Gap Between Need and Approvals in Nonhormonal Menopause Meds

Kate Johnson

October 18, 2013

DALLAS, Texas — This year, 2 nonhormonal menopausal therapies have been approved by the US Food and Drug Administration (FDA), and several others have caught the attention of off-label prescribers.

The need for such therapies was a dominant theme here at the North American Menopause Society (NAMS) 2013 Annual Meeting.

"This is really a wonderful year for having new products available for women's menopausal symptoms," NAMS executive director Margery Gass, MD, told Medscape Medical News during an interview at the meeting.

Still, surveys conducted by NAMS show that consumer and clinician interest in expanding nonhormonal menopausal options further remains high, said Dr. Gass, who is clinical professor of obstetrics and gynecology at the Cleveland Clinic Lerner College of Medicine, Case Western Reserve University School of Medicine.

"Clinicians don't really like to use medications off-label. We would like to have them approved as being effective and safe for the purpose. And women definitely want some other choices," she said.

In February, the FDA approved ospemifene (Osphena, Shionogi), a selective estrogen-receptor modulator (SERM), for menopausal dyspareunia. In June, it approved low-dose paroxetine mesylate (Brisdelle, Noven Pharmaceutics), a serotonin-reuptake inhibitor (SSRI), for hot flashes.

This has given clinicians and patients, for the first time, FDA-approved nonhormonal options for the treatment of menopausal symptoms.

Approval of a nonhormonal candidate for hot flashes, the antiseizure agent gabapentin GR (Sefelsa, Depomed), was declined by the FDA in June. However, combined results from 3 phase 3 studies suggest that there is a place for this drug in the menopause clinician's toolkit. Risa Kagan, MD, clinical professor of obstetrics and gynecology at the University of California, San Francisco, presented the findings here at the NAMS meeting.

"We were disappointed that gabapentin GR was not approved because the pooled analysis of the 1800 mg dose was significant, and many of the secondary end points, especially sleep and Patient Global Impression of Change score, were very significant," she told Medscape Medical News.

"Gabapentin GR is FDA-approved for postherpetic neuralgia (Gralise, Depomed), so we can give this off-label, but it is very expensive." A generic immediate-release gabapentin can also be used off-label, "which is especially helpful with sleep and nighttime vasomotor symptoms," she noted.

There are other potentially effective drug therapies that are being used off-label, said NAMS past president JoAnn Pinkerton, MD, during a plenary session on hot flashes that was partially sponsored by an unrestricted grant from Noven Pharmaceuticals, the manufacturer of low-dose paroxetine.

Among these agents are the antihypertensive clonidine, SSRIs such as fluoxetine, sertraline, citalopram, and escitalopram, and SERMs such as venlafaxine and desvenlafaxine, said Dr. Pinkerton.

However, FDA approval for these and other nonhormonal medications for menopausal symptoms remains elusive.

FDA Approval Elusive

"In general, the FDA requires that therapies for menopausal hot flashes be tested in large, diverse populations of women with 7 or more hot flashes per day or 50 hot flashes per week, and have at least 2 fewer hot flashes per day than placebo," she told Medscape Medical News.

"Hormone therapy easily meets this reduction, but nonhormonal therapies have to prove that their often-more-modest hot flash reductions, particularly with SSRIs, are still associated with a significant benefit, compared with placebo (placebo effects have ranged from 30% to 60%), and that they are safe and well tolerated."

Escitalopram, venlafaxine, desvenlafaxine, and gabapentin GR have all shown improvement in hot flashes over placebo in large clinical trials. Desvenlafaxine and gabapentin GR have gone before the FDA, but neither has been approved for this indication, she explained.

Despite the proven effectiveness of desvenlafaxine in reducing hot flashes, "with significant reductions of more than 2 hot flashes per day, as requested by FDA, the FDA did not approve it," she said. "I don't know the reasons. There was a concern about cardiovascular safety raised in one trial, but no cardiovascular events were found in the subsequent 12-month trial of healthy postmenopausal women."

