October 8, 2012 (Orlando, Florida) —Extended-release (ER) gabapentin (Serada, Depomed), an investigational nonhormonal drug, improves sleep and reduces hot flashes in menopausal women, according to a phase 3 clinical trial known as BREEZE 3.
The results were presented here at the North American Menopause Society (NAMS) 23rd Annual Meeting.
"Right now, if women don't want to take hormones, and if over-the-counter products, acupuncture, and lifestyle changes do not work, we don't have any FDA [US Food and Drug Administration] approved therapies," said lead researcher JoAnn Pinkerton, MD, who is professor of obstetrics and gynecology at the University of Virginia in Charlottesville and past president of NAMS.
A New Drug Application was submitted for gabapentin ER in July. If approved, the drug will be the first nonhormonal, nonantidepressant treatment for the bothersome symptoms of menopause, Dr. Pinkerton explained.
BREEZE 3 looked at the effect of gabapentin ER on hot flashes and on sleep. Data were presented in 2 different abstracts by 2 different investigators.
Gabapentin is used to control epileptic seizures and restless leg syndrome, and recently was approved by the FDA for the treatment of postherpetic neuralgia.
The ER formulation was developed to be taken twice a day instead of 3 times a day, which significantly decreases the adverse-effect profile, Dr. Pinkerton said.
"With the short-acting version, 20% of patients were somnolent or dizzy. In this trial, with the extended-release formulation, the rate of somnolence or dizziness started at 11% and went down to 3% very quickly. It was very well tolerated and very few people discontinued treatment because of those symptoms," she said. At the end of 6 months, people felt significantly better, she added.
Gabapentin Helps Hot Flashes
In BREEZE 3, 600 postmenopausal women (mean age, 54.0 years; mean time since last menstrual period, 114 months; mean body mass index, 29.4 kg/m²) were randomized to receive gabapentin 1800 mg daily (600 mg in the morning and 1200 mg in the evening) or placebo. The prospective double-blind randomized study was conducted at multiple centers and lasted 24 weeks. Of the 600 women, 41% had surgically-induced menopause.
The frequency and severity of hot flashes were measured at weeks 4 and 12 as the primary end point and at week 24 as the secondary end point.
At baseline, the mean number of hot flashes was 11.8 per day in the gabapentin group and 12.0 per day in the placebo group. A total of 397 patients completed 24 weeks of treatment — 206 (68.9%) in the gabapentin group and 191 (65.0%) in the placebo group.
The trial showed that gabapentin significantly reduced the average frequency of hot flashes at 4 weeks by 1.69 (95% confidence interval [CI], 2.29 to 1.08), compared with placebo (P < .0001), and by 1.14 (95% CI, 1.8 to 0.8) at 12 weeks (P = .0007).
Gabapentin also significantly reduced the average severity of hot flashes, compared with placebo, by 0.21 at 4 weeks (95% CI, 0.31 to 0.1; P < .0001) and by 0.19 at 12 weeks (95% CI, 0.33 to 0.04; P = .012).
These reductions were maintained out to 24 weeks.
Patients in the gabapentin group reported that they were "much" or "very much" improved, compared with placebo, on the Patient Global Impression of Change scale at 12 weeks (68% vs 54%; P = .0036) and at 24 weeks (74% vs 54%; P < .0001).
The drug was well tolerated, with only 5% more patients in the gabapentin group than in the placebo group withdrawing because of adverse events (16.7% vs 11.5%), the researchers report. The most common adverse events in the gabapentin and placebo groups were dizziness (13% vs 3%), headache (9% vs 8%), somnolence (6% vs 3%), and upper respiratory tract infections (6% vs 4%).
Patients in the gabapentin group gained slightly more weight over 24 weeks than those in the placebo group (0.8 kg), but this was not significant.
Women "need to be able to individualize their healthcare, talk over their choices with providers, and select the one that's right for them.... This will be another choice they can make."
Gabapentin Improves Insomnia
In the sleep part of BREEZE 3, gabapentin was found to have a positive impact on sleep disturbance. Researchers assessed the impact of gabapentin using 2 measures of sleep: the Insomnia Severity Index (ISI) score and the daily sleep interference (S/I) score.
At baseline, the mean ISI scores were 17.54 in the gabapentin group and 17.33 in the placebo group, indicating moderate insomnia, and the mean S/I scores were 7.3 and 7.4, respectively, indicating a moderate to severe sleep disturbance.
After 12 weeks, there was a clinically meaningful reduction in ISI score in the gabapentin group, compared with the placebo group (8.7 vs 6.3; P = .0044), and in S/I score (3.6 vs 2.8; P = .0056). Reductions out to week 24 were maintained in the ISI score (8.6 vs 6.2; P = .0068) and in the S/I score (3.9 vs 3.0; P = .0084).
"I was happy that sleep was looked at in an objective way. If you ask many women, their hot flushes at night really bother them. If they can't sleep because of hot flushes, they basically cannot function during the day, so we need to look at sleep separately," said Risa Kagan, MD, from East Bay Physicians Medical Group, Alta Bates Summit Medical Center, in Berkeley, and clinical professor in the Department of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Francisco, who led the sleep part of BREEZE 3.
Dr. Kagan added that, although it is fine to look at all of the data objectively, in the end, the aim is to help women transition through the menopause. "This was not just a placebo effect, this was actually a statistically significant improvement in sleep over placebo," she explained.
Nonhormonal Options Welcome
Vanessa M. Barnabei, MD, PhD, the Patrick and Margaret McMahon Endowed Professor of Gynecology and Obstetrics and director of general obstetrics and gynecology at the Medical College of Wisconsin in Milwaukee, and chair of the Department of Gynecology and Obstetrics at the University at Buffalo School of Medicine and Biomedical Sciences in New York, agrees that nonhormonal alternatives to treat hot flashes and sleep disturbances are welcome.
"Patients and providers are always looking for nonhormonal options to treat these symptoms. Gabapentin has been an alternative, but side effects have limited its use. Extended-release gabapentin appears to offer a viable option, particularly for improving the severity of hot flashes and sleep quality," Dr. Barnabei told Medscape Medical News.
"Discussion of potential side effects prior to use is very important, but this drug appears to be a safe alternative to hormones," she said.
BREEZE 3 was sponsored by Depomed. Dr. Pinkerton reports financial relationships with Depomed, Merck, Novogyne, Pfizer, Shionogi, Bionova, Bionovo, and Endoceutics. Dr. Kagan reports financial relationships with Bionovo, BioSante Pharmaceuticals, Merck, Noven, Novo Nordisk, Novogyne, Pfizer, and Shionogi. Dr. Barnabei reports no relevant financial relationships.
North American Menopause Society (NAMS) 23rd Annual Meeting. Abstract S-8, presented October 5; Abstract S-20, presented October 6, 2012.
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