Document Type
Letter to the Editor
Publication Date
5-1-2025
Abstract
Purpose/Background: Clozapine was approved in the United States (US) using 1989 regulations and knowledge. After 30 years, many sections of the US package insert (PI) are outdated. Methods: We comprehensively reviewed the literature to propose PI updates. We present the information in 2 articles. In Part I, we focus on basic pharmacology based on 407 relevant articles. Part II focuses on clinical aspects and pharmacovigilance. Findings/Results: Based on more recent expectations of Food and Drug Administration regulations, we reviewed clozapine basic pharmacology including the following: 1) clearance, 2) pharmacokinetics and pharmacodynamics, and 3) monitoring tools. We identified 9 major problems in the basic pharmacological sections of the PI including the following: 1) in vivo studies indicate that clozapine is dependent on CYP1A2 for its metabolism, 2) the minor role of CYP2D6 in clozapine metabolism requires removing the PI recommendation to lower clozapine doses in CYP2D6 poor metabolizers, 3) in nontoxic concentrations CYP3A4 has a minor role in clozapine metabolism and potent CYP3A4 inhibitors lack clinically relevant effects, 4) several drug-drug interactions need to be updated based on recent literature, 5) systemic inflammation may decrease clozapine metabolism and increase the risk of clozapine intoxication, 6) obesity may decrease clozapine metabolism, 7) patients of Asian and Indigenous American ancestry need lower clozapine doses, 8) personalized titration and c-reactive protein monitoring should be considered until prospective studies are available, and 9) the half-life section needs to be modified to acknowledge that single dosing at night is frequent in the US. Implications/Conclusions: An improvement in the US clozapine PI may lead to improvement in PIs worldwide.
Keywords
clozapine/blood, clozapine/metabolism, clozapine/pharmacokinetics, drug interactions, drug labeling
Language
English
Publication Title
Journal of Clinical Psychopharmacology
Rights
© 2025 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/), which permits non-commercial copying and redistribution of the material in any medium or format, provided the original work is not changed in any way and is properly cited.
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
Recommended Citation
McGrane, I. R., McCollum, B., Rubio, J. M., Leung, J. G., Rothschild, A. J., Sarpal, D. K., Cotes, R. O., Keshavan, M. S., Freudenreich, O., Citrome, L., Sajatovic, M., de Leon, J., Schoretsanitis, G., Davis, J. M., Caroff, S. N., Lam, Y. W. F., Kelly, D. L., Balon, R., Sanz, E. J., … Meyer, J. (2025). Letter to the FDA Proposing Major Changes in the US Clozapine Package Insert Supported by Clozapine Experts Worldwide. Part I: A Review of the Pharmacokinetic Literature and Proposed Changes. Journal of Clinical Psychopharmacology, 45(3), 179–196. https://doi.org/10.1097/JCP.0000000000001987
Manuscript Version
Final Publisher Version