Pharmacology Update

Ospemifene Tablets (Osphena™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.

A selective estrogen receptor modulator (SERM), also known as an estrogen agonist/antagonist, has been approved by the FDA for the treatment of dyspareunia (painful intercourse) in postmenopausal women. Ospemifene is manufactured by Penn Pharmaceuticals Services Ltd. and marketed by Shionogi Inc. as Osphena.

Indications

Ospemifene is indicated for the treatment of moderate-to-severe dyspareunia.1

Dosage

The recommended dose is one tablet (60 mg) taken orally once daily with food.1 Ospemifene is available as 60 mg tablets.

Potential Advantages

Ospemifene may carry a lower risk of stroke and deep vein thrombosis than estrogen therapy.2

Potential Disadvantages

Ospemifene carries a box warning for increased risk of endometrial cancer similar to unopposed estrogen but may be less than that of tamoxifen.1,3

Comments

Vulvovaginal atropy due to menopause is a result of loss of estrogen. Vaginal scraping in postmenopausal women shows a predominance of parabasal cells, decline in superficial squamous cells, and increase in vaginal pH.4 Ospemifene an estrogen agonist/antagonist has an estrogen-like effect on the vaginal epithelium.3,4 It was evaluated in patients with moderate-to-severe symptoms in three randomized, placebo-controlled trials.1,5,6 Two were 12-weeks’ duration and one was a 52-week, long-term safety trial. The study population was generally healthy women, age 41-81 years, with baseline superficial cells on the vaginal smear ≤ 5%, vaginal pH > 5, and who had identified at least one of the following moderate-to-severe symptoms to be the most bothersome: vaginal dryness, pain during intercourse, or vaginal irritation/itching. In trial 1, subjects were randomized to ospemifene 30 mg, 60 mg, or placebo, and in trial 2, ospemifene 60 mg or placebo. Coprimary endpoints were change from baseline to week 12 of the most bothersome symptom (MBS), percent of vaginal superficial and parabasal cells on a vagina smear, and vaginal pH. MBS was self-reported on a 4-point scale (0, none; 1, mild; 2, moderate; 3, severe). Subjects were provided with a non-hormonal lubricant for use as needed. All analyses were conducted on an intent-to-treat basis with last-observation-carried forward. In trial 1 (n = 826), the decrease in symptom score for subjects reporting MBS of vaginal dryness were statistically significant for both strengths of ospemifene compared to placebo. For MBS of dyspareunia, only the 60 mg dose was statistically significant. Significant increase in the percent of superficial cell, decrease in parabasal cells, and decrease in vaginal pH occurred with both strengths. In trial 2 (n = 919), subjects were randomized to ospemifene 60 mg or placebo. Statistically significant improvement from baseline was shown in moderate-to-severe MBS of dyspareunia compared to placebo, (-1.55 vs -1.29, P < 0.0001).1,6 Thirty-eight percent (38%) of subjects reported no vaginal pain with sexual activity compared to 28% for placebo. Fifty-three percent (53%) of subjects showed a two-to-three level improvement in severity compared to 39%. Similar to trial 1, there were significant decreases in parabasal cells (-38% vs. 0.3%) and vaginal pH (-0.82 vs -0.15) and a significant increase in superficial cells (13% vs 2%) compared to placebo by week 4. Long-term follow-up (52 weeks) data suggest that ospemifene had no significant endometrial changes and was well tolerated.1,7 The most frequently reported adverse events (vs placebo) were hot flashes (7.5% vs 2.6%), vaginal discharge (3.8% vs 0.3%), and muscle spasm (3.2% vs 0.9%). There are currently no published studies comparing ospemifene with topical or systemic estrogens.

Clinical Implications

Dyspareunia is among the most frequently reported problems reported by postmenopausal women with vulvovaginal atrophy.2,4 Current hormonal treatment includes vaginal or systemic estrogen therapy. Non-hormonal therapies include vaginal moisturizers or lubricants.4,8 Ospemifene provides an alternative for women with moderate-to-severe dyspareunia. Ospemifene is expected to be available by June 2013. The cost is currently not available.

References

1. Osphena Prescribing Information. Florham Park, NJ: Shionogi Inc.; February 2013.

2. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm341128.htm. Accessed March 9, 2013.

3. Pinkerton JV, et al. Endometrial safety: A key hurdle for selective estrogen receptor modulators in development. Menopause 2010;17:642-653.

4. Tan O, et al. Management of vulvovaginal atrophy-related sexual dysfunction in postmenopausal women: An up-to-date review. Menopause 2012;19:109-117.

5. Bachmann GA, et al. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: Results from a pivotal phase 3 study. Menopause 2010;17:480-486.

6. Portman DJ, et al. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause 2013; Jan 28. [Epub ahead of print.]

7. Simon JA, et al. Impact of denosumab on the peripheral skeleton of postmenopausal women with osteoporosis: Bone density, mass, and strength of the radius, and wrist fracture. Menopause 2013;20:130-137.

8. North American Menopause Society. Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010;17:242-255.