Stevens-Johnson Syndrome After Armodafinil Use

INTRODUCTION

Stevens-Johnson syndrome (SJS) is a rare and severe skin reaction that often occurs after initiation of an implicated medication.^1,2 SJS has been reported as an adverse effect for armodafinil, yet no definitive case has been presented in the literature. Initially, a warning associating modafinil with SJS was primarily based on a rash that formed on one patient during modafinil clinical trials.³ Post-marketing research has indicated that several cases of SJS or toxic epidermal necrolysis (TEN) have recently been reported, but details of these cases have not been published.⁴ SJS and TEN are part of a spectrum of acute inflammatory skin disorders likely due to hypersensitivity-mediated skin reactions.¹ Erythema multiforme presents with similar skin lesions involving targets or raised, edematous papules, but predominantly affecting acral areas of the skin with little or no mucosal involvement. SJS and TEN, however, present as similar multisystem diseases and are characterized by widespread blisters on the trunk and face with erythematous or pruritic macules and one or more mucous membrane erosions.^1,2 SJS is distinguished from TEN by involvement of less than 10% of total body surface area in SJS and greater than 30% of total body surface area in TEN.^1,2 We present a case of a patient in whom SJS developed less than 2 weeks after starting armodafinil.

REPORT OF CASE

A 21-year-old woman on stable long-term maintenance immunotherapy for common allergies presented with excessive daytime sleepiness dating back since childhood despite a reported 9 h/night of sleep. Her identical twin sister had no complaint of excessive sleepiness. The patient denied symptoms of cataplexy or other ancillary symptoms of narcolepsy. She reported no history of drug allergies. Medications included vitamin D3, Ultra Probiotic Complex, Cyclafem, fexofenadine (Allegra) as needed (PRN), bismuth subsalicy-late (Pepto-Bismol) PRN, and ibuprofen PRN. Physical examination was unremarkable.

Testing prior to the initiation of armodafinil included nocturnal polysomnography and a Multiple Sleep Latency Test. The polysomnogram was unremarkable with no indication of sleep-disordered breathing. Results from the Multiple Sleep Latency Test were significant for markedly shortened sleep onset latencies (5 naps, mean 1.6 minutes), but without sleep onset rapid eye movement periods. Sleep logs indicated consistent bedtimes and wake times with an average reported total sleep time of 8.7 h/night 2 weeks prior to the sleep laboratory evaluation. She was given the diagnosis of idiopathic hypersomnia and started on armodafinil (Nuvigil) 150 mg by mouth every morning.

Approximately 12 days after initiation of treatment the patient noticed mild subjective fever and neck swelling consistent with cervical lymphadenopathy, and armodafinil was discontinued at that time. Within 12 hours of discontinuation mucocutaneous ulcerations with irregular purpuric macules appeared over the patient's face, with a generalized rash spreading from her face over her body characteristic of SJS (Figure 1). The following day the patient was hospitalized, receiving supportive care only. Skin biopsy was consistent with the diagnosis of SJS, showing perivascular infiltration of lymphocytes and necrosis of the entire epidermis with the epidermis detached from the dermis. Symptoms resolved after several weeks and, 3 months later, only subtle skin discolorations over previously blistered skin areas remained. The patient and family feared possible recurrence of symptoms if an alternative class of medication were to be initiated. Despite persistent symptoms of severe daytime sleepiness, the patient declined medical advice to consider an alternative agent.

DISCUSSION

SJS and TEN are considered one disease spectrum characterized by a prodrome of fever, painful swallowing, and eye pain followed by a rash 4 to 28 days after starting a new medication.⁵ Skin findings appear as purpuric maculae or blistering with mucosal bullae involving the nares, mouth, and anorectal, ocular, vulvovaginal, and/or urethral regions. Ulcerative stomatitis with hemorrhagic crusting is a typical finding, as was observed in our patient. Moreover, our patient's skin biopsy showing epidermal necrosis and detachment from the dermis is also consistent with SJS.¹

There are many high-risk drugs for SJS/TEN; however, the most associated drugs are sulfa-based antibiotics, allopurinol, carbamazepine, phenobarbital, phenytoin, nevirapine, and oxicam-nonsteroidal anti-inflammatory drugs.⁶ Diagnosis is made by skin biopsy revealing keratinocyte necrosis on pathology, and is preformed if there are atypical appearing lesions. Although the pathogenesis of SJS/TEN is unknown, it is suspected to be an immune-mediated process related to drug metabolites.¹ Treatment involves discontinuation of the suspected drug as soon as SJS is suspected, followed by supportive care.^5,7

This patient had typical findings of SJS including mucocutaneous involvement, a prodrome including fevers, young age, and initiation of an implicated drug (armodafinil). It is unclear if her history of immunotherapy for common allergies played a significant role in increasing the risk of SJS. Other than starting armodafinil, this patient did not have known risk factors and her human leukocyte antigen (HLA) phenotype was not obtained. Known predisposing factors that increase risk of SJS include: human immunodeficiency virus, genetic causes including the HLA-B*15:02 phenotype, lupus, malignancy, and rapid introduction or high doses of implicated medications.^1,8

There are currently no reported cases of SJS after armodafinil use and only one reported case in PubMed of SJS after modafinil use.⁹ Label warnings for both modafinil (Provigil) and armodafinil (Nuvigil) report the risk for serious dermatologic reactions, including SJS and TEN, even though no definitive case has been presented in the literature. Through discussions with colleagues in sleep medicine and leading experts in narcolepsy regarding the risk of developing SJS with armodafinil, two authors (MS and AR) have found a general level of skepticism regarding the validity of this association, likely secondary to the lack of published case reports. Initial clinical trials for modafinil resulted in 13 cases of nonspecific rash resulting in drug discontinuation, and only 1 of these cases was initially reported as possible, but not confirmed, SJS.³ All 13 cases occurred in pediatric patients younger than 17 years old.³ As of February 2017, a post-marketing update of the drug label states that additional skin and mouth sores, blistering, and ulceration have been reported, including rare serious cases of SJS and TEN in adults and children with modafinil and armodafinil.⁴ According to this update, symptom onset ranged from 1 day to 2 months, rarely occurring beyond 3 months after initiation of treatment, and median time to detection was 13 days. One fatal case of drug rash with eosinophilia and systemic symptoms has been reported with armodafinil, and at least one fatality of multiorgan hypersensitivity reactions occurred in association with modafinil.⁴ There are no known predictive risk factors for skin rash prior to starting treatment, nor are there predictive features of rash severity when it appears.^3,4

This case represents the first clear association between initiation of armodafinil therapy and SJS to be reported in the literature. Despite its low incidence, clinicians must maintain a high index of suspicion when starting armodafinil due to the risk of morbidity and mortality associated with SJS. If SJS is suspected after armodafinil use, drug discontinuation must occur immediately, followed by supportive care.^5,7

DISCLOSURE STATEMENT

All authors have seen and approved the manuscript. Dr. Markus Schmidt serves on the Speakers Bureau for Arbor Pharmaceuticals. The other authors report no conflicts of interest.

REFERENCES