Ospemifene

Identification

Summary

Ospemifene is a non-hormonal estrogen receptor modulator (SERM) used to treat moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.

Brand Names

Osphena

Generic Name

Ospemifene

DrugBank Accession Number

DB04938

Background

Ospemifene is a new selective non-hormonal estrogen receptor modulator (SERM) that is used for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. FDA approved on February 26, 2013.

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Ospemifene (DB04938)

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Weight

Average: 378.891
Monoisotopic: 378.138657687

Chemical Formula

C₂₄H₂₃ClO₂

Synonyms

• 2-(4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenoxy)ethanol
• 2-(p-((Z)-4-Chloro-1,2-diphenyl-1-butenyl)phenoxy)ethanol
• Deamino-hydroxytoremifene
• Ospemifene
• Ospemifeno

External IDs

• FC-1271
• FC-1271A

Pharmacology

Indication

Ospemifene is used for the treatment of moderate to dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.

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Associated Conditions

• Moderate Dyspareunia
• Severe Dyspareunia

Contraindications & Blackbox Warnings

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Pharmacodynamics

The half maximal inhibitory concentration (IC50) for estrogen receptor (ER) alpha and beta are 0.8 μM and 1.7 μM, respectively. Ospemifene has potential uses in the management of osteoporosis in postmenopausal women. It interacts with osteoblasts and osteoclasts in such a way that it reduces bone turnover. It also has potential uses in the prevention of breast cancer. Studies suggest that ospemifene, in a dose-dependent manner, reduces the incidence of tumours.

Mechanism of action

Ospemifene is a next generation SERM (selective estrogen receptor modulator) that selectively binds to estrogen receptors and either stimulates or blocks estrogen's activity in different tissue types. It has an agonistic effect on the endometrium.

Target	Actions	Organism
AEstrogen receptor alpha	antagonist agonist	Humans

Absorption

When a single oral dose of ospemifene 60 mg is given to postmenopausal women under fasted conditions, the pharmacokinetic parameters are as follows: Tmax = 2 hours (range of 1 - 8 hours); Cmax = 533 ng/mL; AUC (0-inf) = 4165 ng•hr/mL. When the same aforementioned dose is given to postmenopausal women under fed conditions, the pharmacokinetic parameters are as follows: Tmax = 2.5 hours (1 - 6 hours); Cmax = 1198 ng/mL; AUC (0-inf) = 7521 ng•hr/mL. Accumulation occurs following repeated doses. Time to steady state = 9 days.
Although the bioavailability of ospemifene has not been formally evaluated, it is expected to have a low bioavailability because of its lipophilic nature.

Volume of distribution

448 L

Protein binding

>99% bound to serum proteins

Metabolism

Ospemifene is hepatically metabolized via CYP3A4, CYP2C9, CYP2C19, and CYP2B6. The major metabolite was 4-hydroxyospemifene, 25% of the parent compound will undergo this biotransformation. Other metabolites include 4'-hydroxy-ospemifene, <7% of the parent compound will undergo this biotransformation. In order of decreasing potency, ospemifene was suggested to be a weak inhibitor for CYP2B6, CYP2C9, CYP2C19, CYP2C8, CYP2D6 and CYP3A4.

Route of elimination

Following an oral administration of ospemifene, approximately 75% and 7% of the dose was excreted in feces and urine, respectively. Less than 0.2% of the ospemifene dose was excreted unchanged in urine.

Half-life

Terminal half-life = 26 hours .

Clearance

Total body clearance = 9.16 L/hr.

Adverse Effects

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Toxicity

Adverse reactions (≥1 percent) include: hot flush, vaginal discharge, muscle spasms, genital discharge, hyperhidrosis.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abametapir	The serum concentration of Ospemifene can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Ospemifene can be increased when combined with Abatacept.
Abiraterone	The metabolism of Ospemifene can be decreased when combined with Abiraterone.
Acebutolol	The metabolism of Acebutolol can be decreased when combined with Ospemifene.
Acenocoumarol	The metabolism of Acenocoumarol can be decreased when combined with Ospemifene.
Acetaminophen	The metabolism of Acetaminophen can be decreased when combined with Ospemifene.
Acetohexamide	The metabolism of Ospemifene can be decreased when combined with Acetohexamide.
Acetyl sulfisoxazole	The metabolism of Ospemifene can be decreased when combined with Acetyl sulfisoxazole.
Acetylsalicylic acid	The metabolism of Ospemifene can be decreased when combined with Acetylsalicylic acid.
Adalimumab	The metabolism of Ospemifene can be increased when combined with Adalimumab.

