title: Adverse Drug Reactions for Medicines Newly Approved in Japan from 1999 to 2013: Hypertension and Hypotension.
abstract: In this survey, the correlation between adverse drug reactions (ADRs) in human and animal toxicities was investigated for 393 medicines which were approved in Japan from September 1999 to March 2013. ADRs were collected from each Japanese package insert. Comparable animal toxicities with ADRs were collected by thorough investigation of common technical documents. The results of this survey show that hypertension and/or hypotension were mainly observed in medicines affecting the central nervous system. Hypertension was also observed in antipyretics, analgesics, anti-inflammatory agents, vasoconstrictors and agents using antibody. Concordance between human ADRs and animal toxicities was analysed. True-positive rate for hypertension and hypotension is 0.29 and 0.52, respectively. Positive likelihood ratio and inverse negative likelihood ratio are 1.98 and 1.21, respectively, in hypertension and 1.67 and 1.44, respectively, in hypotension. Concordance between human ADRs and animal toxicities is not so high in hypertension and hypotension. Identified mechanisms as on-target for hypertension and hypotension are 29.8% and 30.5%, respectively. More than half of the causative factors of hypertension and hypotension were unable to be elucidated. Our results show that the intake of medicines is often linked to blood pressure variations that are not predicted in animal toxicity studies. Improvement of drug development processes may be necessary to provide safer medicines because current animal toxicity studies are insufficient to predict all ADRs in human beings.
authors.affiliation: Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nagayama
authors.affiliation: Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Nishida
authors.affiliation: Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hizue
authors.affiliation: Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan.
authors.forename: Yamato
authors.initials: Y
authors.lastname: Ogino
authors.affiliation: Non-Clinical Evaluation Expert Committee, Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Fujiyoshi
mesh_terms: D000818:Animals; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical; D004348:Drug Labeling; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000209:etiology; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000209:etiology; D007022:Hypotension / Q000453:epidemiology / Q000209:etiology; D007564:Japan / Q000453:epidemiology; D016013:Likelihood Functions; D004364:Pharmaceutical Preparations / Q000145:classification; D011237:Predictive Value of Tests
chemical_list: D004364:Pharmaceutical Preparations