title: Safety profile of modafinil across a range of prescribing indications, including off-label use, in a primary care setting in England: results of a modified prescription-event monitoring study.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Drug Safety Research Unit, Bursledon Hall, Southampton, SO31 1AA, UK. miranda.davies@dsru.org
authors.forename: Miranda
authors.initials: M
authors.lastname: Davies
authors.forename: Lynda
authors.initials: L
authors.lastname: Wilton
authors.forename: Saad
authors.initials: S
authors.lastname: Shakir
mesh_terms: D000293:Adolescent; D000328:Adult; D001559:Benzhydryl Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000009:adverse effects*; D002648:Child; D015331:Cohort Studies; D011307:Drug Prescriptions / Q000706:statistics & numerical data*; D004739:England; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D009290:Narcolepsy / Q000188:drug therapy*; D056687:Off-Label Use; D010818:Practice Patterns, Physicians'; D011320:Primary Health Care; D011358:Product Surveillance, Postmarketing / Q000379:methods* / Q000706:statistics & numerical data; D012893:Sleep Wake Disorders / Q000188:drug therapy*; D011795:Surveys and Questionnaires; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D000077408:Modafinil