Hotline Archive - Etanercept (Enbrel) Label Updated Following Post-marketing Infectious Events

July 1999

In May 1999, Immunex and Wyeth-Ayerst announced changes in product labeling for etanercept, based on serious infectious events observed in etanercept-treated rheumatoid arthritis (RA) patients.

Etanercept, a fusion protein composed of dimeric soluble p75 tumor necrosis factor (TNF) receptor and a human IgG Fc fragment, received FDA approval on November 2, 1998, for the treatment of moderate to severe, active RA patients who have not responded to one or more disease-modifying anti-rheumatic drugs (DMARDs). Etanercept was also approved by the FDA on May 28, 1999, for the treatment of JRA.

As TNF plays a crucial role in the inflammatory response, and because the inflammatory response helps provide protection from infectious organisms, investigators and clinicians remain alert to the consideration that inhibition of TNF (e.g., with etanercept) may place patients at a greater risk of infection. Such concerns may further be amplified in RA, where there may be a six- to nine-fold increase of infection-related deaths. This risk is increased further with increasing disease severity.

Clinical Trials Experience¹. In the package insert, etanercept-treated patients in clinical trials were reported to have a greater frequency of upper respiratory tract infections (16% placebo, 29% etanercept). Yet, etanercept patients did not manifest a greater number of "serious" infectious events (1.3% placebo, 0.9% etanercept) in these short term, placebo-controlled clinical trials. Analysis of all etanercept-exposed patients (from both open-label and placebo-controlled trials) shows that 22 of 745 patients (3%) developed serious infections. Only one infection-related death (one of 745 patients or 0.13%) was observed in these clinical trials.

Post-Marketing Experience. In post-marketing surveillance from November 1998 to May 1999, nearly 25,000 patients received etanercept. During this period there were 30 (0.12%) serious infections identified, including several cases of sepsis. This frequency of serious infection was less than that observed in all clinical trials patients exposed to etanercept (3%). Six of the 30 patients with serious infections died from their infections. Of these six patients, all died early (2–16 weeks) after drug initiation and most had pre-existing infections (four had chronic or recurrent cutaneous ulcers). They possessed one or more risk factors for infection, including a history of severe, long-standing RA (six of six patients), extraarticular manifestations (2/6), concomitant prednisone therapy (3/6), methotrexate use (2/6), congestive heart failure (3/6), diabetes mellitus (2/6) or renal insufficiency (1/6).

The infection-related death rate observed with etanercept use in post-marketing surveillance (0.02%) is less than that noted in clinical trials (0.13%). For comparison, historic controls derived from the literature suggest that the infection-related death rate is 2–7% in RA. These comparisons remain valid when data is normalized for the duration of disease or drug exposure (see Table below). Despite these results, data from a sepsis clinical trial (not performed in RA patients) suggest that etanercept may increase the risk of mortality in patients with established sepsis².

Caution should be exercised when comparing these data sets of different centers and purposes. The characteristics of the post-marketing surveillance group is unknown. The etanercept-treated and RA historical populations presented here may differ in disease characteristics (e.g., disease duration, concomitant therapies), site of referral or treatment, and the duration or type of drug exposure. Lastly, the accuracy of adverse event reporting after drug release may tend to underestimate drug-related serious infection rates or deaths.

On May 10, 1999, the Immunex Corporation sent a letter to physicians detailing this information and modifying their product labeling by adding several prescribing suggestions:

• Patients developing a new infection while on etanercept should be monitored closely
• Etanercept should be discontinued in patients with serious infections or sepsis
• Etanercept should not be initiated in patients with active infections, including chronic or localized infections
• Physicians should exercise caution if considering etanercept in patients with a history of recurrent infections or conditions that may predispose to infection (i.e., advanced or poorly-controlled diabetes mellitus)

In summary, physicians should carefully review potential etanercept candidates for active infections, past infections and the disease-related risk of infection before initiating treatment with a TNF inhibitor. All physicians are encouraged to report all serious infections and infection-related deaths to Wyeth-Ayerst at (800) 934-5556 or Immunex at (800) 466-8639 (also 888-4ENBREL) or by contacting the FDA MedWatch program at (800) 332-1088 or www.fda.gov/medwatch.

*estimated patient years

July 28, 1999
John J. Cush, MD
Robert F. Spiera, MD
Co-editors, ACR Hotline

References

1. Enbrel (etanercept) package insert.
2. Fisher CJ Jr., Agosti JM, Opal SM, et al. Treament of septic shock iwth the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 334:1697, 1996.
3. Van den Borne BEEM, Landewe RBM, Houkes I, et al. No increase risk of malignancies and mortality in cyclosporin A-treated patients with rheumatoid arthritis. Arthritis Rheum 41:1930, 1998.
4. Prior P, Symmons DPM, Scott DL, et al. Cause of death in rheumatoid arthritis. Brit J Rheum 23:92, 1984.
5. Duthie JJR, Brown PE, Trueloe LH, et al. Course and prognosis in rheumatoid arthritis: a further report. Ann Rheum Dis 23:193, 1964.

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