Blood disorder side effects have surfaced in some users of Remicade, a long-prescribed biological therapeutic for rheumatoid arthritis and Crohn's disease.

Its manufacturer, Centocor Inc., along with the FDA, issued a letter to advise health care professionals that certain hematologic events, some fatal, have been reported in about 580 patients receiving Remicade (infliximab). The problems include leucopenia, neutropenia, thrombocytopenia and pancytopenia, and there also have been rare cases of a central nervous system manifestation of systemic vasculitis. The FDA has reported a dozen deaths.

"Many of these things were actually characterized in the existing label for Remicade," Craig Buchholz, Centocor's senior director of public relations and corporate communications, told BioWorld Today. "Some additional elements were added in the label change that took place recently, and precipitated the Dear Healthcare Provider' letter."

Such issues are associated with the class of drugs to which Remicade belongs. The product binds to tumor necrosis factor alpha, as do other subsequently approved biological therapeutics such as Enbrel (etanercept, from Amgen Inc. and Wyeth) and Humira (adalimumab, from Abbott Laboratories).

"I think the label we're [now] seeing is pretty immaterial," said Janet Gearlds, an analyst with Wells Fargo Bank in San Francisco. "I don't suspect, at least in the near term, that it will have any impact on sales."

Remicade generated about $2 billion in worldwide sales last year.

Last month, Malvern, Pa.-based Centocor expanded warnings on the product's labeling to indicate that though the underlying relationship between Remicade and hematologic events remains unclear and no high-risk groups have been identified, caution should be exercised in Remicade patients who have ongoing or a history of significant hematologic abnormalities.

"There's no causal relationship that's been determined to Remicade," Buchholz said. "But it's consistent with language that exists in labels for Enbrel and Humira, other elements in this class. And again, on their side, no causal relationship has been determined, either."

Centocor's label revision suggests that Remicade patients should seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection, such as a persistent fever, while on the drug. The added labeling also warns that discontinuation of Remicade should be considered in patients who develop significant central nervous system adverse reactions.

"These events have been seen in patients taking Remicade," Buchholz said, "and it's important to maintain vigilance when you're treating these patients to look for manifestations of these disorders."

The labeling amendment stems from the company's regular post-marketing safety update correspondence it maintains with the FDA.

"If you look at the revisions, they are pretty similar to the other warning conditions found in the other TNF-blocking drugs like Enbrel and Humira," Gearlds told BioWorld Today. "It looks like these sorts of hematological abnormalities, as they call them, are pretty common. So I think it's a non-event."

Centocor, a subsidiary of Johnson & Johnson, of New Brunswick, N.J., noted that 509,000 patients have been treated with Remicade worldwide since it received FDA approval six years ago. Including clinical trials, there have been about 10 years of human use.

Remicade's label already contained cautions related to tuberculosis, invasive fungal infections and other opportunistic infections, heart failure, allergic reactions, nervous system disorders, as well as previous warnings about blood disorders.

In the U.S., it is indicated for rheumatoid arthritis and Crohn's disease, while in Europe Remicade is approved for those same indications as well as psoriatic arthritis and ankylosing spondylitis. Centocor has filed to expand the U.S. label to include ankylosing spondylitis, and plans to follow next year with a filing for psoriatic arthritis.

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