Menopausal women seeking relief from hot flashes (vasomotor symptoms) are constantly on the lookout for new products to relieve the troubling symptoms. However, two new nonhormonal products professing relief from hot flashes were given a thumbs-down by a Food and Drug Administration (FDA) advisory committee on March 4. In contrast, the FDA approved another product on February 6 that relieves vaginal dryness in postmenopausal women.
The advisory committee for reproductive health drugs voted 12 to 2 against approving Depomed’s extended-release gabapentin. In addition, the panel voted 10 to 4 against a low-dose formulation of the antidepressant paroxetine developed by Noven Pharmaceuticals. The advisory committee members acknowledged the need for new drugs; however, they noted that both products offered only marginal benefit, reducing the number of hot flashes by only about one a day compared to a placebo.
The FDA is not obligated to follow the advice of its advisory panels. However, the agency almost always heeds their recommendations, particularly when the vote is strongly on the negative side. The majority of women who enter the menopause experience vasomotor symptoms, which manifest as a sudden heat sensation, often accompanied by sweating; the symptoms can disrupt sleep, relationships, and daily activities. Hormone replacement therapy (HRT), consisting of estrogen or estrogen plus progesterone can relieve the symptoms; however, many women are fearful of hormonal therapy due to possible health risks such as breast cancer.
Some of the committee members noted that since versions of both drugs were already approved for other uses, physicians could prescribe them off-label for hot flashes. In fact, some doctors already do so. Paroxetine, which is typically used for psychiatric ailments, is the active ingredient in Noven, an American subsidiary of the Hisamitsu Pharmaceutical Company of Japan. The amount of paroxetine in Noven is lower than the product used for psychiatric disease., was seeking approval of a lower dose of paroxetine than typically used for psychiatric ailments. Paroxetine is the active ingredient in GlaxoSmithKline’s antidepressant Paxil, which was first approved in 1992.
Depomed’s product contains gabapentin, which was first approved in 1993 as a treatment for epilepsy; it was originally marketed under the name Neurontin by Warner-Lambert, which was later acquired by Pfizer. Depomed currently sells an extended-release formulation of gabapentin under the name Gralise as a treatment for postherpetic neuralgia, which is chronic pain caused by shingles. Depomed planned to name its hot-flash version Sefelsa.
The FDA panel found that for both products, women taking placebos in the trials experienced a substantial reduction in hot flashes that the was comparable to that of the two medications. Women in three Depomed trials started with an average of more than 11 episodes of hot flashes a day. After 12 weeks of treatment, the average had dropped by more than seven episodes a day for those getting gabapentin; however, it dropped by more than six episodes a day for the women taking a placebo. The difference was not statistically significant in any of the trials. Noven’s drug did reduce the frequency of vasomotor symptoms in two trials by statistically significant amounts; however, most panel members noted that the extra reduction (0.9 of a hot flash episode a day in one trial and 1.7 episodes in the other) would not be clinically meaningful to women. Another concern expressed by some panel members was that a known side-effect of gabapentin is dizziness and that paroxetine has been reported to cause suicidal thoughts.
In contrast to the turn-down of the two products for hot flashes was the FDA’s approval of Osphena (ospemifene) for vaginal thinning and dryness. In addition to vaginal irritation, the condition can make intercourse painful or impossible. The medical term for the problem is dyspareunia. The FDA notes that Osphena’s safety and effectiveness were established in three clinical studies of 1,889 postmenopausal women with symptoms of vulvar and vaginal atrophy. Women were randomly assigned to receive Osphena or a placebo. After 12 weeks of treatment, results from the first two trials showed a statistically significant improvement of dyspareunia in Osphena-treated women compared with women receiving placebo. Results from the third study support Osphena’s long-term safety in treating dyspareunia.
Osphena is being approved with a boxed warning alerting women and healthcare professionals that the drug, which acts like estrogen on vaginal tissues, has shown it can stimulate the lining of the uterus (endometrium) and cause it to thicken. In fertile women, this thickening of the endometrium occurs monthly before menstruation. Postmenopausal women no longer experience menstruation, and a stimulated endometrium is not normal. Women should see their health care professional if they experience any unusual bleeding as it may be a sign of endometrial cancer or a condition that can lead to it. Osphena should be prescribed for the shortest duration consistent with treatment goals and risks for the individual woman.
Take home message:
I concur with the panel’s recommendation to disapprove the two products for hot flashes. The drugs were found to have no significant benefit and treating vasomotor symptoms with psychoactive drugs, which can have significant side effects, is illogical. Estrogen will relieve both vasomotor symptoms and vaginal dryness. Low-dose estrogen patches are now available that have less risk of side-effects than the oral medications (i.e., Premarin) for which the breast cancer risk was found. If you are troubled by dyspareunia or hot flashes, it might be prudent to discuss estrogen patches with your gynecologist. As with any medication, risk vs. benefit must be weighed.