WASHINGTON, DC — Ospemifene (Osphena, Shionogi) appears to improve multiple menopause-related vulvar and vaginal symptoms, even though its indication is only for moderate to severe dyspareunia, according to an analysis of data from two pivotal phase 3 trials.
A secondary analysis of the data from trials examining the effect of the oral tissue-selective estrogen agonist/antagonist on subjective end points was presented by Ginger Constantine, MD, from EndoRheum Consultants in Malvern, Pennsylvania, here at the North American Menopause Society 2014 Annual Meeting.
Ospemifene, which was approved by the US Food and Drug Administration (FDA) in 2013, is indicated "for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause." However, in the pivotal phase 3 trials, the drug was shown to significantly reduce moderate to severe vaginal dryness, and there were nonsignificant trends in the relief of other symptoms.
The reason dryness isn't in the label has to do with the FDA 2003 guidance calling for trials to elicit the "most bothersome symptom" of vulvar and vaginal atrophy — dyspareunia, dryness, itching and irritation, bleeding, or dysuria — in addition to objective outcomes, Dr Constantine explained.
The most bothersome symptom is chosen by woman at baseline as the symptom causing her the most bother and judged by her to be moderate or severe.
The mean change from baseline to the last on-treatment visit is used as the outcome for symptomatic improvement, and is measured with a 3-point scoring system, where 2 is moderate and 3 is severe. This leaves the possibility that a patient can score a 3 for vaginal dryness and a 2 for dyspareunia, but deem the dyspareunia to be her most bothersome symptom.
"When we do the calculation for improvement, we're actually getting a delta from 2 to 0 rather than 3 to 0, diminishing the ability to detect statistical significance," Dr Constantine explained.
In the past, pharmaceutical companies could use composite end point scores for all most bothersome symptoms. For example, Femring, a low-dose estradiol-acetate releasing ring, is indicated for the "treatment of moderate to severe symptoms due to menopause" and for the "treatment of moderate to severe vulvar and vaginal atrophy due to menopause."
Recently, the FDA has considered each individual symptom for approval. "Earlier products didn't have to look at symptom relief to the same extent that is being required of sponsors now," Dr Constantine said.
It might not be plausible that "you would just improve dyspareunia if you're actually working on the estrogen receptor," she explained. "Intuitively, one would think it would also be improving dryness, which is what you do see. But when you use the construct of most bothersome symptom, you come out with a different end point."
Lubna Pal, MD, associate professor of reproductive endocrinology and director of the menopause program at the Yale University School of Medicine in New Haven, Connecticut, said she sees no problem with the current FDA label, but suggests caution when using ospemifene, which is marketed as an alternative to estrogens.
"It is an oral agent that is effective against the focal vaginal symptom of dyspareunia. With vaginal estrogen, depending on dose and frequency of use, as well as the severity of vaginal atrophy, you have very little systemic absorption of hormone while achieving targeted benefit. Ospemifene, however, is taken by mouth, gets absorbed into the bloodstream, and is carried to vaginal tissue, but also to the rest of the body."
One of the two randomized double-blind placebo controlled trials, involving 826 women, evaluated objective measures (increase in vaginal superficial cells, decrease in parabasal cells, decrease in vaginal pH) and the subjective most bothersome symptom (Menopause. 2010;17:480-486). Most of the women (80%) reported more than one moderate to severe symptom at baseline. Vaginal dryness was the most common, but the women named dyspareunia as their most bothersome symptom more often.
In that study, at week 12, ospemifene 60 mg led to significant reductions in severity scores for dyspareunia (P = .023) and for the most bothersome symptom of vaginal dryness (P = .021).
In the second pivotal study, 919 women were randomized to ospemifene 60 mg or placebo. For women who reported dryness as their most bothersome symptom, the improvement was not significant (P = .08), although the overall reduction in dryness severity was significant (P < .001). However, dyspareunia was significantly better with ospemifene than with placebo for the most bothersome symptom analysis (P < .0001) and for overall symptom severity (P = .0003).
The reason for the lack of significance for dryness might have to do with the fact that women were allowed to use a lubricant, resulting in a high placebo response for dryness, a researcher from that study said in a separate presentation.
Other symptoms that women reported as moderate to severe at baseline — including vulvar/vaginal itching or irritation, difficult/painful urination, and vaginal bleeding with sexual activity — were also better at 12 weeks, but none reached statistical significance.
"Clinical trials have varied with regard to the way subjective symptoms are measured, and these study variations have led to different indications in the product labeling. Ospemifene provided relief of multiple symptoms commonly associated with vulvar and vaginal atrophy," Dr Constantine concluded.
Placed in Perspective
"Labeling for [ospemifene], as for other FDA-approved products, is based on the clinical trials performed and submitted by the applicant," according to statement from the FDA. "If an applicant seeks approval for additional symptoms or outcomes for a different indication, they may submit additional clinical trial(s) or data to their application as amendments for evaluation."
In addition, the "FDA does not regulate the practice of medicine, and healthcare providers may choose, based on their medical judgment, to prescribe a given product for a use that is different from the labeled indication."
Ospemifene "is the new kid on the block," said Dr Pal. "I think caution is advised until we get real-life use data."
"Whether you call it a hormone or not is a nuance, because this agent acts through the estrogen receptors, and therefore acts like a hormone, and has thrombotic risk that is deemed similar to that of low-dose estrogens," she told Medscape Medical News. "It's potential for risk, while reassuring, cannot be dismissed."
"It is a tremendous achievement to have yet another tool available to address women's needs. Some women don't want to put anything in the vagina. They'd rather take a pill to address their discomfort. It's a great alternative strategy for some, and it works better than placebo," she said.
However, "there's nothing to tell you it works better than estrogen. It's potential for benefit against the focal vaginal symptom of dyspareunia is real, but must be placed in perspective for each symptomatic menopausal woman seeking relief from vaginal atrophy-related bother," Dr Pal explained.
Dr Constantine is a consultant for multiple companies, including Shionogi. Dr Pal is a consultant for Merck.
North American Menopause Society (NAMS) 2014 Annual Meeting: Abstract S-17. Presented October 17, 2014.
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Cite this: Despite Label, Ospemifene Eases Multiple Menopause Symptoms - Medscape - Nov 04, 2014.