Ospemifene (FC-1271a; FC1271a; Osphena) is an orally bioactive medication and a non-hormonal selective estrogen receptor modulator (SERM), used for the treatment of dyspareunia. It has been approved for managing 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.

Physicochemical Properties

Molecular Formula	C24H23CLO2
Molecular Weight	378.89
Exact Mass	378.138
CAS #	128607-22-7
Related CAS #	Ospemifene-d4
PubChem CID	3036505
Appearance	White to off-white solid powder
Density	1.166±0.06 g/cm3
Boiling Point	544.6±50.0 °C at 760 mmHg
Flash Point	283.2±30.1 °C
Vapour Pressure	0.0±1.5 mmHg at 25°C
Index of Refraction	1.608
LogP	6.98
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	2
Rotatable Bond Count	8
Heavy Atom Count	27
Complexity	441
Defined Atom Stereocenter Count	0
SMILES	C1=CC=C(C=C1)/C(=C(/C2=CC=CC=C2)\C3=CC=C(C=C3)OCCO)/CCCl
InChi Key	LUMKNAVTFCDUIE-VHXPQNKSSA-N
InChi Code	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-
Chemical Name	2-(p-((Z)-4-Chloro-1,2-diphenyl-1-butenyl)phenoxy)ethanol
Synonyms	FC-1271a; Osphena;FC 1271a; FC1271a;
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ADME/Pharmacokinetics	Absorption, Distribution and Excretion 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. 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. 448 L Total body clearance = 9.16 L/hr. /MILK/ Human lacatation data is not available, however, the prodrug is rapidly metabolized upon absorption, and this agent is concentrated in the breast milk. /MILK/ It is not known whether Osphena is excreted in human breast milk. In a nonclinical study, ospemifene was excreted in rat milk and detected at concentrations higher than that in maternal plasma. Following a single oral administration of Osphena 60 mg tablet in postmenopausal women under fasted condition, peak median serum concentrations was reached at approximately 2 hours (range: 1 to 8 hours) post-dose. Mean ospemifene C max and AUC 0-inf were 533 ng/mL and 4165 ng/hr/mL, respectively. After a single oral administration of Osphena 60 mg tablet in postmenopausal women with a high fat/high calorie (860 kcal) meal, C max was reached at approximately 2.5 hours (range: 1 to 6 hours) post-dose. Mean ospemifene C max and AUC 0-inf were 1198 ng/mL and 7521 ng/hr/mL, respectively. The absolute bioavailability of ospemifene was not evaluated. Ospemifene exhibits less than dose-proportional pharmacokinetics from 25 to 200 mg with ospemifene capsule formulation. Accumulation of ospemifene with respect to AUC 0-inf was approximately 2 after twelve weeks of daily administration. Steady-state was reached after nine days of ospemifene administration. Osphena is highly (>99 percent) bound to serum proteins. The apparent volume of distribution is 448 L. The apparent terminal half-life of ospemifene in postmenopausal women is approximately 26 hours. 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. Metabolism / Metabolites 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. The objective of these investigations was to determine the possible effects of the novel selective estrogen receptor modulator, ospemifene, on cytochrome P450 (CYP)-mediated drug metabolism. Ospemifene underwent testing for possible effects on CYP enzyme activity in human liver microsomes and in isolated human hepatocytes. Based on the results obtained in vitro, three Phase 1 crossover pharmacokinetic studies were conducted in healthy postmenopausal women to assess the in vivo effects of ospemifene on CYP-mediated drug metabolism. Ospemifene and its main metabolites 4-hydroxyospemifene and 4'-hydroxyospemifene weakly inhibited a number of CYPs (CYP2B6, CYP2C9, CYP2C19, CYP2C8, and CYP2D6) in vitro. However, only CYP2C9 activity was inhibited by 4-hydroxyospemifene at clinically relevant concentrations. Induction of CYPs by ospemifene in cultured human hepatocytes was 2.4-fold or less. The in vivo studies showed that ospemifene did not have significant effects on the areas under the plasma concentration-time curves of the tested CYP substrates warfarin (CYP2C9), bupropion (CYP2B6) and omeprazole (CYP2C19), demonstrating that pretreatment with ospemifene did not alter their metabolism. Therefore, the risk that ospemifene will affect the pharmacokinetics of drugs that are substrates for CYP enzymes is low. Ospemifene and its main metabolites 4-hydroxyospemifene and 4'-hydroxyospemifene weakly inhibited a number of CYPs (CYP2B6, CYP2C9, CYP2C19, CYP2C8, and CYP2D6) in vitro. In vitro experiments with human liver microsomes indicated that ospemifene primarily undergoes metabolism via CYP3A4, CYP2C9 and CYP2C19. The major metabolite was 4-hydroxyospemifene. The apparent total body clearance is 9.16 L/hr using a population approach. Biological Half-Life Terminal half-life = 26 hours . The apparent terminal half-life of ospemifene in postmenopausal women is approximately 26 hours.
Toxicity/Toxicokinetics	Toxicity Summary IDENTIFICATION AND USE: Ospemifene (trade name: Osphena) is a prescription medication approved for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. Ospemifene is an estrogen agonist/antagonist with tissue selective effects. Its biological actions are mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). HUMAN EXPOSURE AND TOXICITY: In epidemiological studies of Ospemifene reported adverse events included hot flushes, a single non-ST elevated myocardial infarct, vaginal bleeding, endometrial thickness, vaginal discharge, muscle spasms, and hyperhidrosis. There is a reported increased risk of stroke, deep vein thrombosis (DVT), endometrial cancer, uterine cancer, and thromboembolic and hemorrhagic stroke. ANIMAL STUDIES: In a 2-year carcinogenicity study in rats, a significant increase in thymomas was recorded for males and females. In the liver, an increase in hepatocellular tumors were recorded for females. In a 2-year carcinogenicity study in female mice, there was significant increase