Objective: It is very difficult to identify the frequency of rare adverse drug reactions (ADRs) precisely.  A study was conducted to estimate the frequency of ADRs that were not observed in clinical studies by referring to the sales volume of the pharmaceuticals until the date when the ADR was first observed after a drug was marketed.
Methods and Subjects: The study was conducted for the 17 pharmaceuticals to estimate the frequency of Hepatopathy.  The date of report of the ADR to the Minister was obtained through information disclosure requests.  The sales volume of the relevant pharmaceuticals was provided by IMS Japan.  On the premise that all the ADRs were detectable, the probability (P) that an ADR was not detected right before drug administration in the first case of the ADR was estimated through Formula 1.
Formula 1 : P=1−{(D₀−S)!÷(D₀−S−D_N)!}/{D₀!÷(D₀−D_N)!} = 1−{(D₀−D₀×F)!÷(D₀−D₀×F−D_N)!}/{D₀!÷(D₀−D_N)!}
  D₀ referred to the estimated person-days for all the patients subject to the drug therapy, S to the number of patients with ADR, D_N to the person-days until the date when the ADR was observed and F to the frequency of the ADR.  F was estimated where the detection P was 0.95 or was close to 0.95.
Results and Discussion: Among the pharmaceuticals investigated, the frequency was highest in product A (0.038%) and was lowest in product X (0.0000088%).  In many cases, the package inserts describe the frequencies of rare ADRs as unknown.  However, the frequency can be estimated relatively precisely through the method stated above using data, which may be kept by pharmaceutical manufacturers.

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Objective: We studied whether the statements made in the “contradicted combinations” package inserts for medications used at the Kitasato Institute Hospital, Kitasato University (henceforth, “the hospital”) and the combinations of medications listed were consistent.
Methods: We studied whether both the “contraindicated combinations” in the package insert and the listed combinations were consistent, and when they were not, we telephoned the pharmaceutical company that did not list it as a “contraindicated combination” and inquired as to the reason it was not listed as such.
Results: 1,347 pharmaceutical products were the target of this study, and among these there were 147 products that had contraindicated combinations listed in its package insert, and there were 239 combinations of contraindicated combinations.  Among the 147 products, most were cardiovascular drugs (40 drugs, 27.2%), followed by central nervous system drugs (30 drugs, 20.4%).  Among the 239 combinations, there were 47 (19.7%) combinations that were inconsistent, and the reasons for the inconsistency were 1) because they would become unusable in the event of an emergency, 2) because there are no safety issues, etc.
Conclusion: In this study, it was clear that pharmaceuticals that are inconsistent in their contraindicated drug combinations are by no means few in number.  A lack of uniformity in what is listed in the package insert regarding contraindicated combinations, which is a public document, is not something to be at all desired, and we believe it is necessary to create consistency by clarifying the standards for listing contraindicated combinations in order to avoid confusion in clinical settings in the future.

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