title: Post-approval appending of CSARs to drug package inserts: an analysis of the types of adverse reactions and time to addition.
abstract: OBJECTIVE
  The aim of this study was to quantitatively analyze clinically significant adverse reactions (CSARs) added to drug package inserts after approval and to investigate the time to these post-approval additions as an indicator of safety-related regulatory actions.
  
  
  METHODS
  Drugs containing new active ingredients that had been approved in Japan from April 2001 to December 2010 were analyzed. We examined CSARs that had been reported in the first version of the package inserts and subsequent additions through notifications from Japan's Ministry of Health, Labour and Welfare until the end of 2011. Relative risks (RRs) for post-approval addition of CSARs were calculated for various categories of disorders. The median lengths of time to post-approval addition of CSARs were compared.
  
  
  RESULTS
  A total of 238 drugs were examined. Of the 2487 CSARs associated with these drugs, 737 had been added after approval. The analysis revealed a higher likelihood for post-approval addition of CSARs for "Hepatobiliary disorders" (RR: 1.41; 95% confidence interval [CI]: 1.19-1.68), "Gastrointestinal disorders" (RR: 1.35; 95%CI: 1.10-1.66), and "Musculoskeletal and connective tissue disorders" (RR: 1.52; 95%CI: 1.11-2.07). In contrast, "Cardiac disorders" showed reduced likelihood in comparison with other disorders. For the time until post-approval addition of CSARs, "Skin and subcutaneous tissue disorders" showed the longest durations, with a median of 3020 days.
  
  
  CONCLUSIONS
  Our quantitative analysis suggests that some CSARs were added more frequently to package inserts after approval and that time to post-approval additions of CSARs varied with the types of adverse drug reactions. These results can support the coherent implementation of pharmacovigilance activities.
authors.affiliation: Department of Pharmaceutical and Medical Device Regulatory Science, Graduate School of Medicine, Yamagata University, Yamagata-shi, Yamagata, Japan; Teikoku Seiyaku Co., Ltd., Higashikagawa, Kagawa, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Tamura
authors.forename: Chieko
authors.initials: C
authors.lastname: Ishiguro
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Matsuda
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000458:organization & administration / Q000706:statistics & numerical data; D004348:Drug Labeling / Q000592:standards*; D004335:Drug and Narcotic Control / Q000331:legislation & jurisprudence; D006801:Humans; D007564:Japan; D007880:Legislation, Drug; D055553:Prescription Drugs / Q000009:adverse effects*; D011358:Product Surveillance, Postmarketing / Q000706:statistics & numerical data; D013997:Time Factors
chemical_list: D055553:Prescription Drugs
keywords: adverse event; drug safety; pharmacoepidemiology; pharmacovigilance; post-approval analysis; safety-related regulatory actions; unknown risk