Postop Ileus Drug Gets FDA Panel Vote Despite Concerns

SILVER SPRING, MD. — The majority of a Food and Drug Administration advisory panel agreed that the mu-opioid receptor antagonist alvimopan hastened gastrointestinal recovery in patients undergoing bowel resection and receiving opioids for pain. But when the panel weighed the benefits of the drug against its risks, panel members only narrowly voted in favor of the drug.

The FDA's Gastrointestinal Drugs Advisory Committee voted 13–0, with 2 abstentions, that clinical studies evaluating the effects of the drug on postoperative ileus (POI) were “clinically meaningful,” and agreed that reductions in recovery time of 12 and 24 hours were significant.

However, the panel voted by a narrower margin of 9–6 that the beneficial effects of the drug outweighed its potential risks.

The manufacturer, Adolor Corp., has proposed that alvimopan, an oral medication, be approved for “acceleration of time to upper and lower gastrointestinal recovery following partial large or small bowel resection surgery with primary anastomosis.” If approved, alvimopan would be the first drug approved for this indication, although surgeons use several drugs off-label for this use. The FDA usually follows the recommendations of its advisory panels, which are not binding.

According to Adolor, alvimopan is a “peripherally acting mu-opioid receptor antagonist that reverses opioid-induced changes in the GI tract without affecting opioid-induced analgesia.” The company plans to market the drug under the trade name Entereg if approved. The recommended dose is one 12-mg capsule taken before surgery, then 12 mg twice daily until discharge for a maximum of 15 doses.

Because of safety concerns raised in a 12-month study of alvimopan as a chronic treatment for opioid-induced bowel dysfunction in patients with chronic, noncancer pain, Adolor has proposed that the drug be limited to short-term, in-hospital use in patients receiving open bowel surgery. The company has proposed a risk management plan aimed at preventing off-label use, long-term use, and use outside acute care hospitals.

In the long-term study of 750 patients, 500 patients received alvimopan 0.5 mg twice daily and 250 received placebo. Compared with the placebo group, the alvimopan group had a greater number of serious cardiovascular events (mostly MI), benign and malignant neoplasms, and bone fractures over a period of 1 year.

However, in short-term POI studies, where patients were treated for 7 days or less, the number of adverse cases was small, and there was no imbalance of these events between placebo and treatment groups, according to Adolor.

In another vote, eight panelists said they remained concerned about the potential risk of cardiovascular events with short-term use, while six panelists, including the cardiologists, said they were not concerned with the risks associated with short-term use. (There was one abstention.)

The nine panel members voting in favor of the overall-risk benefit profile of the drug in this population included the cardiologists and surgeons on the panel, but panelists supported long-term monitoring of cardiovascular effects of the drug and agreed that the risk management plan as proposed by the company was not adequate for monitoring its safety potential.

Cardiologist Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic Foundation, said that in his view, there was no hint of any cardiovascular signal in the short-term follow-up and that he was not concerned about the cardiovascular risks for the short-term indication, even though patients would be taking a higher dose than was used in the long-term trials.

The acting chair of the panel, Dr. Alan L. Buchman, professor of medicine and surgery, division of gastroenterology at Northwestern University, Chicago, said that even though the drug had some physiologic and clinical beneficial effects, they were marginal and POI is a benign condition, so “the risk potential does at a minimum slightly outweigh the potential benefit for the patient.”

Panel members cited the economic benefits of reducing hospital stays by 24 and even 12 hours, opening up more hospital beds for other patients.

The company presented pooled data from four phase III North American studies of more than 1,400 patients undergoing bowel resection (714 on alvimopan 12 mg twice daily and 695 on placebo). The mean age of the patients was about 60 years, and they received opioids via intravenous patient-controlled anesthesia. Alvimopan treatment accelerated GI recovery and reduced the time for the discharge order to be written by about 1 day (18–26 hours).

The proportion of those on alvimopan who met the GI recovery end point, defined as time to tolerating first food (upper GI recovery) and time to first bowel movement (lower GI recovery) by the fifth postsurgical day was 12%–18% higher among those on alvimopan over placebo. The GI recovery time, using this definition, was 13–26 hours faster than with placebo. In addition, the hospital discharge order was written for 85%–89% of those on alvimopan before the seventh day after surgery, compared with 68%–76% for placebo. Moreover, 12% of those on placebo had a nasogastric tube placed, compared with 7% of those on alvimopan, a highly significant difference.