Clark David W J, Strandell Johanna
Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, PO Box 913, Dunedin, New Zealand.
Eur J Clin Pharmacol. 2006 Jun;62(6):473-9. doi: 10.1007/s00228-006-0131-1. Epub 2006 Apr 22.
Polymyositis occurring in patients treated with omeprazole has been signalled as a possible adverse drug reaction (ADR) by the New Zealand Intensive Medicines Monitoring Programme (IMMP) and the WHO Collaborating Centre for International Drug Monitoring: the Uppsala Monitoring Centre (UMC). Polymyositis and other myopathies have also been reported in post-marketing data and in the medical literature in association with proton pump inhibitor (PPI) use. We wished to follow-up these signals and investigate the evidence of causality for the association of polymyositis and other myopathy with PPI use.
Spontaneously reported ADRs from national monitoring centres are sent to the WHO ADR database (VigiBase). VigiBase was searched for case reports of the PPIs, omeprazole, pantoprazole, lansoprazole, esomeprazole and rabeprazole, with terms indicative of myopathy, and further information was elicited from the national centres to help establish causality. Literature sources were reviewed for the occurrence of the above terms in combination with PPIs.
In total, there were 292 reports of various myopathies with PPIs, excluding 868 cases of 'myalgia'. In this analysis, 69 patients recovered when the drug was withdrawn and, in 15 patients, the reaction re-occurred when the drug was reinstated. In one-third of the 292 cases, the PPI was the single administered drug, and the PPI was the single suspected drug by the reporter in 57% of reports where concomitant medication was used. In this analysis, three index cases are documented. One involves the same patient taking three different PPIs (lansoprazole, esomeprazole and rabeprazole) at different time periods, with myalgia and muscle weakness occurring with all three drugs. In the two other index cases, myopathies with esomeprazole and omeprazole were reported with positive rechallenge, and causality was assessed as 'possible' and 'certain' by the reporting centres. In 27 cases myositis or polymyositis was reported. Other myopathies were reported, including 35 cases with rhabdomyolysis. In 9 of these cases, the PPI was withdrawn and the reaction abated. The PPI was reinstated in one patient, but the reaction did not re-occur. Time to onset was given in 17 of the rhabdomyolysis cases, rhabdomyolysis occurred with the first week in 9 cases, and in 3 cases the reaction occurred between 14 days to 3 months of treatment. In 12 of these patients, an HMG-CoA reductase inhibitor (statin) was taken concomitantly.
Case reports from the WHO ADR database, including index cases involving four out of five PPIs, along with evidence of a possible mechanism, provide compelling evidence that there is a causal association between members of the PPI drug class and myopathy including polymyositis. Evidence was also obtained to support the view that PPI use may be associated with occurrence of other myopathies, including the serious reaction rhabdomyolysis.
新西兰强化药物监测计划（IMMP）以及世界卫生组织国际药物监测合作中心——乌普萨拉监测中心（UMC）已发出信号，接受奥美拉唑治疗的患者发生的多发性肌炎可能是一种药物不良反应（ADR）。上市后数据及医学文献中也有与质子泵抑制剂（PPI）使用相关的多发性肌炎及其他肌病的报道。我们希望对这些信号进行追踪，并调查多发性肌炎及其他肌病与PPI使用之间关联的因果证据。
各国监测中心自发报告的ADR会被发送至世界卫生组织ADR数据库（VigiBase）。在VigiBase中搜索有关PPI（奥美拉唑、泮托拉唑、兰索拉唑、埃索美拉唑和雷贝拉唑）且含有提示肌病术语的病例报告，并从各国中心获取更多信息以帮助确定因果关系。对文献来源进行审查，以了解上述术语与PPI联用的情况。
PPI相关的各种肌病报告共有292份，不包括868例“肌痛”病例。在此分析中，69例患者停药后康复，15例患者再次用药时反应复发。在292例病例中，三分之一的患者仅使用了PPI这一种药物，在使用了合并用药的报告中，57%的报告表明PPI是唯一可疑药物。在此分析中，记录了3例索引病例。其中1例涉及同一名患者在不同时间段服用三种不同的PPI（兰索拉唑、埃索美拉唑和雷贝拉唑），三种药物均导致了肌痛和肌肉无力。在另外2例索引病例中，报告了使用埃索美拉唑和奥美拉唑后发生肌病且再次用药反应呈阳性的情况，报告中心将因果关系评估为“可能”和“确定”。报告了27例肌炎或多发性肌炎病例。还报告了其他肌病，包括35例横纹肌溶解症。其中9例病例停用PPI后反应减轻。1例患者再次使用PPI，但反应未复发。17例横纹肌溶解症病例给出了发病时间，9例在第一周内发生横纹肌溶解症，3例在治疗14天至3个月之间出现反应。这些患者中有12例同时服用了HMG-CoA还原酶抑制剂（他汀类药物）。
世界卫生组织ADR数据库中的病例报告，包括涉及五种PPI中四种的索引病例，以及可能机制的证据，提供了令人信服的证据，表明PPI药物类别成员与包括多发性肌炎在内的肌病之间存在因果关联。还获得了证据支持PPI使用可能与其他肌病的发生有关，包括严重的横纹肌溶解反应。
