日本医科大学皮膚科から厚生省に報告した副作用自発報告１，１６７症例の臨床薬理学的分析 因果関係判定に必要な情報と報告用紙に必要な判定項目の検討

Abstract

The Department of Dermatology at Nippon Medical School reported many adverse drug reactions (ADRs) to the Japanese Ministry of Health and Welfare (MHW)'s “Adverse Drug Reaction Monitoring” system. We have assessed causalities of these ADRs (1, 167 cases of 1, 531 ADRs over 10 years), and the suspect drugs. Using theseanalyses, we investigated whether the items on the MHW's report form are sufficient to assess causalities.We investigated 4 aspects of causalities: 1) whether ADRs reappeared after drug reintroduction, 2) whether ADRs are well known, 3) whether ADRs occurred after drug administration and 4) whether ADRs abated after curtailing drug use.As for the first aspect, in 45 cases tested by reintroduction of a drug (po 43, iv 2), the results were positive. In cases where skin tests such as patch tests, scratch-patch tests and other tests were done instead of reintroduction tests, 313, 324 and 22 tests were positive, respectively. We assessed the total 704 ADRs (46%) as “definite”. In most of the patients with rash (74%), contact dermatitis (84%), shock (73%) and photosensitivity reaction (88%), skin tests etc verified the causality.In the second aspect in cases where ADRs are well known, skin tests were not done, because ADRs such as rosacea-like dermatitis and steroid acne occur only after long term use of steroids and because candidiasis, mycosis and futoraful dermatitis were frequent. We assessed these 581 ADRs (38%) as “definite”.Among the rest of the 246 ADRs, 183 occurred after drug administration (aspect 3) in which dechallenge was positive in 128 (8%). We assessed causality of these ADRs as “probable”. Dechallenge was not positive in 55 (4%, including 7 recoveries in which it is unknown whether they came before or after drug curtailment). We assessed causalities of these ADRs as “possible”. In 63 ADRs (4%), it was unclear whether ADR occurred before or after drug administration. We assessed these causalities as “doubtful”.Analysis of MHW's ADR report form revealed cases where the date of onset of administration or the date of ADR occurrence was unknown, and thus whether or not “ADR occurred after drug administration” could not be assessed. The same situation was found in cases in which ADRs abated but the dates of recovery or dates of drug curtailment were unknown, and consequently whether or not “event abated after curtail ment of drug” could not be assessed. The USA's FDA MEDWatch form has a check box for event abated after curtailment of use. MHW's report form has a check box for event recurrence after reintroduction but does not have a check box for whether skin tests were positive or drug concentrations were monitored. These analyses suggest that the MHW's report form needs to be improved.Checking a box indicating that the event occurred after drug administration ranks the causality assessment from “doubtful” up to “possible” or “probable”. Checking a box for event abated after curtailment of drug use changes the causality assessment from “ossible” to “probable”. To improve the assessment of causality, we propose that the MHW form include 4 check boxes for probability of causality: whether the event recurred after reintroduction or not, whether skin tests were positive or negative, whether the event occurred after drug administration or not, and whether the event abated after curtailment of use or not.