As with all medical products, healthcare professionals are strongly encouraged to report any serious adverse events that are associated with the use of Infliximab to either the manufacturer (see letter below) or to the FDA's MedWatch program by phone (1-800-FDA-1088), fax (1-800-FDA-0178), internet (www.fda.gov/medwatch) or mail (using postage-paid form) to FDA, HF-2, 5600 Fishers Lane, Rockville, MD 20852-9787

November 10, 1998

The purpose of this letter is to report a change in the time to onset of previously reported serious adverse events that have occurred in a clinical trial in which patients with moderately to severely active Crohn's disease and fistulizing Crohn's disease were retreated with Infliximab two to four years following their initial Infliximab treatment.

In this clinical trial, ten of forty patients (25%) treated with Infliximab two to four years earlier presented with the following signs and symptoms 3 to 12 days following retreatment:

• myalgia (9/10)
• rash (7/10)
• fever (6/10)
• polyarthralgia (5/10), with three experiencing temporomandibular arthralgia
• pruritus (4/10)
• facial, hand or lip edema (2/10)
• dysphagia (2/10)
• urticaria (2/10)
• sore throat (2/10)
• headache (1/10)

Six of the 10 patients were classified as having serious adverse events because the patients were hospitalized. All 10 patients received medical treatment consisting of one or more of the following: corticosteroids, antihistamines or acetaminophen (paracetamol). One patient also received epinephrine (adrenaline). One patient took acetaminophen but did not seek medical attention. All patients experienced either improvement or resolution of their symptoms within 1-3 days.

The adverse events appear to be related to development of an immune response to Infliximab. In those patients tested, antibodies to Infliximab have been observed and the levels of Infliximab were lower than expected or undetectable following these events. Some investigators have reported that the duration of clinical response may be shortened in some of the patients experiencing these delayed adverse events.

Nine of the 10 patients with these delayed adverse events were initially treated with an investigational liquid formulation which is no longer in use, while one was initially treated with a lyophilized formulation of Infliximab. Whether the investigational liquid formulation of the product may have played a role in causing these delayed adverse reactions is unknown and under investigation.

No similar set of delayed adverse events have been observed in other completed clinical trials involving 216 patients receiving 429 retreatments at intervals ranging from 1 to 55 weeks following an initial regimen with Infliximab. The majority of retreatments (94%) in these earlier studies recurred at intervals of 14 weeks or less. Furthermore, in an ongoing study in rheumatoid arthritis, 340 patients have been retreated every 4 to 8 weeks for a period of greater than 6 months with a lyophilized formulation of Infliximab similar to the currently marketed product. None of these patients have developed a similar set of delayed adverse events.

Centocor is taking this opportunity to advise physicians that caution should be exercised when retreating patients with Infliximab following an extended period without treatment. The risk of potentially serious delayed adverse events should be weighed against the potential benefit of retreatment after a period of more than 2 years without treatment. Patients should be advised to seek medical advice and treatment in the event they develop symptoms suggestive of delayed adverse events after treatment with Infliximab.

If a patient experiences such events, we would like your cooperation in reporting these to Centocor. The toll free telephone number is 1-800-457-6399 and the telefax number is 610-651-6197.

Sincerely,

Richard V. McCloskey
Vice President and Chief Medical Officer