Another Warning Label Change: Rituxan Label Changed Again After RA Patient Contracts Brain Infection

Patient Expert

On September 11, the FDA, Genentech and Biogen Idec (the manufacturers of Rituxan) announced that the labeling for the drug is being revised.   This comes after the first report that a patient taking Rituxan to treat rheumatoid arthritis had died of the brain infection progressive multifocal leukoencephalopathy (PML).   Rituxan is approved to treat RA and non-Hodgkins Lymphoma.  Several cases of PML have previously been reported in patients taking Rituxan for unapproved, or off-label, uses, such as treating blood cancer and lupus.

Rituxan controls cancer and rheumatoid arthritis by suppressing the immune system.  Rituxan is used in combination with methotrexate to treat adults with RA who have moderate to severe disease and who have not responded to one or more TNF-inhibitors such as Humira or Enbrel.  In February 2006, the warning label of Rituxan was updated to include information about the risks of contracting viral infections, including PML.

The actual number of people who have died of PML after being treated with Rituxan is extremely small in relation to the total number of people being treated with the drug.   However, the FDA and the manufacturer have urged physicians who were considering treating a patient with Rituxan for any condition to inform the patient of the risk of developing PML and to consider PML in any patient presenting with new onset neurologic symptoms.    They recommend that consultation with a neurologist, brain MRI and lumbar puncture as well for patients exhibiting new neurologic symptoms. Finally they stated that Rituxan should be discontinued immediately in patients who develop PML.

Genentech and Biogen Idec said that the female RA patient who died had a complicated case and was being treated for RA, Sjogren's Syndrome and cancer.  She had received Rituxan in a long-term safety extension clinical study.   In addition, she was treated with a TNF-inhibitor before the study and methotrexate and steroids during and after the study.   After the last dose of Rituxan, but 9 months prior to being diagnosed with the JC virus infection, she was underwent chemotherapy treatment for oropharyngeal cancer.   She was diagnosed about 18 months after the last dose of Rituxan with a JC virus infection which later resulted in PML and death.

PML causes progressive inflammation of the brain and central nervous system. Patients show neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, and vision problems. PML is a progressive disease and is usually fatal. There is no treatment or cure for the disease.   It is caused by a virus, called the JC virus. The JC virus is commonly acquired during childhood, but remains dormant in the body, so many adults may be infected with the JC virus but never develop PML. The virus stays dormant until a trigger, such as a severely weakened immune system, allows it to become active.   PML has been reported in populations such as: HIV-positive patients, immunosuppressed cancer patients, organ transplant patients, and patients with autoimmune disease who were not receiving Rituxan.

Earlier this summer, the FDA warned that the PML had been associated with Tysabri, a drug for multiple sclerosis (MS) that Biogen Idec markets in a joint effort with Elan Inc.   The FDA warning was prompted by reports of two European MS patients undergoing Tysabri monotherapy had developed PML.

Tysabri was taken off the U.S. market in 2005 after three patients in clinical trials developed PML.  The drug was reapproved in 2006 subject to restrictions. At that time, it was thought that the patients contracting PML had done so because of exposure to multiple medications and that monotherapy with Tysabri was less risky. However, the new European cases caused concern because both patients had been taking Tysabri without other drugs.

To see the letter to Healthcare professionals from Genentech and biogen idec, see:

As a side note, people are of greatly differing viewpoints about the FDA's performance in approving and monitoring the safety of drugs over the years.  Some people think that the FDA doesn't move fast enough to approve drugs that could benefit so many people.  Others think that the current system for approving drugs makes the agency beholden to the drug manufacturers and causes the agency to approve drugs too quickly, resulting in safety fiascos such as Vioxx.  Others blame the drug manufacturers for selective reporting of clinical safety research in order to get their drugs approved and to recoup the billions spent on research and development.  Others also blame the fact that the government agency had lost many employees over the years to the private sector and had been working with few staff, low morale and even lower budgets.  As a federal employee in a sister agency to the FDA, I completely understand the tough positions and staffing and funding situations that the leadership and staff are often faced with.

So whatever your belief, you might be interested to know that the FDA has spent the last six months hiring about 1,300 new professional employees.   An announcement and update on the hiring spree was made on September 11.   Apparently about 1,000 of the new hires have already started, with another 158 due to report later this month. Among those that have already started working for the agency, more than 850 are professionals, including chemists, biologists, pharmacologists, statisticians, medical officers, microbiologists and field inspectors. Many will work in the Center for Drug Evaluation and Research, which is responsible for assessing new drugs and devices and monitoring the safety of drugs on the market. Approximately 40 percent of the total number of positions are being funded with industry user fees, these are fees the drug and device manufacturers pay to the agency in order to go through the process of getting U.S. market approval.   While the issue of user fees is controversial, and may jade one's opinion on the mass hiring, I'm hopeful that this much needed infusion of staff will help to hold the drug manufacturers accountable for safety, quality and honest marketing and will result in safer drugs and devices for all of us.