Severe cutaneous adverse reaction reports with modafinil and armodafinil

HSA has received reports of severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), with the use of modafinil and armodafinil. The patients had obtained the medicines from friends or illegal street peddlers.

Modafinil and armodafinil are used for the treatment of conditions that involve excessive somnolence such as narcolepsy and obstructive sleep apnoea.¹ Both modafinil and armodafinil are not registered in Singapore currently but they may be imported and supplied locally under the special access route (SAR).²

Stevens-Johnson syndrome (SJS) with modafinil and armodafinil

1) Local situation

As at 31 October 2023, HSA has received nine AE reports with modafinil and armodafinil. Seven reports (77.8%) were dermatological/cutaneous reactions*, and of these three reports were SJS. The remaining two reports described increased paranoia and giddiness. From the available information, four patients had obtained their medicines from friends or illegal street peddlers and three of them were self-medicating to stay alert for work. The three reports of SJS involved individuals in their thirties; two were males, and one was a female. The date of onset of SJS ranged from one day to over one month. Modafinil was reported as the suspected drug in two cases and armodafinil in the third case.

*One report each of generalised pruritic rash, angioedema, skin and oral ulcers, fixed drug eruption presented as oral erosions and three reports of SJS

2) Clinical trial findings and overseas reports

The incidence of SJS with modafinil and armodafinil is not well established. In clinical trials of modafinil, the incidence of rash resulting in discontinuation was approximately 0.8% (13 per 1,585) in paediatric patients (age <17 years). These reports included one case of possible SJS and one case of apparent multi-organ hypersensitivity reaction.³

Rare cases of serious or life-threatening rash, including SJS, Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) have been reported in worldwide post-marketing experience with modafinil and armodafinil.^3,4 The reporting rate of TEN and SJS associated with modafinil use worldwide exceeds the background incidence rate.³ Estimates of the background incidence rate for these serious skin reactions in the general population range between 1 to 2 cases per million-person years.³ Given that three cases of SJS have been reported locally despite the low usage of modafinil and armodafinil, this safety concern may warrant closer monitoring.

Conclusion

HSA had issued two press releases⁵ to alert the public on serious adverse reactions, including SJS, with modafinil and armodafinil. The first press release was issued in 2018 and reported the first case of SJS. The second press release was issued more recently, in November 2023, following the receipt of three serious reports (2 SJS and 1 fixed drug eruption requiring hospitalisation) over a three-month period.

Healthcare professionals are advised to consider the possibility of SCARs in patients presenting with prodromal symptoms such as flu-like symptoms, mouth ulcers, sore throat and ditto conjunctivitis. Please report any adverse events, including SCARs, suspected with these medicines to the Vigilance and Compliance Branch of HSA. Information on the source of supply, if available, may be included if healthcare professionals are aware that patients had obtained the medicines from unauthorised sources.

References

1. Micromedex® https://www.micromedexsolutions.com/ (last accessed: 17 Nov 2023)
2. HSA Special Access Route: https://www.hsa.gov.sg/therapeutic-products/register/special-access-routes
3. Provigil US Package Insert (PI): https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf
4. Nuvigil US PI: 
   https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021875s023lbl.pdf
5. HSA Press releases: https://go.gov.sg/hsa-press-releases

Published: 15 Dec 2023

Safety Alerts