Similarly, gabapentin GR was found to be modestly effective at reducing hot flashes and improving sleep, with 76% of women improved at the end of a 24-month study, she said. However, the FDA denial of gabapentin was based on concerns about adverse effects on cognition and other aspects of the central nervous system.

Pooled results from the MsFLASH studies, also presented here at NAMS, showed similar hot flash relief and sleep and sexual function improvement when venlafaxine (Effexor XR, Pfizer) and escitalopram (Lexapro, Forest Laboratories) were compared with 17-beta estradiol.

"However, these studies did not meet the FDA guidance for industry of 7 hot flashes per day or 50 hot flashes per week, and neither agent has gone before the FDA," Dr. Pinkerton explained.

MsFLASH was funded by the National Institutes of Health, not a drug company, countered Andrea LaCroix, PhD, from the Department of Family and Preventive Medicine and director of the Center of Excellence in Women's Health at the University of California, San Diego, and principal investigator of the MsFLASH trials.

"Our trials were all well powered to detect clinically meaningful differences in hot flash frequency and severity," she explained. "We designed these trials to apply to the vast majority of women with vasomotor symptoms. The FDA requirements mean that only the women with the most severe and high-frequency hot flashes are included."

"The issue is that escitalopram and venlafaxine are now generic and very cheap," Dr. LaCroix noted. "Because no drug company will make big bucks getting them approved for the treatment of hot flashes, they will never be submitted for approval. This is purely related to money, not what is best for women. Physicians can prescribe these inexpensive alternatives off-label without FDA approval, and most do. It's all about drug company profits and money."

Is the Bar Too High?

According to Dr. Kagan, who is scientific chair of the NAMS meeting, some feel that the FDA Advisory Board on Reproductive Medicines is not always fully informed when it comes to weighing the risks and benefits of nonhormonal menopause therapies.

"The advisory board was multidisciplinary, but seemed ignorant in the field," she said about her experience presenting the gabapentin GR data to the group.

"Some of us do agree that the FDA guidance for estrogen might not apply as well for the nonhormonals, since they are different and act differently," she explained. "Perhaps some of the secondary end points are more important for these agents. Maybe different guidance and end points need to be entertained for nonhormonals. For many women, it is not the actual number of vasomotor symptoms that matters, but their severity — which is more important for functioning."

With this FDA guidance as the backdrop, the NAMS surveys highlight a conspicuous gap, showing that 94% of clinicians and 89% of consumers see a continuing need for nonhormonal prescription therapy for menopausal symptoms, said Dr. Gass.

Of the 384 NAMS members who responded to the survey (89% of whom were clinicians), 83% said they prescribed off-label nonhormonal therapy, she reported.

The majority of the 1421 women who responded to the consumer survey had tried nonhormonal nonprescription alternatives such as lifestyle changes (72%) and over-the-counter products (53%), 11% had tried off-label nonhormonal prescription therapies, 13% had tried compounded hormone therapy, and 11% had not tried anything.

When asked why they wanted nonhormonal prescription options, 85% said they felt hormones were unsafe, 30% reported having had an adverse event with hormones, and 38% said hormones were contraindicated for them.

Most of the 604 comments provided by consumers described feeling miserable with symptoms.

"This has been a horrible journey for me of many years," wrote one woman. "It can destroy your wellbeing and impact your relationships and day-to-day living in so many negative ways. Please help!" wrote another.

"We absolutely need more nonhormonal options for vasomotor symptoms, and would like more approved," said Dr. Kagan. "Patients and clinicians all want more choices."

Dr. Gass and Dr. LaCroix have disclosed no relevant financial relationships. Dr. Kagan reports financial relationships with Merck, Pfizer, Amgen, Noven, Novo Nordisk, Novogyne, Depomed, Shionogi, and Warner Chilcott. Dr. Pinkerton reports financial relationships with Pfizer, Depomed, Noven, Shionogi, Novo Nordisk, Endoceutics, and Bionova.

North American Menopause Society (NAMS) 2013 Annual Meeting: Abstracts P43 and P45. Presented October 10 and 12, 2013.

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