FDA panel divided on ointment for anal fissures.(Clinical Rounds)

GAITHERSBURG, MD. -- A Food and Drug Administration advisory panel reached a mixed verdict on whether to recommend 0.4% nitroglycerin ointment for the treatment of pain associated with chronic anal fissures.

Half of the 12 voting members of the FDA's Cardiovascular and Renal Drugs Advisory Committee voted for unconditional approval of Cellegy's Cellegesic 0.4%, while the other 6 said it should be deemed "approvable pending another study of effectiveness." The panel spent most of the daylong hearing debating the statistical significance of the manufacturer's three phase III clinical trials. Safety was a lesser concern, although headache is a frequent side effect of the treatment.

Currently, there is no approved medical treatment in the United States for chronic anal fissure, a tear in the mucosal lining of the terminal anal canal that causes severe, often debilitating pain and bleeding. The condition affects about 765,000 people in the United States, Dr. Daniel L. Azarnoff, professor of medicine at the University of Kansas, Kansas City, said in his presentation to the panel on behalf of Cellegy.

Traditional anal fissure treatment options include dietary fiber, stool softeners, anti-inflammatory drugs, local anesthetics, and increased water consumption.

In 2004, both the American Gastroenterological Association and the American Society of Colon and Rectal Surgeons recommended that patients be given a trial of nitroglycerin ointment--which relaxes the internal anal sphincter and increases anodermal blood flow--prior to undergoing surgical correction. Currently, this is accomplished in the United States with extemporaneously compounded nitroglycerin ointment, which has been shown to vary in potency by as much as 46% outside the range specified by the U.S. Pharmacopeia. (The study will be published later this year in the journal Diseases of the Colon and Rectum.)

"My colleagues and I successfully use extemporaneously compounded nitroglycerin ointment, [but] there is a need for an approved product," colorectal surgeon Michael Abel of the University of California, San Francisco, told the panel.

A 0.4% nitroglycerin ointment has been approved in the European Union since 2005, and a 0.2% version is licensed in Australia, New Zealand, Singapore, and South Korea, all under Cellegy's brand name Rectogesic. In the United Kingdom, the label has a "black triangle," which encourages physicians to report side effects. In clinical practice, it is very unusual for patients to stop taking Rectogesic due to a headache, said Dr. Jonathan Lund, a colorectal surgeon at the University of Nottingham, England, who uses the product in his practice.