This information is not for clinical use. These highlights do not include all the information needed to use Osphena safely and effectively. Before taking Osphena please consult with your doctor. See full prescribing information for Osphena.

Warning

WARNING: ENDOMETRIAL CANCER AND CARDIOVASCULAR DISORDERS Endometrial Cancer 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 [see Warnings and Precautions (5.2)]. Cardiovascular Disorders 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) [see Warnings and Precautions (5.1)]. 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 [see Warnings and Precautions (5.1)]. The incidence of DVT was 1.45 per thousand women in OSPHENA 60 mg treatment group and 1.04 per thousand women in placebo [see Warnings and Precautions (5.1)]. OSPHENA should be prescribed for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: ENDOMETRIAL CANCER AND CARDIOVASCULAR DISORDERS See full prescribing information for complete boxed 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 [see Warnings and Precautions (5.2)]. Estrogen-alone therapy has an increased risk of stroke and deep vein thrombosis (DVT). OSPHENA 60 mg had cerebral thromboembolic and hemorrhagic stroke incidence rates of 0.72 and 1.45 per thousand women, respectively vs. 1.04 and 0 per thousand women, respectively in placebo. For deep vein thrombosis, the incidence rate for OSPHENA 60 mg is 1.45 per thousand women vs. 1.04 per thousand women in placebo [see Warnings and Precautions (5.1)].

Recent Changes

CONTRAINDICATIONS (4) 02/2015

Indications And Usage

OSPHENA is indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause. OSPHENA is an estrogen agonist/antagonist indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause (1)

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Dosage Forms And Strengths

OSPHENA tablets are white to off-white, oval, biconvex, film coated tablets containing 60 mg of ospemifene and engraved with "60" on one side. Tablet: 60 mg (3)

Contraindications

OSPHENA is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding Known or suspected estrogen-dependent neoplasia Active DVT, pulmonary embolism (PE), or a history of these conditions Active arterial thromboembolic disease [for example, stroke and myocardial infarctions (MI)], or a history of these conditions Hypersensitivity (for example, angioedema, urticaria, rash, pruritus) to OSPHENA or any ingredients OSPHENA is contraindicated in women who are or may become pregnant. OSPHENA may cause fetal harm when administered to a pregnant woman. Ospemifene was embryo-fetal lethal with labor difficulties and increased pup deaths in rats at doses below clinical exposures, and embryo-fetal lethal in rabbits at 10 times the clinical exposure based on mg/m2. If this drug is used during pregnancy, or if a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to a fetus Undiagnosed abnormal genital bleeding (4) Known or suspected estrogen-dependent neoplasia (4, 5.2) Active DVT, pulmonary embolism (PE), or a history of these conditions (4, 5.1) Active arterial thromboembolic disease (for example, stroke and myocardial infarction [MI]), or a history of these conditions (4, 5.1) Hypersensitivity (for example, angioedema, urticaria, rash, pruritus) to OSPHENA or any ingredients (4) Known or suspected pregnancy (4, 8.1)

