Black Box Warning for ENBREL (etanercept)

The Food and Drug Administration (FDA) has just required that the manufacturer of etanercept (ENBREL), a drug for rheumatoid arthritis, add a black box warning to its label (below) concerning rare but possible tuberculosis (TB) infections.

FDA Black Box Warning  

Etanercept, an effective disease-modifying anti-rheumatic drug (DMARD), now joins adalimubab (HUMIRA) and inflixamib (REMICADE) to be the third of the arthritis disease-modifying drugs (see discussion about disease-modifying drugs) to receive a black box warning concerning infections, calling for TB testing and, if positive, TB treatment before starting these drugs. For some people, the potential benefit of etanercept outweighs the risk of infections, including the very small risk of TB infection.

Etanercept blocks a naturally occurring protein called tumor necrosis factor (TNF) blocker, which clearly plays a role in joint inflammation and damage. Etanercept is used in adults to treat:

• Moderate to severe active rheumatoid arthritis. Etanercept can be used alone or with a medicine called methotrexate.
• Psoriatic arthritis. Etanercept can be used with methotrexate in patients who have not responded well to methotrexate alone.
• Ankylosing spondylitis, a form of arthritis affecting the spine
• Moderate to severe psoriasis.

Etanercept is used in children with a type of moderate to severe juvenile rheumatoid arthritis that attacks many joints.

Disease-Modifying Anti- Rheumatic Drugs (DMARDs)

In contrast to anti-inflammatory drugs such as aspirin, ibuprofen, naproxen and others, DMARDs such as etanercept not only relieve symptoms but may also slow or even modify the rheumatic disease process itself.

Until recently, most doctors reserved the use of DMARDs for patients who failed to respond to other therapies. Now, many physicians use DMARDs earlier and more aggressively in the hope of slowing disease progression and damage to joints.

One of the first (although still widely prescribed) DMARDs, methotrexate (TREXALL), is often recommended as the first drug to be used in this category for patients with moderate to severe rheumatoid arthritis. There are four newer DMARDs, all of which are biologically based immune response modifiers: adalimumab, etanercept, infliximab and anakinra (KINERET). In many patients, adalimumab, etanercept and inflixamib can cause a dramatic improvement in symptoms by blocking the action of TNF, which is found in elevated levels in the joint fluid of rheumatoid arthritis patients. Anakinra is thought to work by blocking the receptor for interleukin-1, another naturally occurring protein that has a role in increasing joint inflammation and damage.

As with many drugs with dramatic benefits, all four of these drugs can also pose serious risks by interfering with the body’s immune mechanisms for fighting infectious diseases. Thus, it is required by the FDA that information about increased risks of such diseases as TB and other infections are included in the warnings for three of the four drugs. Patients who think they are getting any infection should notify their doctor immediately.

Although, unlike the other three drugs in this family, anakinra does not currently have a black box warning about infections, there is a bolded warning on this drug. It says:

Warnings:

Kineret has been associated with an increased incidence of serious infections (2%) vs. Placebo (< 1 %). Administration of Kineret should be discontinued if a patient develops a serious infection. Treatment with Kineret should not be initiated in patients with active infections. The safety and efficacy of Kineret in immunosuppressed patients or in patients with chronic infections have not been evaluated.

What you can do

Infections in patients using these drugs have included bacterial blood infections and tuberculosis. Before starting adalimumab, etanercept, infliximab or anakinra, as well as during treatment, patients should be tested for latent TB infection. Treatment of latent TB infection should be initiated prior to therapy. Treating latent TB in patients with a positive tuberculin test reduces the risk of TB reactivation in patients receiving these drugs.

Physicians should monitor patients receiving these drugs for signs and symptoms of active TB, including patients who tested negative for latent TB. Patients should be educated about the symptoms of infection and closely monitored for signs and symptoms of infection during and after treatment with any of these drugs. Patients who develop an infection should be evaluated for appropriate antimicrobial treatment and, in patients who develop a serious infection, the drug should be discontinued.

Patients taking etanercept, infliximab and adalimumab should immediately notify their doctor if they experience the symptoms of heart failure: fatigue, difficulty breathing, swelling (especially in the legs and ankles) or rapid (“galloping”) heartbeats.

Regardless of the drug therapy chosen by a patient and his or her doctor, an exercise program and physical therapy should be designed within the limits of pain. This will help to strengthen muscular action and maintain or improve range of motion in the joints. Inflammation also occurs in other rheumatologic diseases such as ankylosing spondylitis, scleroderma, temporal arteritis and polymalgia rheumatica. Therapy follows the same general anti-inflammatory guidelines that are used to treat rheumatoid arthritis.