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FDA advisory panel recommends against two drugs for vasomotor symptoms
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The FDA Reproductive Health Drugs Advisory Committee voted against two nonhormonal new drug applications: gabapentin and low-dose paroxetine mesylate. Both proposed therapies were indicated for the treatment of moderate-to-severe vasomotor symptoms caused by menopause.
During a morning session, the panel voted 13-1 that gabapentin (Sefelsa, Depomed) failed to provide clinical significance. The panel also voted 12-2 that its efficacy did not outweigh the risks associated with the therapy.
“Prespecified analyses did not meet the requirements. There certainly seems to be a need for a drug like this, but gabapentin is certainly not the one,” Bart L. Clarke, MD, associate professor of medicine at Mayo Clinic College of Medicine in the department of medicine, endocrinology, diabetes, metabolism and nutrition in Minnesota, said after his vote against the drug’s efficacy.
Gabapentin was proposed as a titrated daily dose of 1,800 mg, taken by mouth at 600 mg with a morning meal, and 1,200 mg with an evening meal. Based on clinical trials, gabapentin only demonstrated partially reduced frequency and severity of hot flashes. Common adverse events included dizziness, fatigue, somnolence and nausea. It also was shown to increase the risk for suicidal ideation. Presenters from the FDA reported that 136 patients assigned gabapentin discontinued treatment due to treatment-emergent adverse events vs. 49 patients who were administered placebo. Only 1.8% of patients discontinued due to dizziness, they added.
Low-dose paroxetine mesylate
In the afternoon session, panel members were asked to consider paroxetine mesylate (Noven Therapeutics) for treatment of vasomotor symptoms associated with menopause. In a 7-7 vote, the panel appeared split over whether there is sufficient evidence to establish the drug’s efficacy.
“The overall thoughts were that there was limited clinical meaningfulness and, indeed, the significance of the change was small. However, severity is a difficult tool to measure and placebo-effect is significant. There was also thought that, in the data presented, there appeared to be long-term benefit and that potentially there was a positive use of this medication,” Julia V. Johnson, MD, panel chairwoman and professor and chair of the department of obstetrics and gynecology at the University of Massachusetts Medical School, said at the conclusion of the vote.
The committee also voted 10-4 that there is insufficient evidence to support that the changes in vasomotor symptom frequency are clinically meaningful to women.
“I know that women are looking for something that works fast and continues to work as long as they’re taking the medication, and this was clearly shown,” Valerie Montgomery Rice, MD, panel member and health research dean and executive vice president in the office of the dean at the Morehouse School of Medicine in Atlanta, said after voting in favor of the second question.
Finally, also in a 10-4 vote, the committee recommended against approval of the drug for the proposed indication.
“I voted no based on previous rationale and lack of strong support and indication,” Clifford J. Rosen, MD, panel member and director of clinical and translational research at Maine Medical Center’s Research Institute in Scarborough, Maine, said after his vote. “I do empathize with the yes voters because in some ways the indication could allow us to have better surveillance over the drug and how it’s being utilized, which we have very strong difficulty figuring out right now.”
Moving forward
Overall, the advisory panel decided that the data presented on gabapentin were modest and limited. Areas of concern regarding paroxetine included suicidality and risk for fracture. Although they all agreed that a nonhormonal treatment is needed for patients with vasomotor symptoms, they could not justify recommending either drug for approval.
Margery Gass
“The Advisory Committee on Reproductive Health Drugs voted against gabapentin ER unanimously, but the vote was somewhat mixed regarding paroxetine mesylate. These votes will be conveyed to the FDA members who will make the final decision on these two drugs in May,” Margery Gass, MD, executive director of the North American Menopause Society (NAMS), and consultant to the Cleveland Clinic Center for Specialized Women’s Health, told Endocrine Today. “I represented NAMS at the meeting to convey the results of our two surveys that were conducted expressly for the meeting. Results indicated that both women and clinicians know that there is a strong need for non-hormonal prescription therapies for menopausal symptoms. Other women who spoke about their symptoms during the public hearing seemed to be saying that their menopausal symptoms are so disruptive in their lives that they are willing to undergo some risk to obtain relief. The ACRHD and the FDA have the difficult task of weighing the risk/benefit balance and deciding if it is appropriate.”
Final decisions will be announced by the FDA no later than May 31 for gabapentin and June 28 for paroxetine mesylate. Although the FDA is not required to follow the recommendations of the advisory committee, it usually does. – by Samantha Costa
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Perspective
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Michelle P. Warren, MD
There are so many women suffering from vasomotor symptoms, and we have nothing to give them if they don’t want to take hormones. We’re giving antidepressants off-label, and it’s very hard to convince patients to try them without an indication. Patients want to be convinced this is going to be worth it for them. The FDA advisory committee decision is disappointing. We really need a good non- hormonal treatment.
A lot of these drugs are on the market for other reasons and it’s for short-term therapy. It’s not for preventive care. I’m sort of perplexed as to why the FDA is being so strict about it. I have so many patients in my practice who are suffering. I haven’t used paroxetine, but I have been using desvenlafaxine. If the FDA supports an indication for paroxetine, I’ll start using that. Gabapentin does work in certain situations.
Perspective
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Robert Rebar, MD
Estrogen remains the treatment of choice for the treatment of vasomotor symptoms. Although non-hormonal options are needed for women who cannot or will not take estrogens, current data indicate that drug therapies tested to date provide only modest relief at best. An FDA advisory panel raised similar issues in not recommending approval for gabapentin and paroxetine. Thus, the search for alternatives to estrogen for the treatment of severe vasomotor symptoms continues. Until more is known about the pathophysiology of vasomotor flushes, the search may well prove frustrating.
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