NEWS - Serious skin reactions reported with TNF-alpha antagonists

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Serious Skin Reactions Reported With TNF-alpha Antagonists

March 18, 2008 — Serious skin reactions have been reported with tumor

necrosis factor (TNF)–alpha antagonists, according to a March 18 US

Food and Drug Administration (FDA) Drug Safety Newsletter.

" Safety reviews of [TNF-alpha] antagonists, infliximab [Remicade,

Centocor Inc], etanercept [Enbrel, Manufactured by Immunex

Corporation; marketed by Amgen and Wyeth Pharmaceuticals], and

adalimumab [Humira, Abbott] identified rare cases of serious skin

reactions, including erythema multiforme (EM), s-

syndrome (SJS), and toxic epidermal necrolysis (TEN), associated with

the use of these biological products, " the newsletter states. " The

product labeling for infliximab has been updated to describe

postmarketing reports of serious skin reactions. [The] FDA is

continuing to analyze what, if any, revisions to product labeling are

needed for etanercept and adalimumab. "

In the interim, the FDA advises healthcare professionals and patients

to monitor for skin reactions associated with the use of these

TNF-alpha antagonists and to report cases to FDA's MedWatch.

The serious skin reactions presented mostly with rash and skin lesions

on the trunk, limbs, shoulder, back, hands, and face. In some SJS

cases, oral mucositis or ulceration, genital ulceration, and/or fever

were also reported. An allergic-type reaction occurred in 1 patient

who first had hives and swollen lips, eyes, and face, followed by EM

lesions on her back and hypoxia.

In a few cases of TEN, the skin reactions consisted of desquamation

and progressive, generalized pruritus and skin peeling; a severe,

scaly, pigmented, necrotizing rash over the body; and erythema with

blepharoconjunctivitis, angioedema, and tightness in the throat.

The newsletter describes in detail 3 cases showing a clear temporal

relationship between treatment with TNF-alpha antagonists and onset of

serious skin reactions.

From approval in August 1998 to August 2006, the FDA received 21

reports of cases in adult patients of severe cutaneous adverse

reactions associated with infliximab, including 16 postmarketing

reports and 5 study/registry cases. These included 15 cases of EM, 5

cases of SJS, and 1 case of TEN. Three quarters of the patients (76%)

were female; 62% had received infliximab for the treatment of

rheumatoid arthritis. Median time to onset between first infusion and

onset of skin reaction was 28 days; median number of infusions before

the skin reaction was 2 (range, 1 – 6).

Twelve patients required hospitalization for skin reactions associated

with infliximab; 1 patient hospitalized with TEN subsequently died of

multiorgan system failure 20 days after the first infusion.

" Despite confounding factors, such as concomitant medications which

have been associated with skin reactions, several cases reported to

[the FDA's Adverse Event Reporting System] described a plausible

temporal relationship, positive dechallenge, and/or positive

rechallenge supporting an association between infliximab and serious

cutaneous skin reactions, " the newsletter notes.

From approval in November 1998 to November 2006, the FDA received 22

reports of cases of severe skin reactions linked to etanercept. There

were 13 reports of EM, 4 of TEN, 4 of SJS, and 1 of SJS/TEN; 64% were

female, and most had received etanercept for the treatment of

rheumatoid arthritis. In 2 cases for which time to onset since last

etanercept dose was provided, this time was 5 days and 9 days,

respectively. Despite limited data on the start/stop dates of

concomitantly used medications, most reported a temporal relationship

with etanercept use. Eleven patients required hospitalization, and 1

died with leukemia and EM.

From approval in December 2002 to November 2006, the FDA received 7

reports of severe cutaneous reactions linked to adalimumab: 4 of EM, 2

of SJS, and 1 of both EM and SJS. Five patients (71%) had used

adalimumab for treatment of rheumatoid arthritis; 85% were female.

Median time to onset from starting adalimumab to skin reaction was 60

days. One patient was hospitalized, and there were no reported deaths.

" As protein products, all three TNF-[alpha] antagonists are

potentially immunogenic and could precipitate immune-mediated serious

skin reactions such as EM, SJS, and/or TEN, " the newsletter concludes.

" Evaluating the association between TNF-[alpha] antagonists and

serious skin reactions can be challenging due to confounding factors,

such as co-administration of one or more medications associated with

EM, SJS, and/or TEN.... The development of any severe skin reaction

while receiving TNF-[alpha] antagonist therapy may require a work-up

to determine the appropriate diagnosis and treatment and consideration

of an alternative therapy. "

http://www.medscape.com/viewarticle/571633

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