New SERM approved for dyspareunia

On February 26, 2013, FDA approved ospemifene (Osphena, Shionogi Inc.) for the treatment of moderate-to-severe dyspareunia resulting from vulvar and vaginal atrophy associated with menopause. Estrogen levels decline during menopause, resulting in a thinning and drying of vaginal tissues. This atrophy can cause a woman to experience pain during intercourse (dyspareunia).

An estrogen receptor agonist, ospemifene counteracts the effects of declining estrogen hormones on vaginal tissue, thereby reducing pain during intercourse.  Previous treatment options for menopause-related dyspareunia include lubricating vaginal products and local and systemic estrogen therapy. While ospemifene is not a panacea, it is an additional tool.

Efficacy

FDA approved ospemifene on the basis of results from two randomized, double-blind, placebo-controlled, parallel-group 12-week trials. The first trial studied the effects of ospemifene 30 mg, 60 mg, and placebo in women 41 to 81 years of age, who had  less than or equal to 5% superficial cells on baseline vaginal smear, vaginal pH>5.0 (both measureable signs of atrophy), and one or more moderate-to-severe vaginal symptoms (vaginal dryness, itching, irritation, or dyspareunia) noted by participants as most troublesome. At week 12, participants were assessed for improvement in the symptoms and changes from baseline for vaginal pH and percentage of superficial cells.

The second trial was similarly structured. Ages ranged from 49 to 79 years (mean of 59 years). However, participants identified either moderate-to-severe vaginal dryness or dysparunia as their most bothersome symptom and were administered either 60 mg of ospemifene or placebo.

Results from an intention-to-treat analysis of both trials indicate statistically significant increases in the percentage of superficial cells, as well as decreases in vaginal pH, in women treated with ospemiphene compared to placebo (P=<.0001). In both trials, women taking ospemifene experienced improvement in moderate-to-severe dyspareunia (P= .0012 in the first trial, P=<.0001 in the second trial) compared to women in the placebo group.

Safety

The safety of ospemifene was evaluated with a 52-week randomized, double-blind, placebo-controlled, long-term safety study comparing ospemifene 30 mg or 60 mg to placebo in 426 participants with an intact uterus who ranged in age from 49 to 79 years.

Ospemifene was generally well tolerated and no clinically significant adverse endometrial changes were observed. However, women in the treatment groups demonstrated a greater incidence of endometrial thickening. The most common adverse effects demonstrated in trials included hot flashes, excessive sweating, muscle spasms, and vaginal or genital discharge. Hot flashes were reported as the most significant adverse effect for most participants.

Ospemifene carries a boxed warning for increased risk of endometrial cancer and cardiovascular disorders. At the endometrium, ospemifene behaves as an agonist, stimulating the proliferation of tissue. In post-menopausal women, any bleeding should be investigated as a possible sign of endometrial cancer or its precursor, endometrial hyperplasia. Ospemifene has demonstrated increased incidence of hemorrhagic and thromboembolic strokes (0.72 and 1.45 per 1,000 women respectively) compared to placebo (1.04 and 0 per 1,000 women, respectively) in trials. The incidence of DVT is increased with ospemifene 60 mg compared to placebo (1.45 v. 1.04 per 1,000 women). This finding led to the recommendation for discontinuation of ospemiphene 4 to 6 weeks before surgery.

Ospemifene has not been well studied in women with breast cancer and should therefore be avoided in women with breast cancer or a history of breast cancer. It has not been studied in comparison to estrogens or in combination with other hormonal therapies for menopausal symptoms. It should be taken for the shortest duration necessary to alleviate troublesome symptoms associated with menopause.

Dosage

Ospemifene is approved for use as a once-daily oral 60-mg tablet. The manufacturer recommends that it be taken with food to increase its bioavailability. No dose adjustment is necessary for renal impairment. Ospemifene has not been studied in women with severe liver disease and should be avoided in women with Child-Pugh class C hepatic impairment. Ospemifene is primarily metabolized by CYP3A4 and CYP2C9 and to a lesser degree CYP2C19. Coadministration with inhibitors and inducers of these enzymes can alter blood levels of ospemifene. Ospemifene was not shown to significantly alter the pharmacokinetics of a single dose of warfarin. However, no study of the effects of ongoing co-administration of ospemifene and warfarin has been performed. Ospemifene is highly plasma protein-bound (>99%). Although not studied, it is expected that ospemifene can increase the free concentration of other highly protein-bound drugs.

Kathryn Wheeler, PharmD, is assistant clinical professor of pharmacy practice, University of Connecticut School of Pharmacy, Storrs, Conn.