Absorption, Distribution and Excretion
When postmenopausal women take a single 60 mg oxperimiphene orally in an empty stomach, the pharmacokinetic parameters are as follows: Tmax = 2 hours (range 1–8 hours); Cmax = 533 ng/mL; AUC (0-inf) = 4165 ng•hr/mL. When postmenopausal women take the same dose with food, 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 with repeated dosing. The time to reach steady state is 9 days. Although the bioavailability of oxperimiphene has not been formally evaluated, it is expected to be low due to its lipophilic nature. Approximately 75% and 7% of the oral dose of oxperimiphene are excreted in feces and urine, respectively. Less than 0.2% of operimiphene is excreted unchanged in the urine. Total clearance = 9.16 L/hr. /Breast milk/ There are currently no data on human breast milk, but the prodrug is rapidly metabolized after absorption and concentrated in breast milk. /Breast milk/ It is unclear whether operimiphene is secreted into human breast milk. In a non-clinical study, operimiphene was secreted into rat breast milk at concentrations higher than those in maternal plasma. In postmenopausal women, after a single oral administration of 60 mg operimiphene tablets on an empty stomach, peak serum drug concentrations were reached approximately 2 hours post-administration (range: 1 to 8 hours). The mean Cmax and AUC0-inf of operimiphene were 533 ng/mL and 4165 ng/hr/mL, respectively. In postmenopausal women, after a single oral dose of 60 mg operimiphene tablets following a high-fat/high-calorie (860 kcal) meal, the Cmax was reached approximately 2.5 hours after administration (range: 1 to 6 hours). The mean Cmax and AUC0-inf of operimiphene were 1198 ng/mL and 7521 ng/hr/mL, respectively. The absolute bioavailability of operimiphene was not assessed. The pharmacokinetic characteristics of operimiphene capsules were dose-independent in the 25 to 200 mg dose range. After 12 weeks of daily administration, the cumulative amount of operimiphene (measured as AUC0-inf) was approximately 2. Steady state was reached after 9 days of administration. operimiphene has a high binding rate to serum proteins (>99%). The apparent volume of distribution is 448 L. The apparent terminal half-life of operimiphene in postmenopausal women is approximately 26 hours. Following oral administration of oxeximiphen, approximately 75% and 7% of the dose are excreted in feces and urine, respectively. Less than 0.2% of the oxeximiphen dose is excreted unchanged in the urine. Metabolism/Metabolites Ospemiphene is primarily metabolized in the liver via CYP3A4, CYP2C9, CYP2C19, and CYP2B6. The major metabolite is 4'-hydroxyoxeximiphene, which undergoes this biotransformation in approximately 25% of the parent compound. Other metabolites include 4'-hydroxyoxeximiphene, which undergoes this biotransformation in approximately 7% of the parent compound. In descending order of potency, oxeximiphene is considered a weak inhibitor of CYP2B6, CYP2C9, CYP2C19, CYP2C8, CYP2D6, and CYP3A4. This study aimed to determine the potential effects of the novel selective estrogen receptor modulator oxeximiphene on cytochrome P450 (CYP)-mediated drug metabolism. We investigated the potential effects of operimiphene on the activity of CYP enzymes in human liver microsomes and isolated human hepatocytes. Based on in vitro results, we conducted three phase I crossover pharmacokinetic studies in healthy postmenopausal women to assess the in vivo effects of operimiphene on CYP-mediated drug metabolism. In vitro studies showed that operimiphene and its major metabolites, 4-hydroxyoperimiphene and 4'-hydroxyoperimiphene, exhibited weak inhibitory activity against multiple CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2C8, and CYP2D6). However, at clinically relevant concentrations, 4-hydroxyoperimiphene only inhibited CYP2C9 activity. The induction of CYP enzymes in cultured human hepatocytes by operimiphene was 2.4-fold or less. In vivo studies showed that operimiphene had no significant effect on the area under the plasma concentration-time curve (AUC) of the tested CYP substrates warfarin (CYP2C9), bupropion (CYP2B6), and omeprazole (CYP2C19), indicating that operimiphene pretreatment does not alter the metabolism of these drugs. Therefore, the risk of operimiphene affecting the pharmacokinetics of CYP enzyme substrate drugs is low. In vitro experiments showed that operimiphene and its major metabolites 4-hydroxyoperimiphene and 4'-hydroxyoperimiphene have weak inhibitory effects on multiple CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2C8, and CYP2D6). In vitro human liver microsomal assays showed that operimiphene is mainly metabolized by CYP3A4, CYP2C9, and CYP2C19, with 4-hydroxyoperimiphene being the major metabolite. The apparent systemic clearance was calculated using a population approach of 9.16 L/hr.

