In the current regulatory system, advisories on drug safety stop at national borders, and information about international postmarketing experience is difficult to obtain. Is a death or a serious adverse event in one country of no interest to those who take the same drug for the same indication in another country? The recent experience with bupropion highlights the need for an international approach to drug safety monitoring and reporting.
Bupropion was licensed in Canada in 1998 for the treatment of depression (Wellbutrin) and for smoking cessation (Zyban). It was licensed only for smoking cessation in the United Kingdom (UK) in June 2000 (Zyban). Bupropion has been the subject of safety advisories in both countries.1,2,3
More Canadians have been prescribed bupropion because it has been on the market longer and has 2 indications. However, physicians and health authorities in the UK have reported 2 times more adverse drug reactions, 11 times more deaths and 3.8 times more seizures per 1000 prescriptions than in Canada (Table 1). Canadian reporting rates also lag for depression and smoking cessation.
Table 1
The UK devotes more resources to postmarketing surveillance than Canada, including adverse event monitoring and the use of a visual symbol, the black triangle, on the product monograph when a drug is under intense surveillance.4 Nonetheless, underreporting seems likely in both countries; the reported seizure rate in the UK was only 34% of the rate reported by the manufacturer in premarketing trials.3
Ample evidence exists for widespread underreporting of adverse drug reactions.5,6,7 The usual estimate is that less than 10% of adverse drug reactions are reported. Our data suggest that 2 industrialized countries may have as much as a 25-fold difference in reporting rates. If the 10% rate applies to the UK, Canada would be missing 99.6% of adverse reactions and nearly 99% of deaths.
These findings reinforce the recent commentary in CMAJ that highlighted the inadequacy of drug safety monitoring and reporting in Canada.8,9 Provision of international postmarketing information in safety advisories is no replacement for an adequately resourced postmarket surveillance system. However, it is an inexpensive step that could immediately help protect public safety.
Barbara Mintzes PhD Candidate Department of Health Care and Epidemiology Ken Bassett Assistant Professor Departments of Family Practice and of Pharmacology and Therapeutics James M. Wright Professor Departments of Medicine and of Pharmacology and Therapeutics University of British Columbia Vancouver, BC
References
- 1.Kumar R. Important safety information regarding bupropion. Mississauga (ON): GlaxoSmithKline; 2001 July 3. Available: www.hc-sc.gc.ca/hpbdgps/therapeut/zfiles/english/advisory/industry/zyban_e.pdf (accessed 2002 July 17).
- 2.Wooltorton E. Bupropion (Zyban, Wellbutrin SR): reports of deaths, seizures, serum sickness. CMAJ 2002;166(1):68. [PMC free article] [PubMed]
- 3.Committee on Safety of Medicines. Zyban (bupropion hydrochloride) — safety update. 2000 Jan 14. Available: www.mca.gov.uk/aboutagency /regframework/csm/csmhome.htm (accessed 2002 June 17).
- 4.Mann RD. Prescription-event monitoring: recent progress and future horizons. Br J Clin Pharmacol 1998;46:195-201. [DOI] [PMC free article] [PubMed]
- 5.Moride Y, Haramburu F, Requejo AA, Begaud B. Under-reporting of adverse drug reactions in general practice. Br J Clin Pharmacol 1997;43 (2): 177-81. [DOI] [PMC free article] [PubMed]
- 6.Lazarou J, Permanz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 1998;279:1200-6. [DOI] [PubMed]
- 7.Bates DW. Drugs and adverse drug reactions. How worried should we be? JAMA 1998; 279 (15):1216-7. [DOI] [PubMed]
- 8.Postmarketing drug surveillance: what it would take to make it work [editorial]. CMAJ 2001;165 (10): 1293. [PMC free article] [PubMed]
- 9.Sibbald B. Cisapride, before and after: still waiting for ADE-reporting reform. CMAJ 2001;165 (10): 1370.