Conference Coverage

Ospemifene’s effect more comprehensive than its FDA indication




NATIONAL HARBOR, MD. – Ospemifene, a treatment for dyspareunia in postmenopausal women, also improved other symptoms of vaginal vulvar atrophy, according to a secondary analysis of two pivotal phase III trials presented here.

Marketed as Osphena (Shionogi), ospemifene is an oral estrogen agonist/antagonist approved in 2013 by the U.S. Food and Drug Administration for use in postmenopausal women with dyspareunia.

Had the drug been approved prior to FDA guidance added in 2013, however, ospemifene’s indications might have been more inclusive.

“A lot of people will look at this indication and [think], ‘Why would you just improve dyspareunia when you’re actually working with the estrogen receptor?’ ” said Dr. Ginger Constantine, a researcher at EndoRheum in Malvern, Pa., and a presenter at this year’s annual meeting of the North American Menopause Society, whose secondary analysis of the studies indicated the drug also eases vaginal dryness, itching, irritation, and painful urination in postmenopausal women.

“One would think that you would also be improving dryness ... and that is what you do see,” she said. However, when the patient-reported most bothersome symptom experienced at baseline is considered, different endpoints are achieved, resulting in packaging inserts that don’t necessarily reflect the full scope of what the product can successfully be used to treat, according to Dr. Constantine.

The estradiol acetate vaginal ring, Femring (Actavis), which was FDA-approved in 2002, has a more general indication, based on several combined study endpoints of relief from moderate to severe menopausal symptoms, including vulvar and vaginal atrophy.

Current guidance is more specific, calling for improvement in the patient-reported most bothersome symptom at baseline, as rated on a scale of 0-3, with 2 being moderate and 3 being severe. Dr. Constantine said this has led to controversy because women often have more than one symptom. “A patient might score a 3 for vaginal dryness and a 2 for dyspareunia, but she may not be so worried about her vaginal dryness,” Dr. Constantine said. “It’s her dyspareunia that’s more problematic [for her].”

Factoring in only the most bothersome symptom could impair investigators’ ability to detect statistical significance, and the result of predicating a product’s indication on the most bothersome symptom as part of a study’s construct has the potential to confuse both the clinician and the patient. “Most [postmenopausal] women have vaginal dryness, and now we’re asking them to tell us what ‘really’ bothers them, and they have to flip a coin,” Dr. Constantine said in response to an audience member’s question about whether the FDA’s labeling was too restrictive.

For the analysis, Dr. Constantine and her associates reviewed data from a 12-week, double-blind, pivotal phase III study of 826 postmenopausal women randomly assigned to either 30 mg of daily oral ospemifene, 60 mg daily of the study drug, or placebo.

Although 544 women across the study reported more than one symptom at baseline, the study’s endpoint was improvement in the most bothersome symptom. At baseline, a third of all participants reported experiencing vaginal dryness; 43% reported dyspareunia; and nearly a fifth reported vaginal itching and irritation. However, the No. 1 most bothersome symptom was dyspareunia, with nearly half, 45%, of all women reporting it as their chief complaint.

By the study’s end, the severity scores for the 120 women who’d reported dyspareunia as their most bothersome symptom were significantly improved from baseline (P = .023).

When dryness was assessed either with or without the consideration of a most bothersome symptom, then significant improvements were found (P = .001 and P = .021, respectively).

In a second pivotal, double-blind, phase III study reviewed by Dr. Constantine and her coinvestigators, 919 postmenopausal women were randomly assigned to 60 mg of daily oral ospemifene or placebo for 12 weeks, and were stratified according to the most bothersome symptom of either dyspareunia or dryness.

When compared with placebo, an improvement in dryness as the most bothersome symptom was not statistically significant (P = .0803), although an improvement from baseline in moderate to severe dryness was (P < .001).

Because the endpoints in both studies were improvement in the most bothersome symptom, the treatment was given the indication for dyspareunia only. As to why the statistical significance for dryness was diminished, Dr. Constantine said that because the women studied were allowed to use lubricants, which meant “the dryness really did get better,” it could have interfered with the results.

Compared with placebo, dyspareunia was significantly improved both as a moderate to severe symptom at baseline, and as the most bothersome symptom (P = .0003 and P < .0001, respectively).


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