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Food Interactions

• Take with food.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Osphena	Tablet	60 mg	Oral	Duchesnay Inc.	Not applicable	Not applicable
Osphena	Tablet, film coated	60 mg/1	Oral	SHIONOGI INC.	2013-02-26	Not applicable
Senshio	Tablet	60 mg	Oral	Shionogi B.V.	2020-12-22	Not applicable
Senshio	Tablet	60 mg	Oral	Shionogi B.V.	2020-12-22	Not applicable
Senshio	Tablet	60 mg	Oral	Shionogi B.V.	2020-12-22	Not applicable

Categories

ATC Codes

G03XC05 — Ospemifene

• G03XC — Selective estrogen receptor modulators
• G03X — OTHER SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM
• G03 — SEX HORMONES AND MODULATORS OF THE GENITAL SYSTEM
• G — GENITO URINARY SYSTEM AND SEX HORMONES

Drug Categories

• Benzene Derivatives
• Benzylidene Compounds
• Cytochrome P-450 CYP2B6 Substrates
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP2D6 Inhibitors
• Cytochrome P-450 CYP2D6 Inhibitors (weak)
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Substrates
• Estrogen Agonist/Antagonist
• Genito Urinary System and Sex Hormones
• Selective Estrogen Receptor Modulators
• Sex Hormones and Modulators of the Genital System
• Stilbenes

Chemical TaxonomyProvided by Classyfire

Description

This compound belongs to the class of organic compounds known as stilbenes. These are organic compounds containing a 1,2-diphenylethylene moiety. Stilbenes (C6-C2-C6 ) are derived from the common phenylpropene (C6-C3) skeleton building block. The introduction of one or more hydroxyl groups to a phenyl ring lead to stilbenoids.

Kingdom

Organic compounds

Super Class

Phenylpropanoids and polyketides

Class

Stilbenes

Sub Class

Not Available

Direct Parent

Stilbenes

Alternative Parents

Diphenylmethanes / Phenoxy compounds / Phenol ethers / Alkyl aryl ethers / Primary alcohols / Organochlorides / Hydrocarbon derivatives / Alkyl chlorides

Substituents

Alcohol / Alkyl aryl ether / Alkyl chloride / Alkyl halide / Aromatic homomonocyclic compound / Benzenoid / Diphenylmethane / Ether / Hydrocarbon derivative / Monocyclic benzene moiety

Molecular Framework

Aromatic homomonocyclic compounds

External Descriptors

aromatic ether, organochlorine compound, primary alcohol (CHEBI:73275)

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

B0P231ILBK

CAS number

128607-22-7

InChI Key

LUMKNAVTFCDUIE-VHXPQNKSSA-N

InChI

InChI=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-

IUPAC Name

2-{4-[(1Z)-4-chloro-1,2-diphenylbut-1-en-1-yl]phenoxy}ethan-1-ol

SMILES

OCCOC1=CC=C(C=C1)C(=C(\CCCl)C1=CC=CC=C1)\C1=CC=CC=C1

References

Synthesis Reference

Marja Sodervall, Maire Eloranta, Arja Kalapudas, Brian Kearton, Michael McKenzie, "METHODS FOR THE PREPARATION OF FISPEMIFENE FROM OSPEMIFENE." U.S. Patent US20080214860, issued September 04, 2008.

US20080214860

General References

1. Taras TL, Wurz GT, DeGregorio MW: In vitro and in vivo biologic effects of Ospemifene (FC-1271a) in breast cancer. J Steroid Biochem Mol Biol. 2001 Jun;77(4-5):271-9. [Article]
2. Voipio SK, Komi J, Kangas L, Halonen K, DeGregorio MW, Erkkola RU: Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women. Maturitas. 2002 Nov 20;43(3):207-14. [Article]
3. Rutanen EM, Heikkinen J, Halonen K, Komi J, Lammintausta R, Ylikorkala O: 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. 2003 Sep-Oct;10(5):433-9. [Article]
4. Ylikorkala O, Cacciatore B, Halonen K, Lassila R, Lammintausta R, Rutanen EM, Heikkinen J, Komi J: Effects of ospemifene, a novel SERM, on vascular markers and function in healthy, postmenopausal women. Menopause. 2003 Sep-Oct;10(5):440-7. [Article]
5. Tolonen A, Koskimies P, Turpeinen M, Uusitalo J, Lammintausta R, Pelkonen O: Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations. Drug Metabol Drug Interact. 2013;28(3):153-61. doi: 10.1515/dmdi-2013-0016. [Article]
6. McCall JL, DeGregorio MW: Pharmacologic evaluation of ospemifene. Expert Opin Drug Metab Toxicol. 2010 Jun;6(6):773-9. doi: 10.1517/17425255.2010.487483. [Article]
7. FDA Approved Drug Products: OSPHENA (ospemifene) tablets [Link]

