|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Pregnancy cat.||X (US)|
|Legal status||℞-only (US)|
|Mol. mass||378.89 g/mol|
Ospemifene (commercial name Osphena produced by Shionogi) is an oral medication indicated for the treatment of dyspareunia - pain during sexual intercourse - encountered by some women, more often in those who are post-menopausal. Ospemifene is a selective estrogen receptor modulator (SERM) acting similarly to an estrogen on the vaginal epithelium, building vaginal wall thickness which in turn reduces the pain associated with dyspareunia. Dyspareunia is most commonly caused by "vulval and vaginal atrophy."
Ospemifene is used to treat dyspareunia. It is available as a 60 mg tablet that is taken by mouth once a day. The fact that ospemifene can be taken orally is an advantage over other products that are used to treat dyspareunia, because these are generally in a topical dosage form and have to be applied locally. The oral dosage form is much easier and more convenient for patients to administer.
Side effects associated with ospemifene include vaginal discharge, hot flashes, and diaphoresis. More serious adverse effects including thromboembolism, allergic reactions, fatigue, and headache, and others could occur. There are other additional adverse effects.
Women with "undiagnosed abnormal genital bleeding; known or suspected estrogen-dependent neoplasia; active or history of deep vein thrombosis; pulmonary embolism; arterial thromboembolic disease; and are or may become pregnant" or "with known or suspected breast cancer or those with extreme hepatic impairment" should not take ospemifene. This is not a full list of contraindications.
The boxed warning of the medication indicates that the drug may thicken the endometrium, which could lead to unusual bleeding and endometrial cancer. Taking a type of drug called a progestin may decrease the occurrence of endometrial hyperplasia. Ospemifene may also increase the risk for cardiovascular events, including "stroke, coronary heart disease, venous thromboembolism," and others. The risk of thrombotic and hemorrhagic strokes is given as 0.72 and 1.45 per 1,000 women, while that of deep vein thrombosis is estimated to be 1.45 per 1,000 women. These risks are lower than those seen with estrogen-alone therapy.
Mechanism of action
It is "an estrogen agonist/antagonist that makes vaginal tissue thicker and less fragile resulting in a reduction in the amount of pain women experience with sexual intercourse." This drug should be used for the shortest amount of time possible due to associated adverse effects.
Hormos Medical Ltd., which is a part of QuatRx Pharmaceuticals, filed a patent on January 19, 2005 for a solid dosage form of ospemifene. In March of 2010, QuatRX Pharmaceuticals licensed ospemifene to Shionogi & Co., Ltd. for them to develop it into a product and put it on the market. A New Drug Application (NDA) was submitted to the FDA on April 26, 2012. Amendments to the NDA were submitted in June, July, August, October, and November 2012, and January and February of 2013. It was ultimately approved by the FDA on February 26, 2013.
Preclinial and clinical trials
Preclinical trials were performed in ovariectomized rats to model menopause. Oral ospemifene was compared with raloxifene (another SERM), its metabolites 4-hydroxy ospemifene and 4'-hydroxy ospemifene, estradiol, and ospemifene administered as an intravaginal suppository. Estradiol was used as a positive control and raloxifene was used because it is in the same drug class as ospemifene. Multiple doses of oral ospemifene were tested. 10 mg/kg/day of Ospemifene was found to cause a greater increase in vaginal weight and vaginal epithelial height than 10 mg/kg/day of raloxifene. Vaginal weight had a 1.46x increase after a two week treatment of 10mg/kg/day of ospemifene. The number of progesterone receptors was increased in the vaginal stroma and epithelium, which indicates that ospemifene has "estrogenic activity."
A binding assay was also performed to measure the affinity of ospemifene for the estrogen receptor (ERα and ERβ). The study showed that ospemifene bound ERα and ERβ with similar affinity. Ospemifene bound the estrogen receptors with a lower affinity than estradiol. Ospemifene was shown to be an antagonist of "ERE-mediated transactivation on MCF-7 cells," which the authors concluded indicates "anti-estrogenic activity in breast cancer cells."
Two 12 week phase 3 clinical trials were performed for ospemifene. To evaluate the efficacy of the drug, 4 signs and symptoms of dyspareunia were measured. These included the "change in percent parabasal cells," "change in percent superficial cells," "change in vaginal pH," and "change in most bothersome symptom (vaginal dryness and vaginal pain associated with sexual activity." Ospemifene was more effective than placebo in all four of these categories. A dose-response was also seen in the trial; ospemifene 60 mg had greater efficacy than ospemifene 30 mg. Safety was also evaluated in these phase 3 trials. There was a 5.2% increase in the incidence of hot flushes, 1.6% increase in urinary tract infections, and 0.5% increase in the incidence of headache with ospemifene over placebo. One of the phase 3 trials was double-blinded and randomized and involved 826 women who were post-menopausal. The women in the study were required to have one or more vulvovaginal atrophy (VVA) symptom that was moderate or severe in nature, no more than 5% of cells that were superficial when given a vaginal smear, and have a vaginal pH of at least 5.0. Another phase 3 trial involved 605 women who were between the ages of 40 and 80, were diagnosed with VVA, and whose worst symptom was dyspareunia.
In the first half of the 2013 fiscal year, Osphena® generated 0.1 B yen in revenue, which is probably roughly equivalent to $974,944 U.S. dollars. When Osphena® was put onto the market, it was predicted to earn $495 million in 2017.
- Rutanen EM, Heikkinen J, Halonen K, Komi J, Lammintausta R, Ylikorkala O (2003). "Effects of ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: a double-blind, randomized trial". Menopause 10 (5): 433–9. doi:10.1097/01.GME.0000063609.62485.27. PMID 14501605.
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- "FDA approves Osphena for postmenopausal women experiencing pain during sex". FDA News Release (U.S. Food and Drug Administration). 2013-02-26.
- "Ospemifene: Indications, Side Effects, Warnings". Drugs.com.
- EP application 2286806, Lehtola V-M, Halonen K, "Solid formulations of ospemifene", published 2011-02-23, assigned to Hormos Medical Ltd.
- "Shionogi Files a New Drug Application for Ospemifene Oral Tablets 60mg for the Treatment of Vulvar and Vaginal Atrophy". Drugs.com.
- Kusiak V (2013-02-13). "NDA Approval" (PDF). U.S. Food and Drug Administration.
- Unkila M, Kari S, Yatkin E, Lammintausta R (November 2013). "Vaginal effects of ospemifene in the ovariectomized rat preclinical model of menopause". J. Steroid Biochem. Mol. Biol. 138: 107–15. doi:10.1016/j.jsbmb.2013.04.004. PMID 23665515.
- Center for Drug Evaluation and Research (2013-02-26). "Clinical Pharmacology and Biopharmaceutics Review Application Number 203505Orig1s000" (PDF). Office of Clinical Pharmacology Review. U.S. Food and Drug Administration.
- Bachmann GA, Komi JO (2010). "Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study". Menopause 17 (3): 480–6. doi:10.1097/gme.0b013e3181c1ac01. PMID 20032798.
- Portman DJ, Bachmann GA, Simon JA (June 2013). "Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy". Menopause 20 (6): 623–30. doi:10.1097/gme.0b013e318279ba64. PMID 23361170.
- http://www.shionogi.co.jp/en/ir/pdf/e_p131101.pdf. First Half of Fiscal 2013 Financial Results. Nov. 1, 2013.
- http://www.thepharmaletter.com/article/fda-approves-shionogi-s-osphena-for-postmenopausal-women-experiencing-pain-during-sex. ThePharmaLetter