FDA Adds Brain Bleed Warning to Avastin (bevacizumab) Label

ROCKVILLE, Md., Sept. 26 -- The FDA has alerted physicians to a new label change for the anti-angiogenic colorectal-cancer drug Avastin (bevacizumab) that cites rare cases of a reversible posterior leukoencephalopathy syndrome.

The brain-capillary leak syndrome has been reported or confirmed in less than 0.1% of the estimated 60,000 cancer patients treated with Avastin, said Genentech, which markets Avastin.

The warning about reversible posterior leukoencephalopathy was added to the Adverse Reactions and Dosage and Administration sections of the Avastin label.

The FDA also added information about nasal septum perforation to the Adverse Events, Other Serious Adverse Events section of the label. In a letter to clinicians, Genentech said there have been seven cases of nasal septum perforation reported in post market surveillance.

Reversible posterior leukoencephalopathy syndrome is associated with hypertension, fluid retention, and the cytotoxic effects of the immunosuppressive drugs on the vascular endothelium.

J. Leonard Lichtenfeld, M.D., deputy medical director of the American Cancer Society in Atlanta, said this not the first time that the anti-angiogenic agent has been linked with bleeding problems. He noted, for example, the perforated colon has been reported in Avastin colorectal cancer studies.

"This is exactly the reason that post marketing surveillance is so important for all drugs and especially for chemotherapy drugs," Dr. Lichtenfeld said.

Avastin, he said, "typically is given to patients with advanced disease and aggressive tumors," a patient population that is compromised by disease and thus at higher risk for side-effects.

Reversible posterior leukoencephalopathy usually presents with "headache, seizure, visual disturbance, and altered mental function, and is characterized by reversibility upon control of hypertension or other instigating factors," according to the Genentech letter to clinicians.

Although mild to severe hypertension is usually present with the syndrome, it is not necessary for a diagnosis of reversible posterior leukoencephalopathy. The onset of symptoms has been reported to occur within 16 hours to one year of initiation of Avastin treatment.

Magnetic resonance imaging studies are needed to confirm diagnosis.

Avastin should be stopped in patients who develop symptoms of reversible posterior leukoencephalopathy and, if necessary, hypertension treatment should be initiated.

Symptoms "usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae," according to Genentech.

Finally, the company said it is not known whether Avastin can safely be reinitiated in patients who developed reversible posterior leukoencephalopathy syndrome.

The company said it began reviewing safety data for Avastin after the brain leak syndrome was described in two letters were published in a March issue of the New England Journal of Medicine.