Two New Warnings! Tuberculosis and Heart Failure with Infliximab (REMICADE)

Two new warnings about increased risk of tuberculosis and heart failure were issued for the arthritis drug infliximab (REMICADE) on October 23, 2001. Infliximab is approved by the Food and Drug Administration (FDA) for use in combination with methotrexate (RHEUMATREX), also an arthritis drug, for treating moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to methotrexate alone. The drug is also approved to manage the symptoms of moderately to severely active Crohn’s disease, an inflammatory bowel disorder, in patients who have had an inadequate response to conventional therapy.

Infliximab was approved by the FDA in August 1998 and is produced by Centocor, Inc. of Malvern, Pennsylvania. It is a monoclonal antibody that binds specifically to a naturally occurring protein known as human tumor necrosis factor alpha, or simply TNF. TNF is believed to play a major role in the chronic inflammation that is seen in rheumatoid arthritis and Crohn’s disease.

The editors of The Medical Letter on Drugs and Therapeutics, a reliable source of objective drug information, made a prophetic observation about infliximab and infection in their

November 20, 1998 issue: “Whether...infliximab could increase the incidence of other autoimmune diseases, serious infections or malignancy remains to be determined.”

A boxed warning is now required on the FDA-approved professional product labeling or “package insert” for infliximab. This type of warning is the strongest that the FDA can require and was brought about by the occurrence of 84 cases of tuberculosis being reported worldwide. Of the 84 patients involved, 14 were reported to have died. The majority of cases of tuberculosis were diagnosed within seven months of beginning treatment with infliximab and most reported the use of other drugs known to suppress the immune system.

The type of tuberculosis most frequently seen in these patients was infection outside the lung known as disseminated or extrapulmonary tuberculosis. The new warning also cautions about infections that usually do not occur in people with normally functioning immune systems. These infections are classified as “opportunistic.”

Infliximab’s boxed warning now contains the following information:

Additionally, the following warning has been added to the drug’s professional product labeling in bold, capital letters:

CASES OF HISTOPLASMOSIS, LISTERIOSIS, PNEUMO-CYSTOSIS AND TUBERCULOSIS, HAVE BEEN OBSERVED IN PATIENTS RECEIVING REMICADE. FOR PATIENTS WHO HAVE RESIDED IN REGIONS WHERE HISTOPLASMOSIS IS ENDEMIC, THE BENEFITS AND RISKS OF REMICADE TREATMENT SHOULD BE CAREFULLY CONSIDERED BEFORE INITIATION OF REMICADE THERAPY.

Health care professionals were notified by the manufacturer about the preliminary results of an ongoing clinical trial in 150 patients with moderate to severe congestive heart failure that had been treated with infliximab or a placebo. A higher incidence of death and hospitalization for worsening heart failure were seen in patients treated with infliximab, particularly at higher doses.

What You Can Do

You should have a tuberculosis skin test before being treated with infliximab.

If you are now using infliximab you should be evaluated for inactive tuberculosis with a skin test.

If the skin test is positive, treatment of latent tuberculosis infection should be initiated prior to therapy with Remicade.

You should not start treatment with infliximab if you have congestive heart failure.

You should discontinue treatment with infliximab if you have congestive heart failure and your symptoms are worsening.

Adverse drug reactions, including infection if you are using infliximab, should be reported to the FDA MedWatch Program.