FDA Panel Nixes 2 Nonhormonal Drugs for Hot Flashes

Fran Lowry

March 04, 2013

The US Food and Drug Administration's (FDA's) expert panel on reproductive health drugs has voted against approval of 2 nonhormonal options for the treatment of moderate to severe vasomotor symptoms resulting from menopause.

Although all panel members of the Advisory Committee for Reproductive Health Drugs agreed that nonhormonal alternatives are truly needed to relieve the hot flashes that make life difficult for many postmenopausal women, they decided to say no to gabapentin 600-mg tablets (Depomed Inc) and paroxetine mesylate 7.5-mg capsules (Noven Therapeutics, LLC).


In the morning session, the panel voted 12 against and 2 for Depomed's request for gabapentin, clearly stating they were unimpressed by the drug's limited efficacy in controlling hot flashes in light of its adverse cognition and other central nervous system effects.

Kathryn M. Curtis, PhD, from the Centers for Disease Control and Prevention, Atlanta, Georgia, called gabapentin's effect "limited and modest" in explaining her no vote.

"We all understand the huge need for a nonhormonal treatment for [vasomotor symptoms], but approving a drug that has a very modest effect is almost misleading to those women who are really looking for something that is very effective," Dr. Curtis said.

Valerie Montgomery Rice, MD, from Morehouse School of Medicine, Atlanta, echoed her sentiments.

"As much as I would love to have nonhormonal alternatives for women, I'm concerned about the sustainability and the limited efficacy of this product. I'm also concerned about the dizziness and disorientation with this drug. We just have to keep trying," she said.

Linda Keyes, a consumer representative on the panel and 1 of the 2 yes voters on the panel, said the demand and desire for such nonhormonal treatment "is high enough that I fell that a very modest reduction is still acceptable, assuming the risks are known and carefully watched, which I believe they can be."

Keyes added that women are very aware of the risks with gabapentin. "It's all over the Internet. While I don't think that's a justification for approval, I do think it might be a reason for increased guidance and regulation. It might be better just putting gabapentin out there."

Paroxetine Mesylate

In the afternoon, the panel disappointed Noven's hopes by voting 10 to 4 against the company's request for paroxetine mesylate, formulated as low-dose mesylate salt of paroxetine (7.5 mg/day), saying the drug's minimal benefit did not outweigh its risks.

A few concerns also were raised about the drug's safety profile, and in particular its association with suicidal thoughts and osteoporosis.

Julia V. Johnson, MD, from the University of Massachusetts Medical School, Worcester, who was chairperson of the day's committee meeting, said she felt those risks were small and did not appear to be different than the risks seen with more standard doses of paroxetine. "Still, we have very little information about this lower dose. We did see some effect on suicidal ideation, and I was somewhat concerned that there may be a greater effect than seen."

A bigger stumbling block for the panel was the relatively small benefit seen with paroxetine mesylate compared with placebo.

"I voted against recommending approval when I looked at the magnitude of the treatment effect relative to the magnitude of the placebo effect where there is no risk involved," said Daniel L. Gillen, PhD, from the University of California, Irvine.

However, some panel members believed they saw some evidence of benefit with the drug.

"I'm not worried about the safety profile, because it's already an FDA-approved drug. If we are worried, the way to address that is to help women access a lower-dose version," said Eleanor Bimla Schwarz, MD, from the University of Pittsburgh School of Medicine in Pennsylvania.

Richard Bockman, MD, PhD, from the Hospital for Special Surgery in New York City, stated it was time to approve this drug because it was already being commonly used off-label to treat hot flashes.

"I think there is a very small beneficial effect from this drug," he said, explaining his yes vote. "It is widely used and there is wide experience with this drug. This very small dose is probably safe. I think it's time to legitimize its use."

Clifford J. Rosen, MD, from Maine Medical Center Research Institute in Scarborough, voted against recommending approval but said he empathized with the yes voters.

"In some ways, having an indication might allow us to have better surveillance over who is getting this drug and how it is being utilized. Right now, we have very strong difficulty figuring this out," he said.

The FDA is expected to make a decision on gabapentin by May 31 and on Noven's paroxetine mesylate by June 28. The agency does not have to follow the advice of its advisory committees, but it usually does.