Accumulating Evidence for a Drug–Drug Interaction Between Methotrexate and Proton Pump Inhibitors

• Published in: The oncologist (Dayton, Ohio) Ohio), 2012-04, Vol.17 (4), p.550-554
• Main Authors: Bezabeh, Shewit, Mackey, Ann Corken, Kluetz, Paul, Jappar, Dilara, Korvick, Joyce
• Format: Article
• Language: English
• Subjects: Adverse Drug Reaction Reporting Systems; Drug interaction; Drug Interactions; Drug Labeling; Humans; Methotrexate; Methotrexate - adverse effects; Methotrexate - pharmacology; Proton pump inhibitor; Proton Pump Inhibitors - adverse effects; Proton Pump Inhibitors - pharmacology; Regulatory Issues: FDA; United States; United States Food and Drug Administration
• ISSN: 1083-7159; 1549-490X
• DOI: 10.1634/theoncologist.2011-0431

Background. A number of medications are known to interact with methotrexate through various mechanisms. The aim of this article is to apprise practitioners of a new labeling change based on the accumulating evidence for a possible drug–drug interaction between methotrexate (primarily at high doses) and proton pump inhibitors (PPIs). Methods. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database of spontaneous adverse event reports and the published literature were searched for cases reporting an interaction between methotrexate and PPIs. Results. A search of the AERS database and existing literature found several individual case reports of drug–drug interactions and three additional supportive studies that suggest potential underlying mechanisms for the interaction. Conclusion. There is evidence to suggest that concomitant use of methotrexate (primarily at high doses) with PPIs such as omeprazole, esomeprazole, and pantoprazole may decrease methotrexate clearance, leading to elevated serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In several case reports, no methotrexate toxicity was found when a histamine H2 blocker was substituted for a PPI. Based on the reviewed data, the FDA updated the methotrexate label to include the possible drug–drug interaction between high‐dose methotrexate and PPIs. Physicians should be alerted to this potential drug–drug interaction in patients receiving concomitant high‐dose methotrexate and PPIs. 摘要 背景。 已知有多种药物可通过各种机制与甲氨蝶呤发生相互作用。 由于越来越多的证据显示甲氨蝶呤 （主要是在大剂量给药时） 与质子泵抑制剂 （PPI） 可能存在药物与药物相互作用，所以本文旨在提醒医疗执业人员注意由此而进行的药物标签更新。 方法。 我们对美国食品药品管理局 （FDA） 不良事件报告系统 （AERS） 数据库中的自主报告不良事件和已发表文献进行了筛选，从中找出了有关甲氨蝶呤与 PPI 相互作用的病例报告。 结果。 经搜索 AERS 数据库和已有文献，我们发现了若干例药物与药物相互作用病例报告以及 3 项探讨这一相互作用的潜在机制的支持性研究。 结论。 有证据表明，甲氨蝶呤 （主要是在大剂量给药时） 与 PPI （如奥美拉唑、埃索美拉唑和泮托拉唑） 的联合使用可能会降低甲氨蝶呤的清除率，导致甲氨蝶呤和/或其代谢物羟基甲氨蝶呤的血清水平升高，从而有可能引发甲氨蝶呤毒性反应。 据若干项病例报告称，当使用组胺 H2 受体阻滞剂替代 PPI 时，甲氨蝶呤的毒性反应消失。 经评估相关数据后，FDA 对甲氨蝶呤的药物标签进行了更新，添加了大剂量甲氨蝶呤可能会与 PPI 发生药物与药物相互作用。 对于联合使用高剂量甲氨蝶呤和 PPI 的患者，医生应警惕这一潜在药物与药物相互作用的发生。The Oncologist 2012;17:550–554 The article apprises practitioners of a new labeling change based on the accumulating evidence for a possible drug–drug interaction between methotrexate (primarily at high doses) and proton pump inhibitors.