A change to the approval of the pharmaceutical product Remicade (Infliximab) came into effect on Friday, 1st February 2002, with the help of an ‘Urgent Safety Restriction‘ (USR). In agreement with the competent German authorities, the companies Essex Pharma GmbH and Centocor disclose these changes to physicians and pharmacists by means of a ‚‘Red Hand Letter‘. The European Medicines Evaluation Agency (EMEA) offers detailed information on the subject on its web-site.
Revised versions of the SPC and package leaflet form part of this information. In addition, the Paul-Ehrlich-Institut offers information for specialist groups with excerpts from the ‘Red Hand Letter‘ on its homepage.
The Following Changes to the Approval will have to be Observed as from Now (Quotes from the Red Hand Letter):
Restricted indications in the treatment of Crohn’s Disease:
Treatment of severe active Crohn’s disease, in patients who have not responded despite a full adequate course of treatment with a corticosteroid and / or an immunosuppressant; or who are intolerant to or have medical contraindications to such therapies.
Treatment of fistulising Crohn’s disease, in patients who have not responded despite a full and adequate course of thearpy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy)
Comprehensive Changes to the Special Warnings and Special Precautions for Use – Safety Profile
Infektions, especially tuberculosis:
Up to mid-2001 approximately 130 cases of active tuberculosis including military tuberculosis and tuberculosis with extrapulmonary location were reported worldwide. Some of these cases had a fatal outcome. Up to the end of 2001, four cases of tuberculosis from Germany were reported to the Paul-Ehrlich-Institut.
As from 1st February 2002, Remicade® is contraindicated in patients with tuberculosis or other severe infections such as sepsis, abscesses or opportunistic infections.
Patients must be monitored closely for infections including tuberculosis before, during and after treatment with Remicade® in compliance with the local applicable recommendations. Further treatment with Remicade® must not be given if a patient develops a serious infection or sepsis.
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. The date of the conduct of these tests should be recorded in the patient’s alert card for Remicade®, provided by Essex Pharma. Prescribers of Remicade® 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® therapy must under no circumstances be initiated.
If inactive (‘latent‘) tuberculosis is diagnosed, prophylactic anti-tuberculosis therapy must be started before the initiation Remicade®. 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 / symptoms suggestive of tuberculosis (e.g. persistent cough, wasting / weight loss, low-grade fever) appear during or after Remicade® treatment.
In agreement with Essex Pharma GmbH, the Paul-Ehrlich-Institut has asked the Central Committee for Combatting Tuberculosis to prepare a statement for the treatment of latent tuberculosis in patients undergoing Remcade treatment, which must then be made accessible to specialist groups immediately.
Patients with Heart Failure:
Remicade® is contraindicated in patients with moderate to severe heart failure (NYHA class III/IV).
Special caution should be exercised if treating patients with Remicade® who have mild heart failure. While being treated with Remicade®, the patient’s heart failure status should be closely monitored.
Remicade® must not be continued in patients who develop new or worsening symptoms of heart failure. Please see SPC for further details.
Other Safety Concerns
These include hypersensitivity reactions including anaphylactic shock, neurological events and malignancies.
As from 1st February 2002, each package leaflet of Remicade must contain a patient’s alert card on Remicade®. This patient’s alert card includes important general safety information and individual therapy details of the patient.
In its Red Hand Letter, Essex Pharma GmbH expressly indicates that ”safety and efficacy of Remicade® for indications outside Crohn’s disease and rheumatoid arthritis have not been established. Use of Remicade® outside these indications should only occur within the framework of clinical trials.” This warning is of special importance since out of those 29 deaths reported to the Paul-Ehrlich-Institut within the framework of spontaneous reporting up to 31 st December 2001, 10 occurred after ‘off-label-use‘ or Remicade.
The distribution of the cases reported is as follows:
12 cases after treatment of rheumatoid arthritis
7 cases after treatment of Crohn’s disease
7 cases after treatment of GVHD (off-label-use – outside the approved indications!)
3 cases after off-label-use in other unapproved indications
However, one must be reminded that not all reported deaths must be seen as resulting from Remicade® treatment. Some patients obviously died of other diseases or the disease to be treated.
In its Red Hand Letter, Essex Pharma GmbH offers a contact address for questions and information on the use of Remicade®: Dr. G. Patterer (Mrs.) – Manager Medical Affairs (Phone: +49-89/62731-220)
Updated: 29.11.2005
