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【drug-news】10月FDA警告：莫达非尼可致严重皮肤反
FDA has been monitoring cases of serious skin reactions, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), in its postmarketing reviews of adverse event reports associated with the use of modafinil. The product labeling for modafinil has been recently updated to include a bolded warning for serious rash, including SJS.1 Based on postmarketing data for modafinil, a recently approved drug with a similar chemical structure, armodafinil, includes a similar bolded warning in the product labeling.2 Healthcare professionals and patients should be watchful for skin reactions associated with the use of modafinil and armodafinil and report cases to FDA's MedWatch.
Modafinil (Provigil) is an oral wakefulness-promoting agent to treat patients with excessive sleepiness (ES) associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome (OSAHS), and shift work sleep disorder (SWSD).1 Modafinil is a controlled substance (C-IV) and has been available in the United States since 1998. The safety and efficacy in children under the age of 16 has not been established.
From the date of initial marketing, December 1998, to January 30, 2007, FDA received six cases of severe cutaneous adverse reactions associated with modafinil, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) involving adult and pediatric patients.
The 6 cases from the United States occurred in four females and two males aged 49, 42, 17, 27, 15, and 7 years old, respectively. The median time-to-onset of adverse dermatologic effects following initiation of modafinil therapy was 17.5 days, ranging from 5 days to 5 weeks (see Table). Patients presented with a rash to either body extremities (arms, hands, and legs) or to the whole body with some experiencing eruptions in the mouth (lips, tongue), eyes, or genitals. In addition, some patients developed skin pigment changes, pruritus, ulcers, burning of the skin, mild skin scaling, sloughing, and/or fever. Skin biopsies from four patients confirmed TEN, SJS/TEN, SJS/EM, and eosinophilia with unspecified findings consistent with a drug hypersensitivity syndrome.3,4
There were no deaths. Five of 6 patients required hospital admission for management, including one patient with TEN who was admitted to the surgical burn unit 20 days after starting modafinil at recommended doses to treat a sleep disorder. In this case, the rash affected 50% of the total body surface area (BSA), with 20 to 30% of the skin denuded. Although this patient had an extensive medication history, modafinil was the primary suspect drug because it was the last agent added to the patient's drug regimen. In addition, modafinil discontinuation upon hospital admission coincided with patient improvement, despite continuation of other concomitant medications, such as celecoxib and propranolol, which have labeled warnings for TEN.
In one case of SJS, although potentially confounded with Lamictal therapy (labeled warning for SJS), rechallenge with modafinil resulted in recurrence of the rash including oral mucosal involvement, which supported a causal association with modafinil use. Modafinil was subsequently discontinued. In the SJS/TEN case, a 42-year-old female received concomitant medications (including escitalopram, which has a labeled warning for TEN) since 2005 without incidence before adding modafinil for sleep disorder in 2006. The patient's extensive body rash (30% of the body surface area), skin biopsy, and clinical presentation all aided the dermatologist in diagnosing SJS with overlapping TEN.
One case of DRESS syndrome was reported in a 15-year-old who was started on modafinil for attention deficit hyperactivity disorder (ADHD), an unapproved indication. After 5 weeks of therapy, the patient developed a skin rash that progressed with multiple organ system involvement, including the cardiac, renal, respiratory, and pancreatic systems. Based on the clinical presentation, increased eosinophil count, and skin biopsy results, the consulting dermatologist diagnosed DRESS syndrome.
Although some cases were potentially confounded by drugs known to be associated with serious skin reactions, all cases had features that implicate modafinil. The cases described a temporal relationship with detailed clinical descriptions, relevant laboratory data, dermatologist-substantiated diagnoses, skin biopsy confirmation, positive dechallenges, and/or a positive rechallenge, all of which support an association between modafinil use and serious cutaneous skin reactions.
Case summaries of serious skin reactions (SJS, TEN, EM, and DRESS) following use of modafinil
Age/Sex ：49/F
Event Time ： TEN
to onset Biopsy ： 20 days
Case Summary ：Yes
A patient who initiated recommended doses of modafinil for a sleep disorder was hospitalized on day 20 in the burn unit for a severe life-threatening exfoliating skin reaction. Although the patient had an extensive medication history, modafinil was the primary suspect drug because it was the last agent added to the drug regimen. The patient improved, despite the continuation of several concomitant medications, some of which, such as celecoxib and propranolol, have labeled warnings for TEN.
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作者:admin@医学,生命科学 2011-03-28 17:11
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