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Biological Half-Life
Terminal half-life = 26 hours.
The apparent terminal half-life of ospermiphene in postmenopausal women is approximately 26 hours.

Toxicity Summary
Identification and Use: Osperimiphene (brand name: Osperimiphene) is a prescription drug approved for the treatment of moderate to severe dyspareunia, a symptom of vaginal and vulvar atrophy caused by menopause. Osperimiphene is an estrogen agonist/antagonist with tissue-selective action. Its biological action is mediated by binding to estrogen receptors. This binding results in the activation of estrogen pathways in some tissues (agonist effect) and the blockage of estrogen pathways in others (antagonist effect). Human Exposure and Toxicity: In epidemiological studies of osperimiphene, reported adverse events include hot flashes, single non-ST-segment elevation myocardial infarction, vaginal bleeding, endometrial thickening, vaginal discharge, muscle cramps, and hyperhidrosis. Osperimiphene has been reported to increase the risk of stroke, deep vein thrombosis (DVT), endometrial cancer, uterine cancer, and thromboembolic and hemorrhagic stroke. Animal Studies: In a two-year rat carcinogenicity study, the incidence of thymoma was significantly increased in both male and female rats. In the liver, the incidence of hepatocellular tumors was significantly increased in female rats. In a two-year carcinogenicity study in female mice, the incidence of both subcapsular adrenal adenomas and adrenocortical tumors was significantly increased. Researchers investigated the effects of operimiphene on prenatal and postnatal development in pregnant rats treated from implantation to lactation. Results showed significantly prolonged and difficult gestation in pregnant rats, increased post-implantation embryo loss, increased stillbirths, and increased postpartum mortality. In a similar rabbit study, the incidence of complete embryo resorption was also increased. In the in vitro Ames assay, operimiphene showed no genotoxicity against the thymidine kinase (tk) locus in either Salmonella typhimurium strains or mouse lymphoma L5178Y cells, regardless of the presence of metabolic activation systems. In in vivo, operimiphene showed no genotoxicity in the standard mouse bone marrow micronucleus assay or rat liver DNA adduct assay. Protein Binding: 99% binds to serum proteins. Interactions: Multiple enzyme inhibition: Concomitant use of opemiphene with drugs known to inhibit CYP3A4 and CYP2C9 isoenzymes may increase the risk of opemiphene-related adverse reactions. High Protein Binding Drugs: Opemiphene binds to serum proteins at a rate exceeding 99%, which may affect the protein binding of other drugs. Concomitant use of oxifene with other high protein binding drugs may increase exposure to these drugs or oxifene. Ketoconazole: Ketoconazole is a potent CYP3A4 inhibitor that can increase systemic exposure to oxifene by 1.4 times. Long-term use of ketoconazole and oxifene may increase the risk of oxifene-related adverse reactions. Rifampin: Rifampin is a potent CYP3A4/medium-potency CYP2C9/medium-potency CYP2C19 inducer that can reduce systemic exposure to oxifene by 58%. Therefore, concomitant use of oxifene with drugs that can induce CYP3A4, CYP2C9, and/or CYP2C19 activity, such as rifampin, is expected to reduce systemic exposure to oxifene, potentially thereby decreasing its clinical efficacy. For more complete (6 items) data on drug interactions with oxifene, please visit the HSDB record page.

Menopause.2013 Jun;20(6):623-30.

Ospemifen is an organochlorine compound, belonging to the class of selective estrogen receptor modulators, used to treat dyspareunia. It possesses estrogen receptor modulating, antitumor, and anti-inflammatory effects. Ospemifen is an organochlorine compound, an aromatic ether, and a primary alcohol, derived from the hydrogenated form of stilbene. Ospemifen is a novel selective non-hormonal estrogen receptor modulator (SERM) used to treat moderate to severe dyspareunia, a symptom of vaginal and vulvar atrophy associated with menopause. It was approved by the U.S. Food and Drug Administration (FDA) on February 26, 2013. Ospemifen is an estrogen agonist/antagonist. Its mechanism of action is as a selective estrogen receptor modulator.