External Links

KEGG Drug

D08958

PubChem Compound

3036505

PubChem Substance

175426911

ChemSpider

2300501

RxNav

1370971

ChEBI

73275

ChEMBL

CHEMBL2105395

ZINC

ZINC000001550766

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Ospemifene

FDA label

Download (350 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Painful Intercourse / Vulvo Vaginal Atrophy	1
4	Recruiting	Health Services Research	Genitourinary Syndrome of Menopause (GSM) / Sexual; Disorder, Arousal, Female / Vulvovaginal signs and symptoms	1
4	Terminated	Treatment	Sexual Dysfunctions, Physiological	1
3	Completed	Treatment	Atrophy / Vaginal Diseases	5
3	Completed	Treatment	Vaginal Dryness	1
2	Completed	Treatment	Atrophy / Vaginal Diseases	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet, film coated	Oral	60 mg/1
Tablet	Oral	60 mg
Tablet, film coated	Oral	60 MG

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8470890	No	2013-06-25	2024-02-13
US6245819	No	2001-06-12	2020-07-21
US8236861	No	2012-08-07	2026-08-11
US8772353	No	2014-07-08	2024-02-13
US9241915	No	2016-01-26	2024-02-13
US8642079	No	2014-02-04	2028-07-09
US9566252	No	2017-02-14	2020-07-21
US9855224	No	2018-01-02	2024-02-13

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Insoluble	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	0.000526 mg/mL	ALOGPS
logP	5.7	ALOGPS
logP	5.56	ChemAxon
logS	-5.9	ALOGPS
pKa (Strongest Acidic)	15.1	ChemAxon
pKa (Strongest Basic)	-2.8	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	2	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	29.46 Å2	ChemAxon
Rotatable Bond Count	8	ChemAxon
Refractivity	121.68 m3·mol-1	ChemAxon
Polarizability	41.97 Å3	ChemAxon
Number of Rings	3	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	Yes	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	0.9972
Blood Brain Barrier	+	0.7095
Caco-2 permeable	+	0.6894
P-glycoprotein substrate	Non-substrate	0.587
P-glycoprotein inhibitor I	Inhibitor	0.7541
P-glycoprotein inhibitor II	Inhibitor	0.5935
Renal organic cation transporter	Non-inhibitor	0.6587
CYP450 2C9 substrate	Non-substrate	0.7712
CYP450 2D6 substrate	Non-substrate	0.8459
CYP450 3A4 substrate	Non-substrate	0.5552
CYP450 1A2 substrate	Non-inhibitor	0.5168
CYP450 2C9 inhibitor	Non-inhibitor	0.7604
CYP450 2D6 inhibitor	Non-inhibitor	0.8754
CYP450 2C19 inhibitor	Inhibitor	0.5512
CYP450 3A4 inhibitor	Non-inhibitor	0.7578
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.6072
Ames test	Non AMES toxic	0.597
Carcinogenicity	Non-carcinogens	0.767
Biodegradation	Not ready biodegradable	0.5073
Rat acute toxicity	2.3083 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.5657
hERG inhibition (predictor II)	Non-inhibitor	0.6556

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Details1. Estrogen receptor alpha

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

Agonist

General Function

Zinc ion binding

Specific Function

Nuclear hormone receptor. The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissu...

Gene Name

ESR1

Uniprot ID

P03372

Uniprot Name

Estrogen receptor

Molecular Weight

66215.45 Da

References

1. Komi J, Heikkinen J, Rutanen EM, Halonen K, Lammintausta R, Ylikorkala O: Effects of ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women. Gynecol Endocrinol. 2004 Mar;18(3):152-8. [Article]
2. Wurz GT, Read KC, Marchisano-Karpman C, Gregg JP, Beckett LA, Yu Q, Degregorio MW: Ospemifene inhibits the growth of dimethylbenzanthracene-induced mammary tumors in Sencar mice. J Steroid Biochem Mol Biol. 2005 Nov;97(3):230-40. Epub 2005 Sep 8. [Article]

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Drug created on October 21, 2007 22:23 / Updated on August 13, 2021 04:44