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
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 indicated for the treatment of moderate to severe dyspareunia and vaginal dryness associated with menopause.7

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofModerate dyspareunia••••••••••••••••••••••••••••
Treatment ofModerate vaginal dryness••••••••••••••••••••••••••••
Treatment ofSevere dyspareunia••••••••••••••••••••••••••••
Treatment ofSevere vaginal dryness••••••••••••••••••••••••••••
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.

TargetActionsOrganism
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.
DrugInteraction
AbametapirThe serum concentration of Ospemifene can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Ospemifene can be increased when combined with Abatacept.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Ospemifene.
AcebutololThe metabolism of Acebutolol can be decreased when combined with Ospemifene.
AcenocoumarolThe metabolism of Ospemifene can be decreased when combined with Acenocoumarol.
Food Interactions
  • Take with food.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
OsphenaTablet60 mgOralDuchesnay Inc.2022-01-13Not applicableCanada flag
OsphenaTablet, film coated60 mg/1OralDuchesnay USA, Inc.2023-04-01Not applicableUS flag
OsphenaTablet, film coated60 mg/1OralSHIONOGI INC.2013-02-262025-07-31US flag
OsphenaTablet, film coated60 mg/1OralPharma Packaging Solutions2013-02-26Not applicableUS flag
SenshioTablet60 mgOralShionogi B.V.2020-12-22Not applicableEU flag

Categories

ATC Codes
G03XC05 — Ospemifene
Drug Categories
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 for oral use [Link]
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
PhaseStatusPurposeConditionsCount
4CompletedTreatmentPainful Intercourse / Vulvo Vaginal Atrophy1
4RecruitingHealth Services ResearchGenitourinary Syndrome of Menopause (GSM) / Sexual; Disorder, Arousal, Female / Vulvovaginal signs and symptoms1
4TerminatedTreatmentSexual Dysfunctions, Physiological1
3CompletedTreatmentAtrophy / Vaginal Diseases5
3CompletedTreatmentVaginal Dryness1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral60 mg
Tablet, film coatedOral60 mg/1
Tablet, film coatedOral60 MG
Tablet, film coatedOral60.0 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8470890No2013-06-252024-02-13US flag
US6245819No2001-06-122020-07-21US flag
US8236861No2012-08-072026-08-11US flag
US8772353No2014-07-082024-02-13US flag
US9241915No2016-01-262024-02-13US flag
US8642079No2014-02-042028-07-09US flag
US9566252No2017-02-142020-07-21US flag
US9855224No2018-01-022024-02-13US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilityInsoluble FDA label
Predicted Properties
PropertyValueSource
Water Solubility0.000526 mg/mLALOGPS
logP5.7ALOGPS
logP5.56Chemaxon
logS-5.9ALOGPS
pKa (Strongest Acidic)15.1Chemaxon
pKa (Strongest Basic)-2.8Chemaxon
Physiological Charge0Chemaxon
Hydrogen Acceptor Count2Chemaxon
Hydrogen Donor Count1Chemaxon
Polar Surface Area29.46 Å2Chemaxon
Rotatable Bond Count8Chemaxon
Refractivity121.68 m3·mol-1Chemaxon
Polarizability41.97 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterYesChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleYesChemaxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9972
Blood Brain Barrier+0.7095
Caco-2 permeable+0.6894
P-glycoprotein substrateNon-substrate0.587
P-glycoprotein inhibitor IInhibitor0.7541
P-glycoprotein inhibitor IIInhibitor0.5935
Renal organic cation transporterNon-inhibitor0.6587
CYP450 2C9 substrateNon-substrate0.7712
CYP450 2D6 substrateNon-substrate0.8459
CYP450 3A4 substrateNon-substrate0.5552
CYP450 1A2 substrateNon-inhibitor0.5168
CYP450 2C9 inhibitorNon-inhibitor0.7604
CYP450 2D6 inhibitorNon-inhibitor0.8754
CYP450 2C19 inhibitorInhibitor0.5512
CYP450 3A4 inhibitorNon-inhibitor0.7578
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6072
Ames testNon AMES toxic0.597
CarcinogenicityNon-carcinogens0.767
BiodegradationNot ready biodegradable0.5073
Rat acute toxicity2.3083 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.5657
hERG inhibition (predictor II)Non-inhibitor0.6556
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-0119000000-0ad11fad6604ebaa2e3f
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9011000000-9f08bb3bcb5fdd7baefe
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-002b-0296000000-4173730cbf16290cc0f6
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9010000000-b4976b200e1af665c3af
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-05o0-1971000000-8cfd79f8c4fae0ae6489
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001j-3095000000-eff407bd9d99bb7cc788
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-189.62126
predicted
DeepCCS 1.0 (2019)
[M+H]+191.97926
predicted
DeepCCS 1.0 (2019)
[M+Na]+199.51192
predicted
DeepCCS 1.0 (2019)

Targets

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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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. 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]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. 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]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. 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]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. 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]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da

Drug created at October 21, 2007 22:23 / Updated at March 18, 2024 16:48