Can Modafinil Cause Stevens-Johnson Syndrome?

Modafinil, commonly prescribed to treat conditions like narcolepsy and obstructive sleep apnea, is generally considered safe. However, a rare and serious adverse reaction—Stevens-Johnson Syndrome (SJS)—has been reported in association with modafinil and its enantiomer, armodafinil (U.S. Food and Drug Administration, 2015). Understanding the risks and early symptoms of SJS is crucial for timely intervention.

What Is Stevens-Johnson Syndrome?

Stevens-Johnson Syndrome (SJS) is a life-threatening hypersensitivity reaction that affects the skin and mucous membranes. It is characterized by flu-like symptoms followed by a painful rash, blistering, and the detachment of the epidermis (Frantz et al., 2021). Mucosal involvement is seen in over 90% of cases and can affect the eyes, mouth, and genitalia (Hazin et al., 2008).

SJS is part of a spectrum of disease that includes toxic epidermal necrolysis (TEN), with severity defined by the percentage of body surface area affected.

Evidence Linking Modafinil to SJS

Armodafinil Case Study

Holfinger et al. (2018) reported a case of a 21-year-old woman who developed SJS 12 days after initiating armodafinil therapy. Symptoms included fever, lymphadenopathy, and a widespread purpuric rash. Biopsy confirmed SJS, and symptoms resolved following discontinuation of the drug and supportive care.

“This case, in addition to an update of the drug’s label after post-marketing research, both support the link between armodafinil and SJS” (Holfinger et al., 2018, p. 885).

Modafinil-Induced SJS

Prince et al. (2018) described a biopsy-confirmed case of modafinil-induced SJS in a 40-year-old woman. After three weeks of high-dose use, she presented with mucosal erosions and atypical targetoid lesions. Treatment with corticosteroids and topical agents resulted in full recovery.

“Our case is therefore the first definitive report of SJS induced by modafinil” (Prince et al., 2018, p. 191).

Regulatory Warnings

The U.S. FDA prescribing information for Provigil (modafinil) includes warnings for serious rash, including SJS. It recommends immediate discontinuation at the first sign of rash unless an alternate cause can be clearly identified (U.S. Food and Drug Administration, 2015).

Mechanisms Behind SJS

SJS is considered a cytotoxic, immune-mediated reaction, primarily involving CD8+ T cells and the Fas–Fas ligand pathway. Granulysin and TNF-α play key roles in inducing keratinocyte apoptosis (Oakley & Krishnamurthy, 2023). Genetic predispositions, such as certain HLA-B alleles, have been identified in some populations (Hazin et al., 2008).

Treatment and Management

Management strategies include:

• Immediate cessation of the offending drug
• Hospitalization in a burn unit or ICU
• Supportive care (fluids, wound care, pain management)
• Consideration of therapies like corticosteroids or IVIg in severe cases (Frantz et al., 2021)

Early consultation with specialists (e.g., ophthalmology, dermatology) is crucial, especially if mucosal surfaces are affected (Hazin et al., 2008).

Conclusion

Though rare, Stevens-Johnson Syndrome is a serious and potentially fatal reaction linked to modafinil and armodafinil. Case reports and FDA documentation (Holfinger et al., 2018; Prince et al., 2018; U.S. Food and Drug Administration, 2015) underscore the importance of awareness among clinicians and patients. Prompt recognition and drug cessation are essential to improve outcomes.

References

• Frantz, R., Huang, S., Are, A., & Motaparthi, K. (2021). Stevens–Johnson syndrome and toxic epidermal necrolysis: A review of diagnosis and management. Medicina, 57(9), 895. https://doi.org/10.3390/medicina57090895
• Hazin, R., Ibrahimi, O. A., Hazin, M. I., & Kimyai-Asadi, A. (2008). Stevens-Johnson syndrome: Pathogenesis, diagnosis, and management. Annals of Medicine, 40(2), 129–138. https://doi.org/10.1080/07853890701753664
• Holfinger, S., Roy, A., & Schmidt, M. (2018). Stevens-Johnson syndrome after armodafinil use. Journal of Clinical Sleep Medicine, 14(5), 885–887. https://doi.org/10.5664/jcsm.7132
• Oakley, A. M., & Krishnamurthy, K. (2023). Stevens-Johnson syndrome. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK459323/
• Prince, V., Philippidou, M., Walsh, S., & Creamer, D. (2018). Stevens–Johnson syndrome induced by modafinil. Clinical and Experimental Dermatology, 43(2), 191–192. https://doi.org/10.1111/ced.13282
• U.S. Food and Drug Administration. (2015). PROVIGIL® (modafinil) tablets, for oral use, C-IV [Prescribing information]. U.S. Department of Health and Human Services. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020717s037s038lbl.pdf