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May 10, 1999
Dear Healthcare Professional:
This communication is to inform you of important post-marketing safety information for ENBREL® (etanercept), a new treatment for moderate to severe rheumatoid arthritis. Some of this safety information was already described in the package insert. The new information provides additional data on serious infections reported with the use of ENBREL. Over the five month period following the drug's approval in November 1998, thirty of the estimated 25,000 patients treated with ENBREL are reported to have developed serious infections including several with sepsis. Six of these patients died within two to sixteen weeks after initiation of treatment. In addition to their rheumatoid arthritis, a number of these patients had a history of chronic or recurrent infections, preexisting infections, diabetes mellitus or other conditions that predisposed them to infections. Infections, including serious infections, are more common in the rheumatoid arthritis population than in the general public.
Based on the current information, we ask you to consider the following recommendations regarding the use of ENBREL.
Treatment with ENBREL should not be initiated in patients with active infections including chronic or localized infections. Physicians should exercise caution when considering the use of ENBREL in patients with a history of recurring infections or with underlying conditions, which may predispose patients to infections such as advanced or poorly controlled diabetes.
The Warnings, Precautions, and Adverse Events sections of the labeling for ENBREL have been revised to incorporate this new information and these revised sections are included in the attached sheet.
A revised package insert is enclosed. Should you have questions regarding the use of ENBREL, please call Wyeth-Ayerst at 1 800-934-5556.
Healthcare professionals should report any serious adverse events possibly associated with the use of ENBREL to Wyeth-Ayerst at 1 800-934-5556. Alternatively, this information may also be reported to FDA's MedWatch reporting system by phone (1-800-FDA-1088), Fax (1-800-FDA-0178), via the MedWatch website at www.fda.gov/medwatch, or by mail (using postage-paid form) to MedWatch, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787. Health professionals and consumers should use the Form 3500 for adverse event/product problem reporting.
IN POST MARKETING REPORTS, SERIOUS INFECTIONS AND SEPSIS, INCLUDING FATALITIES, HAVE BEEN REPORTED WITH THE USE OF ENBREL. MANY OF THESE SERIOUS EVENTS HAVE OCCURRED IN PATIENTS WITH UNDERLYING DISEASES THAT IN ADDITION TO THEIR RHEUMATOID ARTHRITIS COULD PREDISPOSE THEM TO INFECTIONS. PATIENTS WHO DEVELOP A NEW INFECTION WHILE UNDERGOING TREATMENT WITH ENBREL SHOULD BE MONITORED CLOSELY. ADMINISTRATION OF ENBREL SHOULD BE DISCONTINUED IF A PATIENT DEVELOPS A SERIOUS INFECTION OR SEPSIS. TREATMENT WITH ENBREL SHOULD NOT BE INITIATED IN PATIENTS WITH ACTIVE INFECTIONS INCLUDING CHRONIC OR LOCALIZED INFECTIONS. PHYSICIANS SHOULD EXERCISE CAUTION WHEN CONSIDERING THE USE OF ENBREL IN PATIENTS WITH A HISTORY OF RECURRING INFECTIONS OR WITH UNDERLYING CONDITIONS WHICH MAY PREDISPOSE PATIENTS TO INFECTIONS SUCH AS ADVANCED OR POORLY CONTROLLED DIABETES. (SEE PRECAUTIONS, ADVERSE REACTIONS, INFECTIONS).
The possibility exists for anti-TNF therapies, including ENBREL, to affect host defenses against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 49 patients with RA treated with ENBREL, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector cell populations. The impact of treatment with ENBREL on the development and course of malignancies, and active and/or chronic infections is not fully understood (see WARNINGS, ADVERSE REACTIONS, Infections and Malignancies). The safety and efficacy of ENBREL in patients with immunosuppression or chronic infections have not been evaluated.
Upper respiratory infections ("colds") and sinusitis were the most frequently reported infections in patients receiving ENBREL or placebo. In placebo-controlled trials, the incidence of upper respiratory tract infections was 16% in the placebo treatment group and 29% in the group treated with ENBREL; and 0.68 events per patient year in the placebo group and 0.82 events per patient year in the group treated with ENBREL when the longer observation of patients on ENBREL was accounted for.
In placebo-controlled trials evaluating ENBREL, no increase in the incidence of serious infections was observed (1.3% placebo, 0.9% ENBREL). In open-label and placebo-controlled trials, 22 serious infections were observed in a total of 745 subjects exposed to ENBREL, including: pyelonephritis, bronchitis, septic arthritis, abdominal abscess, cellulitis, osteomyelitis, wound infection, pneumonia, foot abscess, leg ulcer, diarrhea, sinusitis, and sepsis. Serious infections, including sepsis and death, have also been reported during post-marketing use of ENBREL. Some have occurred within a few weeks after initiating treatment with ENBREL. Many of the patients had underlying conditions (e.g., diabetes, congestive heart failure, history of active or chronic infections) in addition to their rheumatoid arthritis. See WARNINGS. Data from a sepsis clinical trial not specifically in patients with RA suggest that ENBREL treatment may increase mortality in patients with established sepsis.
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