Ospemifeneのソースを表示

{{Short description|Selective estrogen receptor modulator}}
{{Drugbox
| IUPAC_name = 2-(''p''-((''Z'')-4-chloro-1,2-diphenyl-1-butenyl)phenoxy)ethanol
| image = Ospemifene.svg
| width = 250
| alt = 

<!-- Clinical data -->
| tradename = Osphena, Senshio
| Drugs.com = 
| MedlinePlus = 
| DailyMedID = Ospemifene
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_category =
| routes_of_administration = [[Oral administration|By mouth]]
| class = [[Selective estrogen receptor modulator]]
| ATC_prefix = G03
| ATC_suffix = XC05

| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_CA = Rx-only
| legal_CA_comment = <ref>{{Cite web |date=23 October 2014 |title=Summary Basis of Decision (SBD) for Osphena |url=https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?linkID=SBD00564&lang=en |access-date=29 May 2022 |website=Health Canada}}</ref><ref>{{Cite web |date=3 August 2022 |title=Health product highlights 2021: Annexes of products approved in 2021 |url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/health-product-highlights-2021/appendices.html |access-date=25 March 2024 |website=[[Health Canada]]}}</ref>
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM -->
| legal_US = Rx-only
| legal_EU = Rx-only
| legal_status =

<!-- Pharmacokinetic data -->
| bioavailability = 
| protein_bound = 
| metabolism = 
| elimination_half-life = 
| excretion =

<!-- Identifiers -->
| CAS_number = 128607-22-7
| PubChem = 3036505
| DrugBank = DB04938
| ChemSpiderID = 2300501
| UNII = B0P231ILBK
| ChEMBL = 2105395
| ChEBI = 73275
| KEGG = D08958
| synonyms = Deaminohydroxytoremifene

<!-- Chemical data -->
| C=24 | H=23 | Cl=1 | O=2
| SMILES = OCCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
| StdInChI=1S/C24H23ClO2/c25-16-15-23(19-7-3-1-4-8-19)24(20-9-5-2-6-10-20)21-11-13-22(14-12-21)27-18-17-26/h1-14,26H,15-18H2/b24-23-
| StdInChIKey = LUMKNAVTFCDUIE-VHXPQNKSSA-N
}}

'''Ospemifene''' (brand names '''Osphena''' and '''Senshio''' produced by [[Shionogi]]) is an oral medication indicated for the treatment of [[dyspareunia]]{{spaced ndash}}pain during sexual intercourse{{spaced ndash}}encountered by some women, more often in those who are [[menopause|post-menopausal]]. Ospemifene is a [[selective estrogen receptor modulator]] (SERM)<ref name="pmid14501605">{{Cite journal |vauthors=Rutanen EM, Heikkinen J, Halonen K, Komi J, Lammintausta R, Ylikorkala O |year=2003 |title=Effects of ospemifene, a novel SERM, on hormones, genital tract, climacteric symptoms, and quality of life in postmenopausal women: a double-blind, randomized trial |journal=Menopause |volume=10 |issue=5 |pages=433–9 |doi=10.1097/01.GME.0000063609.62485.27 |pmid=14501605 |s2cid=25481518}}</ref> 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."<ref name="test">{{Cite journal |last=Tanzi MG |date=April 2013 |title=Ospemifene: New treatment for postmenopausal women. |url=http://www.pharmacist.com/node/205934 |url-status=dead |journal=Pharmacy Today. American Pharmacists Association. |archive-url=https://web.archive.org/web/20171201043112/http://www.pharmacist.com/node/205934 |archive-date=2017-12-01 |access-date=2013-12-02}}</ref>

The medication was approved by the [[Food and Drug Administration|FDA]] in February 2013<ref>{{Cite news |date=2013-02-26 |title=FDA approves Osphena for postmenopausal women experiencing pain during sex |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm341128.htm |work=FDA News Release |publisher=U.S. Food and Drug Administration}}</ref> and by the European Commission for marketing in the EU in January 2015.<ref>{{Cite web |title=European Medicines Agency |url=http://www.ema.europa.eu/en/medicines/human/EPAR/senshio}}</ref>

==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.{{cn|date=January 2025}}

==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.<ref name="test" /> This is not a full list of contraindications.

==Side effects==
Side effects associated with ospemifene include vaginal discharge, hot flashes, and diaphoresis.<ref name="test4">{{Cite web |title=Ospemifene: Indications, Side Effects, Warnings |url=https://www.drugs.com/cdi/ospemifene.html |publisher=Drugs.com}}</ref> 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.<ref name="test4" /> 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.<ref name="test" /> 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.<ref name="test" /> 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 administration|oral]] [[conjugated estrogens]]. Studies have not documented the relative risk compared with women taking estrogen/progestin therapy.{{cn|date=January 2025}}

==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."<ref name="test" /> This medication should be used for the shortest amount of time possible due to associated adverse effects.<ref name="test" /> Ospemifene might not have an adverse influence on [[coagulation]], in contrast to estrogens and other SERMs like [[tamoxifen]] and [[raloxifene]].<ref name="pmid20429673" />

A binding assay was also performed to measure the affinity of ospemifene for the [[estrogen receptor]] ([[estrogen receptor alpha|ERα]] and [[estrogen receptor beta|ERβ]]).<ref name="test7" /> The study showed that ospemifene bound ERα and ERβ with similar affinity.<ref name="test7" /> Ospemifene bound the estrogen receptors with a lower affinity than estradiol.<ref name="test7" /> 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."<ref name="test7" />