in adrenal subcapsular cell adenomas and adrenal cortical tumors. The effects of ospemifene on pre-and postnatal development were studied in pregnant rats treated from implantation through lactation. Pregnant rats had a significantly prolonged and difficult gestation, increased post-implantation loss, increased number of dead pups at birth, and an increased incidence of postnatal loss. In a similar study in rabbits, there was an increase in the incidence of total resorption. Ospemifene was not genotoxic in vitro in the Ames test in strains of Salmonella typhimurium or at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells in the absence and in the presence of a metabolic activator system. In in vivo testing, ospemifene was not genotoxic in a standard mouse bone marrow micronucleus test or in a determination of DNA adducts in the liver of rats. Protein Binding >99% bound to serum proteins Interactions Multiple Enzyme Inhibition: Co-administration of Osphena with a drug known to inhibit CYP3A4 and CYP2C9 isoenzymes may increase the risk of Osphena-related adverse reactions. Highly Protein-Bound Drugs: Ospemifene is more than 99% bound to serum proteins and might affect the protein binding of other drugs. Use of Osphena with other drug products that are highly protein bound may lead to increased exposure of either that drug or ospemifene. Ketoconazole, a strong CYP3A4 inhibitor increases the systemic exposure of ospemifene by 1.4-fold. Administration of ketoconazole chronically with ospemifene may increase the risk of Osphena-related adverse reactions. Rifampin, a strong CYP3A4 / moderate CYP2C9 / moderate CYP2C19 inducer, decreases the systemic exposure of ospemifene by 58%. Therefore, co-administration of Osphena with drugs such as rifampin which induce CYP3A4, CYP2C9 and/or CYP2C19 activity would be expected to decrease the systemic exposure of ospemifene, which may decrease the clinical effect. For more Interactions (Complete) data for Ospemifene (6 total), please visit the HSDB record page.
References	Menopause.2013 Jun;20(6):623-30.
Additional Infomation	Ospemifene is an organochlorine compound that is a selective estrogen receptor modulator; used for treatment of dyspareunia. It has a role as an estrogen receptor modulator, an antineoplastic agent and an anti-inflammatory agent. It is an organochlorine compound, an aromatic ether and a primary alcohol. It derives from a hydride of a stilbene. 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. Ospemifene is an Estrogen Agonist/Antagonist. The mechanism of action of ospemifene is as a Selective Estrogen Receptor Modulator. Drug Indication Ospemifene is indicated for the treatment of moderate to severe dyspareunia and vaginal dryness associated with menopause. FDA Label Senshio is indicated for the treatment of moderate to severe symptomatic vulvar and vaginal atrophy (VVA) in post-menopausal women. 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. OSPHENA is an estrogen agonist/antagonist with tissue selective effects. Its biological actions are mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). Therapeutic Uses /CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Ospemifene is included in the database. Osphena is indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. /Included in US product label/ Drug Warnings /BOX WARNING/ There is a reported increased risk of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) who received daily oral conjugated estrogens (CE) (0.625 mg)-alone therapy over 7.1 years as part of the Women's Health Initiative (WHI). In the clinical trials for Osphena (duration of treatment up to 15 months), the incidence rates of thromboembolic and hemorrhagic stroke were 0.72 and 1.45 per thousand women, respectively in Osphena 60 mg treatment group and 1.04 and 0 in placebo. The incidence of DVT was 1.45 per thousand women in Osphena 60 mg treatment group and 1.04 per thousand women in placebo. Osphena should be prescribed for the shortest duration consistent with treatment goals and risks for the individual woman. /BOX WARNING/ Osphena is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, Osphena has estrogen agonistic effects. There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin to estrogen therapy reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed and random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. /BOX WARNING/ What is the most important information I should know about Osphena? Osphena is a medicine that works like estrogen in the lining of the uterus (womb), but can work differently in other parts of the body. Taking estrogen-alone or Osphena may increase your chance of getting cancer of the lining of the uterus (womb). Vaginal bleeding after menopause may be a warning sign of cancer of the lining of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause. Tell your healthcare provider right away if you have any unusual vaginal bleeding while you are taking Osphena. Osphena may increase your chance of getting strokes and blood clots. You and your healthcare provider should talk regularly about whether you still need treatment with Osphena. The pharmacokinetics of ospemifene has not been studied in women with severe hepatic impairment (Child-Pugh Class C); therefore, Osphena should not be used in women with severe hepatic impairment. For more Drug Warnings (Complete) data for Ospemifene (16 total), please visit the HSDB record page. 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.

Solubility Data

Solubility (In Vitro)

DMSO: 75 mg/mL (197.9 mM) Water:<1 mg/mL Ethanol: 71 mg/mL (187.4 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.60 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.60 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.6393 mL	13.1964 mL	26.3929 mL
	5 mM	0.5279 mL	2.6393 mL	5.2786 mL
	10 mM	0.2639 mL	1.3196 mL	2.6393 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.