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FDA Safety Changes: Humira

Authors: News Author: Yael Waknine CME Author: Yael WaknineFaculty and Disclosures


Jan. 19, 2006 — The U.S. Food and Drug Administration (FDA) approved in October 2005 safety labeling revisions for adalimumab to warn of the risks for serious infections, neurologic events, and malignancies associated with its use.

Adalimumab (Humira) Linked to Risk for Infections, Malignancies, and Neurologic Events

On October 3, the FDA approved safety labeling revisions for adalimumab injection (Humira , made by Abbott Laboratories) to warn of the risk for serious infections, neurologic events, and malignancies associated with its use.

Serious infections, sepsis, tuberculosis, and rare cases of opportunistic infections have been reported with use of tumor necrosis factor (TNF)–blocking agents, such as adalimumab. Some cases of opportunistic infections and tuberculosis have resulted in fatality.

In placebo-controlled clinical trials of rheumatoid arthritis, the rate of serious infections was 0.04/patient-year in adalimumab-treated patients vs 0.02/patient-year in those receiving placebo. Serious infections observed included pneumonia, septic arthritis, prosthetic and postsurgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis.

In completed and ongoing global clinical studies (n = 13,000), the overall rate of tuberculosis is approximately 0.26/100 patient-years. In the United States and Canada (n = 4,500), the rate is about 0.07/100 patient-years. The studies included cases of miliary, lymphatic, peritoneal, and pulmonary tuberculosis. According to the FDA, most cases occurred during the first 8 months of therapy and may represent recrudescence of latent disease.

Opportunistic infections have been reported in clinical trails at an overall rate of approximately 0.075 per 100 patient-years. Postmarketing reports have included cases of bacterial, viral, fungal, and protozoal infection. Infections were reported in all organ systems and in patients receiving adalimumab alone or in combination with other agents.

The FDA notes that many of the serious infections have occurred in patients receiving concomitant immunosuppressive therapy that may, in conjunction with rheumatoid arthritis, predispose them to infections.

Adalimumab therapy should not be initiated in patients with active chronic or localized infections. Those who develop a new infection during treatment should be closely observed; in the event of a serious infection, adalimumab should be discontinued.

Adalimumab should be used with caution following careful consideration risks and benefits in patients with a history of recurring infection, underlying conditions that may increase their risk for infection, or of residing in regions endemic for tuberculosis or histoplasmosis.

The FDA also warned that use of TNF-blockers (including adalimumab) has also been linked to rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease. Adalimumab should be used with caution in patients with preexisting or recent-onset central nervous system–demyelinating disorders.

In clinical trials, adalimumab and other TNF-blockers (including adalimumab) have also been associated with a higher frequency of malignancies relative to placebo.

In controlled rheumatoid arthritis trials, the rate (per 100 patient-years) of malignancies other than lymphoma and nonmelanoma skin cancer was 0.7 (95% confidence interval [CI], 0.4 - 1.3) in patients receiving adalimumab for a median duration of 5.6 months (n = 1,922) compared with 0.4 (95% CI, 0.1 -1.2) in those given placebo for a median of 5.2 months (n = 947).

The FDA notes that conclusions based on these data remain unclear due to the size of the control group and the limited duration of the studies. Moreover, combined data from controlled and open-label adalimumab studies showed that malignancies of the breast, colon, prostate, lung, and uterus were most commonly observed and occurred at similar rates in the treatment and control groups compared with the general population.

In the controlled portion of rheumatoid arthritis trials, adalimumab was linked to an increased rate of nonmelanoma skin cancer per 100 patient-years (0.9; 95% CI, 0.56 - 1.55), relative to placebo (0.3; 95% CI, 0.07 - 1.07). According to the FDA, the potential role of TNF-blockers in the development of malignancies remains unknown.

TNF-blockers have also been linked to an increased rate of lymphoma in clinical trials. In the controlled rheumatoid arthritis trials, lymphomas were observed in 2 of 1,922 adalimumab-treated patients compared with 1 of 947 patients receiving placebo. In addition, combined data from controlled and open-label studies (median duration, 3 years; 8,500 patient-years) indicated that the rate of lymphoma was 0.15/100 patient-years, a rate 4-fold of that expected in the general population.

The FDA notes that malignancy rates derived from adalimumab clinical trials cannot be compared to that of clinical trials for other TNF-blockers and may not be indicative of rates in a broader patient population. However, patients with rheumatoid arthritis and especially those with active rheumatoid arthritis are at higher risk for developing lymphoma.

Adalimumab has also been studied in 2 placebo-controlled studies and in an open-label extension study of patients with psoriatic arthritis (n = 395). The safety profile for patients with psoriatic arthritis receiving 40 mg of adalimumab every other week was similar to that observed in patients with rheumatoid arthritis.

Adalimumab is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. It is also indicated for reducing signs and symptoms of active arthritis in patients with psoriatic arthritis. For both indications, it may be used alone or in combination with other disease-modifying antirheumatic drugs.