{{Tissue-specific estrogenic and antiestrogenic activity of SERMs}}

===Pharmacokinetics===
The [[pharmacokinetics]] of ospemifene were [[dose dependency|dose-dependent]] over a dose range of 10 to 800&nbsp;mg/day.<ref name="pmid20429673">{{Cite journal |vauthors=McCall JL, DeGregorio MW |date=June 2010 |title=Pharmacologic evaluation of ospemifene |journal=Expert Opin Drug Metab Toxicol |volume=6 |issue=6 |pages=773–9 |doi=10.1517/17425255.2010.487483 |pmid=20429673 |s2cid=38803935}}</ref>

==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.<ref name="test3">{{ cite patent | country = EP | number = 2286806 | status = application | title = Solid formulations of ospemifene | pubdate = 2011-02-23 | inventor = Lehtola V-M, Halonen K | assign1 = Hormos Medical Ltd.}}</ref> In March 2010, QuatRX Pharmaceuticals licensed ospemifene to Shionogi & Co., Ltd. for clinical development and marketing.<ref name="test6">{{Cite web |title=Shionogi Files a New Drug Application for Ospemifene Oral Tablets 60mg for the Treatment of Vulvar and Vaginal Atrophy |url=https://www.drugs.com/nda/ospemifene_120509.html |publisher=Drugs.com}}</ref> A [[New Drug Application]] (NDA) was submitted to the FDA on April 26, 2012.<ref name="test2" /> Amendments to the NDA were submitted in June, July, August, October, and November 2012, and January and February 2013.<ref name="test2">{{Cite web |last=Kusiak V |date=2013-02-13 |title=NDA Approval |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2013/203505Orig1s000ltr.pdf |publisher=U.S. Food and Drug Administration}}</ref> It was ultimately approved by the FDA on February 26, 2013.<ref name="test6" /> Ospemifene (under the brand name Senshio) was subsequently approved by the European Commission for marketing in the EU in January 2015.{{cn|date=January 2025}}

===Preclinial and clinical trials===
Preclinical trials were performed in ovariectomized rats to model menopause.<ref name="test7">{{Cite journal |vauthors=Unkila M, Kari S, Yatkin E, Lammintausta R |date=November 2013 |title=Vaginal effects of ospemifene in the ovariectomized rat preclinical model of menopause |journal=J. Steroid Biochem. Mol. Biol. |volume=138 |pages=107–15 |doi=10.1016/j.jsbmb.2013.04.004 |pmid=23665515 |s2cid=20363618}}</ref> 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.<ref name="test7" /> Estradiol was used as a positive control and raloxifene was used because it is in the same drug class as ospemifene.<ref name="test7" /> Multiple doses of oral ospemifene were tested.<ref name="test7" /> 10&nbsp;mg/kg/day of Ospemifene was found to cause a greater increase in vaginal weight and vaginal epithelial height than 10&nbsp;mg/kg/day of raloxifene.<ref name="test7" /> Vaginal weight had a 1.46x increase after a two-week treatment of 10&nbsp;mg/kg/day of ospemifene.<ref name="test7" /> The number of progesterone receptors was increased in the vaginal stroma and epithelium, which indicates that ospemifene has "estrogenic activity."<ref name="test7" />

Two 12-week phase 3 clinical trials were performed for ospemifene.<ref name="test5">{{Cite web |last=Center for Drug Evaluation and Research |date=2013-02-26 |title=Clinical Pharmacology and Biopharmaceutics Review Application Number 203505Orig1s000 |url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/203505Orig1s000ClinPharmR.pdf |website=Office of Clinical Pharmacology Review |publisher=U.S. Food and Drug Administration}}</ref> 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."<ref name="test5" /> Ospemifene produced more changes in vaginal tissue and greater reduction in dyspareunia symptoms than placebo.<ref name="test5" /> A dose-response also was observed in the trial; ospemifene 60&nbsp;mg had greater efficacy than ospemifene 30&nbsp;mg.<ref name="test5" /> 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.<ref name="test5" /> One of the phase 3 trials was a randomized, double-blind placebo-controlled trial in 826 post-menopausal women.<ref name="test8">{{Cite journal |vauthors=Bachmann GA, Komi JO |year=2010 |title=Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study |journal=Menopause |volume=17 |issue=3 |pages=480–6 |doi=10.1097/gme.0b013e3181c1ac01 |pmid=20032798 |s2cid=6081373}}</ref> 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.<ref name="test8" /> 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.<ref name="pmid23361170">{{Cite journal |vauthors=Portman DJ, Bachmann GA, Simon JA |date=June 2013 |title=Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy |journal=Menopause |volume=20 |issue=6 |pages=623–30 |doi=10.1097/gme.0b013e318279ba64 |pmid=23361170 |s2cid=33822608 |doi-access=free}}</ref>

==Society and culture==

=== Economics ===
In the first half of the 2013 fiscal year, Osphena generated 0.1 B yen in revenue, which is roughly equivalent to $974,944 U.S. dollars.<ref>http://www.shionogi.co.jp/en/ir/pdf/e_p131101.pdf. First Half of Fiscal 2013 Financial Results. Nov. 1, 2013.</ref> When Osphena was put onto the market, it was predicted to earn $495 million in 2017.<ref>http://www.thepharmaletter.com/article/fda-approves-shionogi-s-osphena-for-postmenopausal-women-experiencing-pain-during-sex. ThePharmaLetter</ref>

==References==
{{Reflist}}

{{Estrogens and antiestrogens}}
{{Estrogen receptor modulators}}
{{Other sex hormones and modulators of the genital system}}
{{Portal bar | Medicine}}

[[Category:Organochlorides]]
[[Category:Phenol ethers]]
[[Category:Selective estrogen receptor modulators]]
[[Category:Triphenylethylenes]]