Advertisement

Drug Safety

, Volume 36, Issue 4, pp 237–246 | Cite as

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
  • Miranda DaviesEmail author
  • Lynda Wilton
  • Saad Shakir
Original Research Article

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.

Keywords

Multiple Sclerosis Skin Reaction Modafinil Narcolepsy Toxic Epidermal Necrolysis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The DSRU, a registered independent charity (No. 327206) that works in association with the University of Portsmouth, has received an unconditional donation from the manufacturer of modafinil.

Conflict of interest

The authors have no conflicts of interest that are directly relevant to the content of this study.

References

  1. 1.
    European Medicines Agency (EMA). Assessment report for modafinil containing medicinal products. London: EMA; 2011.Google Scholar
  2. 2.
    Cephalon Inc. Dear Healthcare Professional letter. Updated safety information: warnings regarding serious rash, including Stevens–Johnson Syndrome and hypersensitivity reactions, and psychiatric symptoms. Silver Spring: US FDA. 2007. http://www.fda.gov/medwatch/safety/2007/Provigil_dhcpletter091207_final.pdf. Accessed May 2012.
  3. 3.
    Cephalon (UK) Limited. Summary of product characteristics: Provigil®. Castleford: Cephalon UK Limited; 2012.Google Scholar
  4. 4.
    Mariani JJ, Hart CL. Psychosis associated with modafinil and shift work. Am J Psychiatry. 2005;162(10):1983.PubMedCrossRefGoogle Scholar
  5. 5.
    Ranjan S, Chandra PS. Modafinil-induced irritability and aggression? A report of 2 bipolar patients. J Clin Psychopharmacol. 2005;25(6):628–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Vorspan F, Warot D, Consoli A, Cohen D, Mazet P. Mania in a boy treated with modafinil for narcolepsy. Am J Psychiatry. 2005;162(4):813–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Kruszewski SP. Euphorigenic and abusive properties of modafinil. Am J Psychiatry. 2006;163(3):549.PubMedCrossRefGoogle Scholar
  8. 8.
    Oskooilar N. A case of premature ventricular contractions with modafinil. Am J Psychiatry. 2005;162(10):1983–4.PubMedCrossRefGoogle Scholar
  9. 9.
    Boellner SW, Earl CQ, Arora S. Modafinil in children and adolescents with attention-deficit/hyperactivity disorder: a preliminary 8-week, open-label study. Curr Med Res Opin. 2006;22(12):2457–65.PubMedCrossRefGoogle Scholar
  10. 10.
    Lindsay SE, Gudelsky GA, Heaton PC. Use of modafinil for the treatment of attention deficit/hyperactivity disorder. Ann Pharmacother. 2006;40(10):1829–33.PubMedCrossRefGoogle Scholar
  11. 11.
    Swanson JM, Greenhill LL, Lopez FA, Sedillo A, Earl CQ, Jiang JG, et al. Modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, fixed-dose study followed by abrupt discontinuation. J Clin Psychiatry. 2006;67(1):137–47.PubMedCrossRefGoogle Scholar
  12. 12.
    Ivanenko A, Tauman R, Gozal D. Modafinil in the treatment of excessive daytime sleepiness in children. Sleep Med. 2003;4(6):579–82.PubMedCrossRefGoogle Scholar
  13. 13.
    Layton D, Hazell L, Shakir SA. Modified prescription-event monitoring studies: a tool for pharmacovigilance and risk management. Drug Saf. 2011;34(12):e1–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Shakir S. Causality and correlation in pharmacovigilance. In: Talbot J, Waller P, editors. Stephens’ detection of new adverse drug reactions. 5th ed. Chichester: Wiley; 2004. p. 329–43.Google Scholar
  15. 15.
    CIOMS, WHO. International ethical guidelines for biomedical research involving human subjects. Geneva: Switzerland. 2002. http://www.cioms.ch/publications/guidelines/guidelines_nov_2002_blurb.htm. Accessed May 2012.
  16. 16.
    Drug Safety Update. Monthly newsletter from MHRA. Vol 1. Issue 8, March 2008.Google Scholar
  17. 17.
    Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group. Ann Neurol. 1998; 43(1):88–97.Google Scholar
  18. 18.
    Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group. Neurology. 2000; 54(5):1166–5.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Drug Safety Research UnitBursledon HallSouthamptonUK
  2. 2.University of PortsmouthPortsmouthUK

Personalised recommendations