Public statement on infliximab (Remicade): Update on safety concerns

1 February 2002

The following public statement from the European Agency for the Evaluation of Medicinal Products (EMEA) contains essential information for anyone prescribing or taking Remicade (infliximab)1.

Further to the EMEA public statements on 20 December 2000 (EMEA/CPMP/4445/00) and 24 October 2001 (CPMP/3257/01), the Agency's scientific committee, the Committee for Proprietary Medicinal Products (CPMP), has continued to review clinical efficacy and safety information on Remicade.

The CPMP concluded in its meeting on 17 January 2002, that Remicade continues to have a positive benefit/ risk balance in both Crohn's disease and Rheumatoid arthritis, provided that specific changes to the Product Information restricting the indication in Crohn's disease and reinforcing the special precautions and warnings have been made. Because of safety concerns, the indications for treatment of Crohn' s disease have been restricted as follows:

• Treatment of severe, active Crohn's disease, in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and /or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies.
• Treatment of fistulising Crohn's disease, in patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy)

The indication for rheumatoid arthritis remains unchanged [see attached Summary of Product Characteristics (SPC)].

To further guarantee the safe use of Remicade, the EMEA draws attention to the following important safety information:

Remicade should only be administered under the supervision and monitoring of specialised physicians experienced in the diagnosis and treatment of rheumatoid arthritis or inflammatory bowel diseases.

Information for Health Care Professionals:

• Infections including tuberculosis: Remicade is contraindicated in patients with tuberculosis or other severe infections such as sepsis, abscesses, or opportunistic infections. Patients must be closely monitored for infections including tuberculosis before, during and after Remicade treatment, in accordance with local recommendations. Treatment with Remicade must not be continued if a patient develops serious infections or sepsis.

In postmarketing spontaneous reporting, infections are the most common serious adverse event. Some of the cases have resulted in fatal outcome. Up to the middle of 2001, 202 deaths have been reported. Nearly 50% of these have been associated with infections.

Up to 31 October 2001, approximately 130 cases of active tuberculosis including miliary tuberculosis and tuberculosis with extrapulmonary location have been reported in patients treated with Remicade. Some of these cases had a fatal outcome.

Before starting treatment with Remicade, all patients must be evaluated for both active and inactive ('latent') tuberculosis. This evaluation should include a detailed medical history with personal history of tuberculosis or possible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests i.e., tuberculin skin test and chest x-ray should be performed in all patients (local recommendations may apply). It is recommended that the conduct of these tests is recorded on the patient's alert card, which will be provided with the Remicade packages. Prescribers are reminded of the risk of false negative tuberculin skin test results especially in patients who are severely ill or immunocompromised. If active tuberculosis is diagnosed, Remicade treatment must not be initiated.

If inactive ('latent') tuberculosis is diagnosed, prophylactic anti-tuberculosis therapy must be started before the initiation of Remicade, and in accordance with local recommendations. In this situation, the benefit/ risk balance of Remicade therapy should be very carefully considered.

All patients should be informed to seek medical advice if signs or symptoms suggestive of tuberculosis (e.g. persistent cough, wasting / weight loss, low-grade fever) appear during or after Remicade treatment.

• Heart Failure: Remicade is contraindicated in patients with moderate to severe heart failure (NYHA class III/IV). Caution should be exercised if treating patients with Remicade who have mild heart failure (NYHA class I/II). While being treated with Remicade, the patient's heart failure status should be closely monitored. Remicade treatment must not be continued if the patient develops symptoms of heart failure or experiences worsening heart failure (see SPC for further details).
• Other safety concerns: These include hypersensitivity reactions including anaphylactic shock, neurological events and malignancies (see SPC for further details).
• Care should be taken in selecting appropriate patients while observing the above safety information in order to minimise the risks associated with Remicade therapy.
• All patients treated with Remicade should be given the package leaflet and a special patient's alert card.
• The safety and efficacy of Remicade for indications outside of Crohn's disease and rheumatoid arthritis have not been established.

Information for Patients

• Remicade continues to be an effective and safe medicine. However, it is important that the patients are selected carefully and the warnings indicated below are respected.
• Remicade increases the risk of getting infections. Infections may progress more rapidly and be more severe. This includes tuberculosis (TB).
• You should not be treated with Remicade, if you have a severe infection. 3
• You should be tested for TB prior to Remicade treatment. Tell your doctor if you have ever had TB or if you have been in close contact with someone who has had TB.
• Contact your doctor if symptoms suggestive of infections appear, such as fever, persistent cough, weight loss, or listlessness.
• Remicade should not be used if you have moderate or severe heart failure.
• Contact your doctor if you experience symptoms like shortness of breath, especially with exertion or upon lying down, or swelling of your feet which might indicate heart failure.

As an urgent measure, the patient and prescribing information has been amended accordingly through a rapid procedure at the request of the marketing authorisation holder and a patient's alert card has been introduced

EMEA public statement on infliximab (Remicade): Update on safety concerns

Reference Number: CPMP/32/02