Heart Failure After Treatment With Etanercept (ENBREL) and Infliximab (REMICADE) - Drugs Used For Rheumatoid Arthritis and Crohn's Disease

Staff from the Food and Drug Administration (FDA) and the Duke Clinical Research Institute reviewed 47 cases of heart failure, reported the FDA’s adverse drug reaction reporting system associated with the use of the drugs etanercept (ENBREL) and infliximab (REMICADE), and the results were published in the May 20, 2003 issue of Annals of Internal Medicine.

Etanercept (ENBREL) is approved by the FDA for the treatment of rheumatoid and psoriatic arthritis. Infliximab has approval to treat the gastrointestinal disorder Crohn’s disease and to treat rheumatoid arthritis in combination with methotrexate. Etanercept is marketed by Wyeth Pharmaceuticals of Philadelphia, PA and Amgen located in Thousand Oaks, CA. Infliximab is a product of Centocor, Inc. of Malvern, PA.

Etanercept and infliximab belong to a family of genetically engineered drugs known as tumor necrosis factor (TNF) antagonists, or blockers. A third TNF blocker, adalimumab (HUMIRA), was approved in December 2002 but is too new to be included in this examination of heart failure with TNF blockers. Adalimumab is produced by Abbott Laboratories.

The authors of the Annals of Internal Medicine report examined the FDA MedWatch system adverse reaction database for cases in which the TNF antagonists made heart failure worse or caused heart failure. This review found 47 patients who developed heart failure or a worsening of their existing heart failure while taking a TNF blocker.

Of these 47 patients, nine experienced a worsening of their heart failure and 38 developed heart failure for the first time. In the group of first time heart failure cases, 19 (50%) had no identifiable risk factors for heart failure such as a previous heart attack, coronary heart disease, high blood pressure or diabetes, and ten of these patients were less than 50 years of age.

After the TNF drugs were stopped in the ten patients under 50, treatment for heart failure was started, three had complete remission, six improved, and one died.

Since the FDA’s adverse drug reaction reporting system relies on voluntary reports and under-reporting is common, the cases identified in this review represent only a fraction of actual heart failure cases following treatment with TNF blockers.

The professional product labeling, or package insert, for etanercept carries the following heart failure warning:

Patients with Heart Failure

Two large clinical trials evaluating the use of ENBREL in the treatment of heart failure were terminated early due to lack of efficacy. Although the studies did not demonstrate harm, there was a suggestion of worse heart failure outcomes with ENBREL treatment in one of the two trials. There have been post-marketing reports of worsening of congestive heart failure (CHF), with and without identifiable precipitating factors, in patients taking ENBREL. Physicians should exercise caution when using ENBREL in patients who also have heart failure.

The professional labeling for infliximab states that the drug should not be used in patients with moderate or severe heart failure. The labeling for adalimumab indicates that in clinical trials conducted before the drug was approved heart failure was seen in less than five percent of the patients who received the drug.

Another major safety concern with the TNF blocker family of drugs is the possibility of life threatening infections. The professional labeling for etanercept carries the following bolded warning:

WARNINGS
INFECTIONS:

IN POST-MARKETING REPORTS, SERIOUS INFECTIONS AND SEPSIS, INCLUDING FATALITIES, HAVE BEEN REPORTED WITH THE USE OF ENBREL. MANY OF THE SERIOUS INFECTIONS HAVE OCCURRED IN PATIENTS ON CONCOMITANT IMMUNOSUPPRESSIVE THERAPY THAT, IN ADDITION TO THEIR UNDERLYING DISEASE, COULD PREDISPOSE THEM TO INFECTIONS. RARE CASES OF TUBERCULOSIS (TB) HAVE BEEN OBSERVED IN PATIENTS TREATED WITH TNF ANTAGONISTS, INCLUDING ENBREL. PATIENTS WHO DEVELOP A NEW INFECTION WHILE UNDERGOING TREATMENT WITH ENBREL SHOULD BE MONITORED CLOSELY. ADMINISTRATION OF ENBREL SHOULD BE DISCONTINUED IF A PATIENT DEVELOPS A SERIOUS INFECTION OR SEPSIS. TREATMENT WITH ENBREL SHOULD NOT BE INITIATED IN PATIENTS WITH ACTIVE INFECTIONS INCLUDING CHRONIC OR LOCALIZED INFECTIONS. PHYSICIANS SHOULD EXERCISE CAUTION WHEN CONSIDERING THE USE OF ENBREL IN PATIENTS WITH A HISTORY OF RECURRING INFECTIONS OR WITH UNDERLYING CONDITIONS WHICH MAY PREDISPOSE PATIENTS TO INFECTIONS, SUCH AS ADVANCED OR POORLY CONTROLLED DIABETES.

The professional labeling for infliximab carries a black box warning about the possibility of infection from using the drug. A black box warning is the strongest type of warning that the FDA can require and it is usually reserved for when serious injury or death has been associated with the use of a drug. The text of infliximab’s black box warning follows:

WARNINGS
RISK OF INFECTIONS:

TUBERCULOSIS (FREQUENTLY DISSEMINATED OR EXTRAPULMONARY AT CLINICAL PRESENTATION), INVASIVE FUNGAL INFECTIONS, AND OTHER OPPORTUNISTIC INFECTIONS, HAVE BEEN OBSERVED IN PATIENTS RECEIVING REMICADE. SOME OF THESE INFECTIONS HAVE BEEN FATAL. PATIENTS SHOULD BE EVALUATED FOR LATENT TUBERCULOSIS INFECTION WITH A TUBERCULIN SKIN TEST. TREATMENT OF LATENT TUBERCULOSIS INFECTION SHOULD BE INITIATED PRIOR TO THERAPY WITH REMICADE.

Adalimumab carries the following black box warning about the risk of infection:

WARNINGS
RISK OF INFECTIONS:

Cases of tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) have been observed in patients receiving HUMIRA.

Patients should be evaluated for latent tuberculosis infection with a tuberculin skin test. Treatment of latent tuberculosis infection should be initiated prior to therapy with HUMIRA.

What You Can Do

If you are taking etanercept, infliximab, or adalimumab and experience the symptoms of heart failure, fatigue, difficulty breathing, swelling (especially in the legs and ankles), rapid or “galloping” heartbeats, or any infection, notify the prescribing physician immediately.