ST LOUIS (MD Consult) - On November 17, 2009, the US Food and Drug Administration (FDA) issued an alert about new safety information regarding an interaction between the antiplatelet agent clopidogrel (Plavix) and the proton-pump inhibitor (PPI) omeprazole (Prilosec/Prilosec OTC). New data show that when clopidogrel and omeprazole are taken concurrently, the effectiveness of clopidogrel is reduced. Moreover, separating the dose of each of the drugs does not seem to impact this interaction. Patients at risk for myocardial infarction or stroke who take clopidogrel to prevent thrombosis will therefore not receive the full benefit of the drug if they are also taking omeprazole.
Omeprazole inhibits the drug-metabolizing enzyme (CYP 2C19) that is responsible for the conversion of clopidogrel into its active form (active metabolite). New studies compared the blood levels of clopidogrel's active metabolite and its effect on platelets in persons who were receiving clopidogrel plus omeprazole versus persons who were taking clopidogrel alone. A reduction in active metabolite levels of about 45% was found in patients who received clopidogrel with omeprazole compared with patients who received clopidogrel alone. In addition, the therapeutic effect of clopidogrel on platelets was reduced by as much as 47% in persons receiving clopidogrel and omeprazole together. These reductions were seen whether the drugs were given at the same time or 12 hours apart.
Other drugs that are potent inhibitors of the CYP 2C19 enzyme would be expected to have a similar effect and should be avoided in combination with clopidogrel. These include cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine. Because the level of inhibition among other PPIs varies, it is unknown to what extent other PPIs may interfere with the effectiveness of clopidogrel. However, esomeprazole, a PPI that is a component of omeprazole, inhibits CYP 2C19 and should also be avoided in combination with clopidogrel.
The clopidogrel label has been updated with new warnings on omeprazole and the use of other drugs that inhibit CYP 2C19. In addition, the manufacturer of Plavix is conducting follow-up studies to explore this and other drug interactions.
At this time, the FDA does not have sufficient information about drug interactions between clopidogrel and PPIs other than omeprazole and esomeprazole to make specific recommendations about their coadministration.
Clinicians should be aware that no evidence currently exists that shows that other gastric-acid reducing agents, such as antacids and most of the H2-receptor antagonists including ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid), interfere with the anticlotting activity of clopidogrel. However, the H2-receptor antagonist cimetidine (Tagamet and Tagamet HB) is an exception because it is a known CYP 2C19 inhibitor.
The FDA advises health care professionals to discuss this issue with their patients, especially in regard to any over-the-counter use of omeprazole and cimetidine.
圣路易斯(MDConsult)—2009年11月17日，美国食品药品管理局(FDA)发布了一项警告，是有关抗血小板药氯吡格雷(Plavix)与质子泵抑制剂(PPI)奥美拉唑(Prilosec/Prilosec，非处方药)之间相互作用的最新安全性信息。最新数据显示，氯吡格雷与奥美拉唑同服时，氯吡格雷的疗效降低，而两药间隔服用看似并不影响这种相互作用。因此，有心肌梗死或卒中风险的患者若在服用氯吡格雷预防血栓的同时还服用奥美拉唑，则无法达到最佳预防效果。
奥美拉唑可抑制药物代谢酶CYP 2C19，此酶能将氯吡格雷转换成活性形式(活性代谢产物)。新近有研究对接受氯吡格雷+奥美拉唑治疗的患者与仅服用氯吡格雷者的氯吡格雷活性代谢产物血药浓度及其对血小板的效应进行了比较。研究结果表明，与氯吡格雷单药治疗组患者相比，接受氯吡格雷+奥美拉唑治疗的患者活性代谢产物水平降低大约45%。此外，在氯吡格雷与奥美拉唑联合用药组患者中，氯吡格雷对血小板的效应降低多达47%。无论两药同时服用抑或间隔12小时服用均如此。
据预测，可高效抑制CYP 2C19酶的其他药物也会产生相同的效应，故应避免与氯吡格雷配伍用药。这些药物包括西咪替丁、氟康唑、酮康唑、伏立康唑、依曲韦林、非氨酯、氟西汀、氟伏沙明以及噻氯匹定。由于其他PPI的抑制程度不同，故尚不清楚其他PPI对氯吡格雷疗效的干扰程度。然而埃索美拉唑(一种PPI，是奥美拉唑的一个组分)可抑制CYP 2C，故亦应避免其与氯吡格雷联用。
氯吡格雷的说明书已进行了更新，增加了有关奥美拉唑及应用其他抑制CYP 2C19的药物的警告。此外，Plavix生产厂家正在进行随访研究，探讨这种相互作用和其他药物相互作用。
目前，在氯吡格雷与奥美拉唑和埃索美拉唑以外其他PPI之间的相互作用方面，FDA尚无足够的资料制定有关其联合用药的具体建议。
临床医生应知道，当前尚无证据显示其他胃酸抑制药可以干扰氯吡格雷的抗凝活性，其中包括制酸剂及雷尼替丁(Zantac)、法莫替丁(Pepcid)及尼扎替丁(Axid)等大多数H2受体拮抗剂，但H2受体拮抗剂西咪替丁(Tagamet 和Tagamet HB)作为一种已知的CYP 2C 19抑制剂除外。
FDA建议医护专业人员就此问题与其患者进行讨论，特别是有关非处方药奥美拉唑和西咪替丁的应用方面。
