Sept. 4, 2008 — The FDA today ordered stronger warnings about the risk of potentially deadly fungal infections, especially one called histoplasmosis, in people taking the drugs Cimzia, Enbrel, Humira, and Remicade, which are called TNF blockers.
The FDA has received 240 reports of patients taking TNF blockers who developed histoplasmosis, a fungal infection that starts as a respiratory infection and can spread throughout the body.
Of those 240 patients, 45 patients died, including at least 12 who hadn’t been diagnosed with histoplasmosis right away, according to Jeffrey Siegel, MD, clinical team leader in the division of anesthesia, analgesia, and rheumatology products at the FDA’s Center for Drug Evaluation and Research. The histoplasmosis patients ranged in age from 8 to 86 years; none of the deaths involved children.
“Our advice to patients is don’t hesitate to call your doctor if you see these signs and symptoms that are related to these types of infection,” Siegel said at a news conference today.
Known Risk of Histoplasmosis
It’s not news that TNF blockers can raise the risk of infection, including histoplasmosis and other fungal infections. The FDA and doctors already knew about that. Today’s FDA action is about how that risk is noted on the drugs’ labels.
TNF blockers suppress the immune system and are used to treat conditions including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, and Crohn’s disease.
All TNF blockers already have “black box” warnings, the FDA’s sternest warning, about infection risk. And Cimzia, Remicade, and Humira — but not Enbrel — already mention the risk of invasive fungal infections in their black-box warnings.
But no TNF blockers single out histoplasmosis in their black box warning, and the FDA wants that to change.
Stronger Warning for Fungal Infections
“We’re going to make sure that all the boxed warnings state clearly that fungal infections — including in particular histoplasmosis, which is the main one that has come to our attention as having been missed in a number of cases — will be highlighted,” says Siegel.
He says the strengthened warnings will also encourage doctors to identify at-risk patients (including people who live in the Ohio and Mississippi River valleys, where histoplasmosis is more common), and to consider starting certain patients on antifungal therapy if it’s likely that they have histoplasmosis — even if that hasn’t been confirmed by lab tests.
Antifungal treatment is effective but can be “highly toxic,” says Siegel, warning that the decision to start such antifungal treatment is “not to be taken lightly.”
Histoplasmosis can be “particularly difficult to diagnose,” says Siegel, adding that histoplasmosis tests sometimes miss histoplasmosis.
Drug Companies Respond
Seigel says all drug companies that make TNF blockers are cooperating with the FDA.
WebMD contacted the makers of all four TNF blockers for their comments. Humira is made by the drug company Abbott. Cimzia is made by the drug company UCB. Remicade is made by the drug company Centocor. Enbrel is marketed by the drug companies Amgen and Wyeth. .
Laureen Cassidy, a spokeswoman for Abbott, tells WebMD that Abbott “will comply with the FDA’s request.” Cassidy notes that Humira’s black-box warning already mentions fungal infections and refers to a bolded warning elsewhere in Humira’s label about histoplasmosis, and that the infection is rare but can go unrecognized.
Sonia Fiorenza, director of corporate communications for Amgen, told WebMD via email that Amgen will work with the FDA to “finalize and communicate revised product labeling for Enbrel to both physicians and patients.”
Bert Kelly, spokesman for UCB, says his company will “certainly” work with the FDA. “We had very strong safety language; if the FDA thinks there needs to be some stronger language, we’ll work to get that done,” Kelly tells WebMD.
Centocor did not provide comments to WebMD in time for publication.