Ospemifene

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.

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 micronucleu

/SIGNS AND SYMPTOMS/ 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.

/SIGNS AND SYMPTOMS/ 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.

/ALTERNATIVE and IN VITRO TESTS/ Ospemifene (FC-1271a) is a novel selective estrogen receptor modulator under development for osteoporosis prevention. In the present paper, we examine both the in vitro and in vivo effects of FC-1271a in breast cancer models. In vitro, the growth inhibitory effects of FC-1271a and its main metabolite are investigated in MCF-7 and MDA-MB-231 human breast cancer cells at doses ranging from 0.1 to 10 microM. Modulation of pS2 expression, an indicator of estrogen activity, was also examined in all experiments using reverse transcription-polymerase chain reaction. In vivo, the effects of treatment with 10, 25, 50, or 100 mg/kg FC-1271a on MCF-7 and MDA-MB-231 human tumor xenografts in athymic, ovariectomized mice were determined. For MCF-7 cells, FC-1271a and its main metabolite, toremifene VI (TOR VI) displayed anti-estrogenic effects in vitro as shown through growth inhibition and decreased expression of pS2. Treatment with FC-1271a in vivo inhibited MCF-7 tumor growth, compared with control (P< or =0.05). FC-1271a and TOR VI did not inhibit the growth of MDA-MB-231 cells in vitro, and no clear effects of FC-1271a treatment were seen on MDA-MB-231 tumor growth in vivo. In conclusion, FC-1271a appears to exert anti-estrogenic effects dependent on estrogen receptor positivity in vitro and in vivo on the growth of MCF-7 cells.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Ospemifene

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Acute Exposure/ To investigate the differential short-term effects of selective estrogen receptor (ER) modulators (SERMs) on uterus, we treated adult ovariectomized rats with a novel SERM, ospemifene (Osp), two previously established SERMs (tamoxifen and raloxifene (Ral)) and estradiol. The expression of two estrogen-regulated early response genes c-fos and vascular endothelial growth factor (VEGF), and DNA synthesis were analysed at 1-24 hrs after treatment of ovariectomized rats. Induction of c-fos mRNA by each of the SERMs showed a biphasic pattern with peaks at 3 and 20 hrs, respectively. The maximum level of VEGF mRNA was observed at 1 hrs after raloxifene and 6 hrs after tamoxifen or ospemifene treatment. Maximum levels of the c-fos and VEGF mRNA after raloxifene treatment were higher than those seen after treatments with E2 or a corresponding dose of tamoxifen or ospemifene. DNA synthesis was significantly increased by ospemifene, tamoxifen and raloxifene both in luminal and glandular epithelium. The stimulation was transient, peaking at 16 hrs. In comparison, the maximum level observed at 16 hrs after E2 treatment sustained at least until 24 hrs. DNA synthesis in stromal cells was increased by the SERMs but not by E2 at 24 hrs. When treated together with E2, the SERMs were able to antagonise E2-stimulated DNA synthesis at 16 hrs. Our results demonstrate that the initial response of uterus to ospemifene, raloxifene and tamoxifen includes activation of early response genes and even transient stimulation of DNA synthesis in spite of their different long-term effects. However, the early stimulatory events may be mediated by different mechanisms leading to diverging pathways in various tissue compartments and development of differential SERM-specific long-term responses of uterus.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ FC1271a is a novel triphenylethylene compound with a tissue-selective profile of estrogen agonistic and weak antagonistic effects. It specifically binds to the estrogen receptor alpha and beta with affinity closely similar to that of toremifene and tamoxifen. To study the in vivo effects of the compound, 4-month-old rats were sham operated (sham) or ovariectomized (OVX) and treated daily for 4 weeks with various doses of FC1271a or vehicle (orally). FC1271a was able to oppose OVX-induced bone loss by maintaining the trabecular bone volume of the distal femur. Accordingly, the OVX-induced loss of bone strength was prevented at doses of 1 and 10 mg/kg. FC1271a also prevented the OVX-induced increase in serum cholesterol in a dose-dependent manner. No significant changes in uterine wet weight or morphology were observed in the OVX-rats treated with 0.1 or 1 mg/kg FC1271a, but at a dose of 10 mg/kg it had a slightly estrogenic effect. In immature rats the effect of FC1271a on uterine wet weight was less stimulatory than that of toremifene or tamoxifen, but more stimulatory than that of raloxifene or droloxifene. The appearance of the dimethylbenzanthracene (DMBA)-induced mammary tumors was inhibited by treatment of DMBA-treated rats with FC1271a in a dose-dependent manner. In human MCF-7 breast cancer cell tumors raised in nude mice in the presence of estrogen, the growth and expression of pS2 marker gene could not be maintained after estrogen withdrawal by treatment with FC1271a. No formation of DNA adducts was observed in the liver of the FC1271a-treated rats. In conclusion, the bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.

Ospemifene has not been adequately studied in women with breast cancer. Therefore, it should not be used in women with known or suspected breast cancer or with a history of breast cancer.

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.

The drug also is contraindicated in women with active deep-vein thrombosis (DVT), pulmonary embolism (PE), active arterial thromboembolic disease (e.g., stroke, myocardial infarction (MI)), or history of these conditions.

Ospemifene is contraindicated in women with undiagnosed abnormal genital bleeding and in women with known or suspected estrogen-dependent neoplasia.

Ospemifene is contraindicated in women who are or may become pregnant.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ospemifene, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.