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Drug Indications
Ospemifen 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 vulvovaginal atrophy (VVA) in postmenopausal women.

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Mechanism of Action
Ospemiphene is a new generation selective estrogen receptor modulator (SERM) that selectively binds to estrogen receptors and stimulates or blocks estrogen activity in different tissue types. It has an agonistic effect on the endometrium.
Ospemiphene is a tissue-selective estrogen agonist/antagonist. Its biological action is mediated by binding to estrogen receptors. This binding leads to the activation (agonistic effect) of estrogen pathways in some tissues and the blockage (antagonistic effect) of estrogen pathways in others.

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Therapeutic Use
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that includes human clinical studies funded by public and private institutions worldwide. This website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being studied); the title, description, and design of the study; participation requirements (eligibility criteria); the location where the study is conducted; contact information for the study location; and links to other relevant health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). Ospemifen is listed in the database. Ospemifen is indicated for the treatment of moderate to severe dyspareunia, a symptom of vaginal and vulvar atrophy caused by menopause. /Contains on US product label/

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Drug Warning
/Black Box Warning/ It has been reported that postmenopausal women (50 to 79 years of age) receiving daily oral conjugated estrogen (CE) (0.625 mg) monotherapy for 7.1 years have an increased risk of stroke and deep vein thrombosis (DVT) in the Women's Health Initiative (WHI). In clinical trials of Osphena (treatment duration up to 15 months), the incidence of thromboembolic stroke and hemorrhagic stroke was 0.72 and 1.45 per 1,000 women, respectively, in the Osphena 60 mg treatment group, compared to 1.04 and 0 per 1,000 women, respectively, in the placebo group. The incidence of deep vein thrombosis (DVT) was 1.45 per 1,000 women in the Osphena 60 mg treatment group, compared to 1.04 per 1,000 women in the placebo group. The duration of Osphena prescription should be as short as possible to align with treatment goals and individual woman risk. Osphena is a tissue-selective estrogen agonist/antagonist. In the endometrium, Osphena has estrogen-agonistic effects. For women with a uterus, estrogen alone increases the risk of endometrial cancer. Adding progesterone to estrogen therapy reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. For postmenopausal women experiencing unexplained, persistent, or recurrent abnormal vaginal bleeding, adequate diagnostic measures should be taken, including targeted and randomized endometrial sampling if necessary, to rule out malignancy. /Warning/ What is the most important information I should know about Osphena? Osphena is a medication that acts like estrogen in the uterine lining, but its effects may differ in other parts of the body. Taking estrogen or Osphena alone may increase the risk of endometrial cancer. Postmenopausal vaginal bleeding can be a warning sign of endometrial cancer. Your healthcare provider should examine for any unusual vaginal bleeding to determine the cause. If you experience any unusual vaginal bleeding while taking Osphena, inform your healthcare provider immediately. Osphena may increase your risk of stroke and blood clots. You and your healthcare provider should discuss periodically whether you still need to use Osphena for treatment. The pharmacokinetics of Osphena have not been studied in women with severe hepatic impairment (Child-Pugh C); therefore, Osphena should not be used in women with severe hepatic impairment.
For more complete (16) drug warnings for oxifene, please visit the HSDB record page.

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Pharmacodynamics
The half-maximal inhibitory concentrations (IC50) of estrogen receptor (ER) α and β are 0.8 μM and 1.7 μM, respectively. Osifene has potential use in the treatment of osteoporosis in postmenopausal women. It interacts with osteoblasts and osteoclasts, thereby reducing bone turnover. It also has potential use in the prevention of breast cancer. Studies have shown that oxifene reduces the incidence of tumors in a dose-dependent manner.

C24H23CLO2

378.89

378.138

128607-22-7

Ospemifene-d4

3036505

White to off-white solid powder

1.166±0.06 g/cm3

544.6±50.0 °C at 760 mmHg

283.2±30.1 °C

0.0±1.5 mmHg at 25°C

1.608

6.98

1

2

8

27

441

0

C1=CC=C(C=C1)/C(=C(/C2=CC=CC=C2)\C3=CC=C(C=C3)OCCO)/CCCl

LUMKNAVTFCDUIE-VHXPQNKSSA-N

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-

2-(p-((Z)-4-Chloro-1,2-diphenyl-1-butenyl)phenoxy)ethanol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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.

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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.

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 (Please use freshly prepared in vivo formulations for optimal results.)