The globalization of drug development has resulted in an increasing implementation of multiregional clinical trials (MCTs) in Japan. However, ethnic variations and low Japanese patient population in MCTs may impact post-marketing drug safety. This study compared the frequency of safety-related package insert revisions between drugs developed through MCTs and those developed otherwise (non-MCTs) in Japan and the United States. The analysis also investigated factors contributing to racial differences and the prevalence of MCTs. We retrospectively analyzed 227 new active-ingredient drugs approved in Japan between 2012 and 2021. Data on package insert revisions within 5 years of approval were collected from the Pharmaceuticals and Medical Devices Agency and the U.S. Food and Drug Administration databases. Comparisons were made by development method (MCT vs. non-MCT), metabolic enzyme polymorphisms, drug classification, approval process, and manufacturer. In Japan, the mean number of package insert revisions within 5 years was significantly higher for MCT drugs than for non-MCT drugs (0.28 vs. 0.17, p = 0.040). In the United States, no significant difference between MCT and non-MCT drugs was observed. Antineoplastic drugs and immunosuppressants demonstrated higher revision frequencies in both countries, with overall revisions greater in the United States than in Japan. MCT-developed drugs and antineoplastic/immunosuppressant drugs require careful post-marketing safety evaluation in Japanese patients. Differences in regulatory systems and post-marketing surveillance likely contribute to the observed variation in revision frequency between Japan and the United States.