ABSTRACT
The package inserts revision regarding prescription drugs is an ongoing process. In this study, we examined the status of this revision and how the content of the information provided has been updated with the new instructions, including the rationale for contraindications for pregnant and breast-feeding women. A total of 407 prescription drugs for pregnant and breast-feeding women were contraindicated, accounting for approximately 15% of the 2,627 nonproprietary names. The number of contraindicated drugs for pregnant, breast-feeding, and both pregnant and breast-feeding women were 406, 44, and 43, respectively. The majority of the contraindications were based on nonclinical data, such as teratogenicity and fetotoxicity data in reproductive toxicity studies involving pregnant animals and pharmacokinetic information in breast-feeding animals. The overall revision rate for the new instructions was 16.2% after three years of revision work for each drug. The alert wording has been revised to provide more clarity and consistency, with three categories of statements: “should not be administered/avoid breastfeeding,” “advisable not to administer/breastfeed,” and “should be administered/breastfeed in consideration of the therapeutic benefit (benefit-risk consideration).” The statement indicating that the drug should not be administered to pregnant women remained in the revised instructions. Conversely, the revision of the description for breast-feeding women from “should be discontinued/avoided” to “benefit-risk consideration” may have improved the usefulness of the product, allowing healthcare professionals to make more informed decisions after considering the transfer of the drug into milk, its pharmacological effects, and other factors.
ABSTRACT
Objective: In Japan, the Guideline on Drug Interaction for Drug Development and Appropriate Provision of Information (GL) was notified in 2018. In the GL and the associated document, it was determined that package inserts of drugs which need to be categorized as precaution due to the significant degree of drug interactions by CYP3A inhibition should describe possible perpetrator drugs using designated expressions, such as “strong CYP3A inhibitor.” For contraindication, it was decided that all drugs should be described individually. In 2021, as supplementary information to the GL, a list of CYP substrates, inhibitors and inducers, classified based on interaction strength and CYP isoenzymes (i.e., the drug list), was published. In this study, we aimed to survey the information on drug interactions by CYP3A inhibition described in the package inserts based on information in the drug list, and to clarify the status and issues.Methods: The package inserts of 24 substrate drugs of CYP3A with contraindications for itraconazole, a strong CYP3A inhibitor, were examined, and the descriptions of strong, moderate, and other CYP3A inhibitors were studied.Results: The frequencies of contraindication for strong CYP3A inhibitors were cobicistat (75%), grapefruit juice (0%), ritonavir (92%), voriconazole (67%), clarithromycin (50%), ceritinib (0%), and posaconazole (33%). On the other hand, some CYP3A substrate drugs was contraindicated with moderate CYP3A inhibitors but not with these strong CYP3A inhibitors. Furthermore, 19 CYP3A inhibitors, which were not on the drug list published in 2021, were identified as contraindications for co-administration. Majority of these were protease inhibitors, and some have been discontinued or not available in Japan.Conclusion: The findings of this study imply the necessity of organizing scientific description based on the GL strength classification. Moreover, it is important to disseminate the information and precautions for drug interactions provided in the package inserts to medical practice.