, lack of trust. JAMA 2004; 292: 2647–50PubMedCrossRefGoogle Scholar
  18. 18.
    Traversa G, Bianchi C, Da Cas R, et al. Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs. BMJ 2003; 327: 18–22PubMedCrossRefGoogle Scholar
  19. 19.
    Italian Ministry of Health. Dear Doctor letter on nimesulide. Bollettino di Informazione sui Farmaci Genn 2002 Apr [online]. Available from URL: http://www.agenziafarmaco.it/wscs_render_attachment_by_id/111.33840.1150359346504a37e.pdf?.html [Accessed 2007 Sep 28]
  20. 20.
    Irish Medicines Board. Human medicines: urgent recall nimesulide-containing oral products 2007 May 15 [online]. Available from URL: http://www.imb.ie/controls/showpdf.ashx?type=NOTICE&pageid=1943&filename=Human% [Accessed 2008 May 14]
  21. 21.
    European Medicines Agency (EMeA). Press release. European Medicines Agency recommends restricted use of nimesulide-containing medicinal products [online]. Available from URL: http://www.emea.europa.eu/pdfs/general/direct/pr/43260407en.pdf [Accessed 2007 Sep 28]
  22. 22.
    Lenzer J. FDA is incapable of protecting US “against another Vioxx”. BMJ 2004; 329: 1253PubMedCrossRefGoogle Scholar
  23. 23.
    Laine L, Curtis SP, Cryer B, et al. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2007; 369: 465–73PubMedCrossRefGoogle Scholar
  24. 24.
    Hippisley-Cox J, Coupland C, Logan R. Risk of adverse gastrointestinal outcomes in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005; 331: 1310–6PubMedCrossRefGoogle Scholar
  25. 25.
    Lanas A, Garcia-Rodriguez LA, Arroyo MT, et al. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclooxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut 2006; 55: 1731–8PubMedCrossRefGoogle Scholar
  26. 26.
    Kesselheim AS, Avorn J. The role of litigation in defining drug risks. JAMA 2007; 297: 308–11PubMedCrossRefGoogle Scholar
  27. 27.
    Waller PC, Evans SJ, Beard K. Drug safety and regulation. BMJ 2005; 331: 4–5PubMedCrossRefGoogle Scholar
  28. 28.
    Krumholz HM, Ross JS, Presler AH, et al. What have we learnt from Vioxx? BMJ 2007; 334: 120–3PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Domenico Motola
    • 1
  • Antonio Vargiu
    • 1
  • Roberto Leone
    • 2
  • Anita Conforti
    • 2
  • Ugo Moretti
    • 2
  • Alberto Vaccheri
    • 1
  • Giampaolo Velo
    • 2
  • Nicola Montanaro
    • 1
  1. 1.Department of PharmacologyUniversity of BolognaBolognaItaly
  2. 2.Clinical Pharmacology UnitPoliclinico G.B. RossiVeronaItaly

Personalised recommendations