Drug Safety Research Unit, Bursledon Hall, Southampton, SO31 1AA, UK.
Drug Saf. 2013 Apr;36(4):237-46. doi: 10.1007/s40264-013-0025-y.
Modafinil (Provigil) was marketed in the UK in 1998 to promote wakefulness in the treatment of narcolepsy. In April 2004, the licence was extended to include chronic pathological conditions; 2 years later, the prescription of modafinil was restricted to patients with shift work sleep disorder, narcolepsy and obstructive sleep apnoea/hypopnoea syndrome. Following a recent review of the safety data, the licence has been further restricted to only treat patients with narcolepsy. The review highlighted the degree of off-label usage of modafinil, including patients with multiple sclerosis.
The aim of this study was to examine the safety profile of modafinil in real-world clinical usage and across a range of prescribing indications, including multiple sclerosis.
The study was conducted using the observational cohort technique of Modified Prescription-Event Monitoring. Patients were identified from dispensed prescriptions issued by primary care physicians from July 2004 to August 2005. Patient demographics and information on prescribing behaviour were included in the questionnaire sent to the prescribing general practitioner (GP) 6 months after the initial prescription for each patient. The questionnaire sought data on any events that patient may have experienced during that time, reasons for stopping treatment with modafinil, adverse drug reactions (ADRs), potential interaction with contraceptives, and pregnancies. Incidence densities (IDs) were calculated for all events, and stratified according to indication and dose. Specific events were evaluated by requesting further information.
Of the 4,023 questionnaires sent to GPs, 2,416 were returned (response rate 60.1 %). Of these, only those patients issued modafinil after April 2004 (with the associated broadening of the indications for treatment) were included in the study, resulting in a final cohort of 1,096 patients: 497 (45.3 %) male, median age of 52 years (interquartile range [IQR] 41-63), and 599 (54.7 %) female, median age of 47 years (IQR 38-57). Nine patients were aged 16 years or younger; no serious skin reactions were reported in this group. Thirty-four percent of the cohort had an indication of multiple sclerosis. In this study, the majority of the clinical events that were most frequently reported as ADRs or reasons for stopping or that occurred in month 1 have been previously documented with modafinil. The results of the study show that less than half of the women of child-bearing potential were established on a recommended contraceptive programme; three women became pregnant whilst taking modafinil and the oral contraceptive pill. Stratification of IDs by dose revealed certain additional events occurred during month 1 of treatment at the higher dose only. Assessment of individual cases of cardiac, psychiatric and skin events indicated causal associations with modafinil.
This study provides important additional safety data on the use of modafinil in patients in 'real-world' use, including those for whom the prescribing indication is outside the terms of licence, as per recent changes to the licensed indications for treatment. In addition to safety data, our study provides useful utilization data. Results from this study indicate that a significant number of women of child-bearing potential had not been commenced on appropriate contraceptive programmes prior to starting modafinil. There were three pregnancies that occurred whilst taking contraception, highlighting the necessity of ensuring effective contraceptive cover for women during and after stopping treatment with modafinil. Analysis of the data showed that the majority of events reported as ADRs or reasons for stopping and ranked events during the first month of treatment had been previously documented with the use of modafinil. Stratification of events according to dose revealed a number of events that occurred at the higher dose only, including serious events such as psychosis. The targeted events for which causality assessments were undertaken confirmed the potential of modafinil to induce certain types of events in individual patients, including cardiac and psychiatric events.
莫达非尼（Provigil）于 1998 年在英国上市，用于治疗嗜睡症以促进清醒。2004 年 4 月，许可证扩展到包括慢性病理状况；2 年后，莫达非尼的处方仅限于患有轮班工作睡眠障碍、嗜睡症和阻塞性睡眠呼吸暂停/低通气综合征的患者。在最近对安全性数据进行审查后，许可证的使用范围进一步限于仅用于治疗嗜睡症患者。该审查强调了莫达非尼的非适应证使用程度，包括多发性硬化症患者。
本研究旨在检查莫达非尼在真实世界临床应用中的安全性概况，并在一系列适应证中进行评估，包括多发性硬化症。
该研究使用改良处方事件监测的观察性队列技术进行。从 2004 年 7 月至 2005 年 8 月，从初级保健医生开出的处方中确定患者。问卷中包括患者的人口统计学信息和处方行为信息，在每位患者首次处方后的 6 个月发送给开处方的全科医生。问卷询问了患者在此期间可能经历的任何事件、停止使用莫达非尼的原因、药物不良反应（ADR）、与避孕药具的潜在相互作用以及妊娠情况。根据适应证和剂量计算了所有事件的发生率密度（ID），并进行了分层。通过进一步要求提供信息来评估特定事件。
共向全科医生发送了 4023 份问卷，收回了 2416 份（回复率为 60.1%）。其中，只有在 2004 年 4 月后开出莫达非尼的患者（与治疗适应证的扩大相关）被纳入研究，最终纳入了 1096 名患者：497 名（45.3%）男性，中位年龄 52 岁（四分位间距 [IQR] 41-63），599 名（54.7%）女性，中位年龄 47 岁（IQR 38-57）。9 名患者年龄在 16 岁以下；该组未报告严重皮肤反应。34%的患者有多发性硬化症的适应证。在本研究中，大多数最常报告为 ADR 或停药原因或在第 1 个月发生的临床事件之前已在莫达非尼的使用中记录。研究结果表明，不到一半有生育能力的女性已开始接受推荐的避孕方案；3 名女性在服用莫达非尼和口服避孕药期间怀孕。按剂量分层显示，在较高剂量下仅在治疗的第 1 个月发生某些其他事件。对心脏、精神科和皮肤事件的个别病例进行评估表明，这些事件与莫达非尼之间存在因果关系。
本研究提供了关于莫达非尼在“真实世界”中使用的重要额外安全性数据，包括那些适应证不在许可范围内的患者，如最近对治疗适应证的许可变更。除了安全性数据外，我们的研究还提供了有用的利用数据。研究结果表明，在开始服用莫达非尼之前，有相当数量的有生育能力的女性尚未开始服用适当的避孕方案。有 3 例怀孕是在服用避孕药期间发生的，这突出表明在治疗期间和治疗结束后，必须确保女性有效的避孕措施。数据分析表明，报告为 ADR 或停药原因的大多数事件以及在治疗的第一个月排名靠前的事件之前已经在使用莫达非尼的过程中记录在案。根据剂量分层显示，只有在较高剂量下才会发生一些事件，包括严重的事件，如精神病。对进行因果关系评估的目标事件的确认表明，莫达非尼可能会在个别患者中引发某些类型的事件，包括心脏和精神科事件。
