Ospemifene

Ospemifene (brand names Osphena and Senshio 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)[1] 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 "vulvar and vaginal atrophy."[2]

Ospemifene
Clinical data
Trade namesOsphena; Senshio
Other namesDeaminohydroxytoremifene
License data
Pregnancy
category
  • US: X (Contraindicated)
  • EU: X
Routes of
administration		By mouth
Drug classSelective estrogen receptor modulator
ATC code
Legal status
Legal status
  • US: Rx-only; EU = Rx-only
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
ECHA InfoCard100.190.672
Chemical and physical data
FormulaC24H23ClO2
Molar mass378.90 g·mol−1
3D model (JSmol)

The medication was approved by the FDA in February 2013[3] and by the European Commission for marketing in the EU in January 2015.[4]

Medical uses

Ospemifene is used to treat dyspareunia. In the US it is indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy (VVA), due to menopause. In the EU it is indicated for the treatment of moderate to severe symptomatic VVA in post-menopausal women who are not candidates for local vaginal oestrogen therapy.

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 advertised as an advantage over other products that are topically applied in the vaginal canal. Ospemifene has not demonstrated any effects on libido, arousal, duration of intercourse or quality of orgasm in controlled clinical trials.

Contraindications

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.[2] This is not a full list of contraindications.

Side effects

Side effects associated with ospemifene include vaginal discharge, hot flashes, and diaphoresis.[5] More serious adverse effects are similar to those of estrogens and estrogen receptor modulators. These include, but are not limited to, thromboembolism, allergic reactions, fatigue, and headache, and others could occur.[5] There are other additional adverse effects.

Ospemifene is a selective estrogen receptor modulator. As such, many of the effects produced by estrogens are produced by ospemifene. The boxed warning of the medication indicates ospemifene may thicken the endometrium, which could lead to unusual bleeding and endometrial cancer. For women taking estrogens, concurrently taking a type of drug called a progestin has been shown to decrease the occurrence of endometrial hyperplasia.[2] In theory, progestins may be expected to attenuate ospemifene's effects on endometrial thickening. However clinical trials confirming this have not been conducted. Like estrogens, ospemifene also may increase the risk for cardiovascular events, including "stroke, coronary heart disease, venous thromboembolism," and others.[2] 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. The risks of these adverse events in women taking ospemifene are lower than those in women taking estrogen alone in the form of oral conjugated estrogens. Studies have not documented the relative risk compared with women taking estrogen/progestin therapy.

Pharmacology

Pharmacodynamics

Ospemifene 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."[2] This medication should be used for the shortest amount of time possible due to associated adverse effects.[2]

Tissue-specific estrogenic and antiestrogenic activity of SERMs
MedicationBreastBoneLiverUterusVaginaBrain
LipidsCoagulationSHBGIGF-1Hot flashesGonadotropins
Estradiol++++++++++
"Ideal SERM"–++±±±–++±
Bazedoxifene–++++?–±–?
Clomifene–++?++–?–±
Lasofoxifene–+++??±±–?
Ospemifene–+++++±±–±
Raloxifene–+++++±––±
Tamoxifen–++++++––±
Toremifene–++++++––±
Effect: + = Estrogenic / agonistic. ± = Mixed or neutral. – = Antiestrogenic / antagonistic. Note: SERMs generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic). Sources: See template.

History

Approval process

Hormos Medical Ltd., which is a part of QuatRx Pharmaceuticals, filed a patent on January 19, 2005 for a solid dosage form of ospemifene.[6] In March 2010, QuatRX Pharmaceuticals licensed ospemifene to Shionogi & Co., Ltd. for clinical development and marketing.[7] A New Drug Application (NDA) was submitted to the FDA on April 26, 2012.[8] Amendments to the NDA were submitted in June, July, August, October, and November 2012, and January and February 2013.[8] It was ultimately approved by the FDA on February 26, 2013.[7] Ospemifene (under the brand name Senshio) was subsequently approved by the European Commission for marketing in the EU in January 2015.

Preclinial and clinical trials

Preclinical trials were performed in ovariectomized rats to model menopause.[9] 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.[9] Estradiol was used as a positive control and raloxifene was used because it is in the same drug class as ospemifene.[9] Multiple doses of oral ospemifene were tested.[9] 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.[9] Vaginal weight had a 1.46x increase after a two-week treatment of 10 mg/kg/day of ospemifene.[9] The number of progesterone receptors was increased in the vaginal stroma and epithelium, which indicates that ospemifene has "estrogenic activity."[9]

A binding assay was also performed to measure the affinity of ospemifene for the estrogen receptor (ERα and ERβ).[9] The study showed that ospemifene bound ERα and ERβ with similar affinity.[9] Ospemifene bound the estrogen receptors with a lower affinity than estradiol.[9] 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."[9]

Two 12-week phase 3 clinical trials were performed for ospemifene.[10] One evaluated the effects of Ospemifene on vaginal tissue thickness, composition and vaginal pH. The other evaluated the effects of Ospemifene on vaginal tissue and on symptoms of dyspareunia. Between the two trials, 4 signs and symptoms were measured. These included three tissue-related signs, two of which represented histological changes in the vaginal tissue (change in percent parabasal cells and change in percent superficial cells) and the third was "change in vaginal pH". Dyspareunia was evaluated in one of the trials. It was defined as "change in most bothersome symptom" of discomfort during sexual activity and further limited to symptoms of either vaginal dryness or vaginal pain."[10] Ospemifene produced more changes in vaginal tissue and greater reduction in dyspareunia symptoms than placebo.[10] A dose-response also was observed in the trial; ospemifene 60 mg had greater efficacy than ospemifene 30 mg.[10] 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.[10] One of the phase 3 trials was a randomized, double-blind placebo-controlled trial in 826 post-menopausal women.[11] The trial patients were required to have one or more symptom of vulvovaginal atrophy (VVA) that was moderate or severe in nature with fewer than 5% of cells that were superficial when examined by a vaginal smear and a vaginal pH of at least 5.0.[11] This trial did not quantify relief of dyspareunia as a study outcome measure. The other phase 3 trial was conducted in 605 women aged 40 to 80, who were diagnosed with VVA, and whose worst symptom was dyspareunia.[12]

Society and culture

Osphena® Sales

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.[13] When Osphena® was put onto the market, it was predicted to earn $495 million in 2017.[14]

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See also

References
  1. 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.
  2. Tanzi MG (April 2013). "Ospemifene: New treatment for postmenopausal women". Pharmacy Today. American Pharmacists Association.
  3. "FDA approves Osphena for postmenopausal women experiencing pain during sex". FDA News Release. U.S. Food and Drug Administration. 2013-02-26.
  4. "European Medicines Agency".
  5. "Ospemifene: Indications, Side Effects, Warnings". Drugs.com.
  6. EP application 2286806, Lehtola V-M, Halonen K, "Solid formulations of ospemifene", published 2011-02-23, assigned to Hormos Medical Ltd.
  7. "Shionogi Files a New Drug Application for Ospemifene Oral Tablets 60mg for the Treatment of Vulvar and Vaginal Atrophy". Drugs.com.
  8. Kusiak V (2013-02-13). "NDA Approval" (PDF). U.S. Food and Drug Administration.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. http://www.shionogi.co.jp/en/ir/pdf/e_p131101.pdf. First Half of Fiscal 2013 Financial Results. Nov. 1, 2013.
  14. http://www.thepharmaletter.com/article/fda-approves-shionogi-s-osphena-for-postmenopausal-women-experiencing-pain-during-sex. ThePharmaLetter


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