Severe Adverse Events Lead to a Change in the Marketing Authorisation of the Medicinal Product Remicade®

On Friday, 1st February 2002, a change in the marketing authorisation for the medicinal product Remicade® (Infliximab) came into effect by means of an emergency measure, the so-called 'Urgent Safety Restriction' (USR) (see attachment). This change in the marketing authorisation takes into account the results of an expert meeting at the EMEA (European Medicines Evaluation Agency), in which the Paul-Ehrlich-Institut played a decisive part.

Remicade® is a monoclonal antibody approved by the EU Commission for the treatment of two chronic inflammatory diseases (Crohn's disease, a disease of the bowel, in August 1999, and rheumatoid arthritis, a form of inflammatory disease of the joints, in June 2000). The indications comprise only those cases in which patients did not at all or not sufficiently respond to other forms of treatment.

Essex Pharma GmbH has informed expert groups on the change in the marketing authorisation by means of a so-called 'Red Hand Letter'. The EMEA has provided detailed information on this measure in a ‚'Public Statement' on its homepage. The Paul-Ehrlich-Institut will offer information for physicians and pharmacists on its homepage.

Reasons for this change in the marketing authorisation are risks which became known in the course of the use of Remicade® . Thus, from 1998 (first approval in the United States) up to mid 2001, 202 deaths occurred world-wide out of roughly 200,000 patients treated with Remicade® . Nearly half of these cases were due to severe infections, including cases of tuberculosis. Because of the occurrence of cases of tuberculosis, the EMEA had already updated the Summary of Product Characteristics (SPC) on 14th December 2000 by means of a USR in the sections 'Special warnings and special precautions for use' and 'Undesirable Effects'.

The EMEA has now again updated the warnings on tuberculosis extensively. All patients must be evaluated for both active and inactive (latent) tuberculosis prior to treatment with Remicade.

From Germany, 29 deaths as well as four cases of tuberculosis were reported to the Paul-Ehrlich-Institut up to 31st December 2001 in post-marketing spontaneous reporting. In this context, however, it must be considered that not all notifications confirming death should be seen in connection with Remicade. Some patients obviously died of other diseases or the disease for which they were originally treated. Ten of the deaths occurred following so-called 'off-label use', i.e. use not within the approved indication. In most of these cases, the patients were suffering from life-threatening conditions, so that Remicade® was evidently used as the treatment of last resort in these cases.

Remicade® plays an important part in the treatment of rheumatoid arthritis and Crohn's disease. Therefore, the EMEA continues to evaluate the benefit / risk balance of Remicade® as positive, taking into account the updates carried out. This is important, especially considering the fact that some patients treated with Remicade® did not respond to other forms of treatment. In co-operation with health care professionals, the Paul-Ehrlich-Institut is currently working on a publication of the adverse reactions profile for Remicade®. The notifications which the PEI received from Germany form the basis for this profile.

Attachment: Change in the Marketing Authorisation of Remicade®

• Restriction of the indication in the treatment of Crohn's disease

• Extensive changes in the warnings section (especially in view of infections, tuberculosis)

• Information on special precautions to be taken for patients with heart failure. Some stages of heart failure present a contraindication.

• As from 1st February 2002, each package of Remicade® must contain a Remicade® Patient's Alert Card. The alert card contains important general safety information and individual treatment information for the patient.

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