Warning and Cautions

Venous Thromboembolism: Risk of DVT and pulmonary embolism (5.1) Known, suspected, or history of breast cancer (5.2) Severe Hepatic Impairment (5.3, 8.7, 12.3) 5.1 Cardiovascular Disorders Risk factors for cardiovascular disorders, arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus), should be managed appropriately. Stroke In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per ten thousand women-years). The increase in risk was demonstrated in year 1 and persisted. 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 per thousand women in placebo. Should thromboembolic or hemorrhagic stroke occur or be suspected, OSPHENA should be discontinued immediately. Coronary Heart Disease In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) was reported in women receiving estrogen-alone compared to placebo. In the OSPHENA clinical trials, a single MI occurred in a woman receiving 60 mg of ospemifene. Venous Thromboembolism In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE), was increased for women receiving daily CE (0.625 mg)-alone compared to placebo (30 versus 22 per ten thousand women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per ten thousand women-years). The increase in VTE risk was demonstrated during the first 2 years. In the OSPHENA clinical trials, the incidence of DVT was 1.45 per thousand women in OSPHENA 60 mg treatment group and 1.04 per thousand women in placebo. Should a VTE occur or be suspected, OSPHENA should be discontinued immediately. If feasible, OSPHENA should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 5.2 Malignant Neoplasms Endometrial Cancer OSPHENA is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, OSPHENA has agonistic effects. In the OSPHENA clinical trials (60 mg treatment group), no cases of endometrial cancer were seen with exposure up to 52 weeks. There was a single case of simple hyperplasia without atypia. Endometrial thickening equal to 5 mm or greater was seen in the OSPHENA treatment groups at a rate of 60.1 per thousand women vs. 21.2 per thousand women for placebo. The incidence of any type of proliferative (weakly plus active plus disordered) endometrium was 86.1 per thousand women in OSPHENA vs. 13.3 per thousand women for placebo. Uterine polyps occurred at an incidence of 5.9 per thousand women vs. 1.8 per thousand women for placebo. An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than 1 year. The greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Adding a progestin to postmenopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer. The use of progestins with OSPHENA therapy was not evaluated in the clinical trials. Clinical surveillance of all women using OSPHENA is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Breast Cancer OSPHENA 60 mg 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. 5.3 Severe Hepatic Impairment OSPHENA should not be used in women with severe hepatic impairment [see Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

Adverse Reactions

The following serious adverse reactions are discussed elsewhere in the labeling: Cardiovascular Disorders [see Boxed Warning, Warnings and Precautions (5.1)] Malignant Neoplasms [see Boxed Warning, Warnings and Precautions (5.2)] Adverse reactions (≥1 percent) include: hot flush, vaginal discharge, muscle spasms, genital discharge, hyperhidrosis. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Shionogi Inc. at 1-855-OSPHENA (1-855-677-4362) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of OSPHENA has been assessed in nine phase 2/3 trials (N=1892) with doses ranging from 5 to 90 mg per day. The duration of treatment in these studies ranged from 6 weeks to 15 months. Most women (N=1370) had a treatment period of at least 12 weeks, 409 had at least 52 weeks (1 year) of exposure. The incidence rates of thromboembolic and hemorrhagic stroke were 0.72 per thousand women (1 reported case of thromboembolic stroke) and 1.45 per thousand women (2 reported cases of hemorrhagic stroke), respectively in OSPHENA 60 mg treatment group and 1.04 and 0 per thousand women, respectively in placebo. The incidence of deep vein thrombosis (DVT) was 1.45 per thousand women in OSPHENA 60 mg treatment group (2 reported cases of DVT) and 1.04 (1 case of DVT) in placebo. Table 1 lists adverse reactions occurring more frequently in the OSPHENA 60 mg treatment group than in placebo and at a frequency ≥1%. Table 1: Adverse Reactions Reported More Common in the OSPHENA Treatment Group (60 mg Once Daily) and at Frequency ≥1.0% in the Double-Blind, Controlled Clinical Trials with OSPHENA vs. Placebo Ospemifene 60 mg (N=1242) % Placebo (N=958) % Vascular Disorders Hot flush 7.5 2.6 Reproductive System and Breast Disorders Vaginal discharge 3.8 0.3 Genital discharge 1.3 0.1 Musculoskeletal and Connective Tissue Disorders Muscle spasms 3.2 0.9 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 1.6 0.6 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ospemifene. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: allergic conditions including hypersensitivity, angioedema Skin and Subcutaneous Tissue Disorders: rash, rash erythematous, rash generalized, pruritus, urticaria

Drug Interactions

OSPHENA is primarily metabolized by CYP3A4 and CYP2C9. CYP2C19 and other pathways contribute to the metabolism of ospemifene. Do not use estrogens or estrogen agonist/antagonist concomitantly with OSPHENA (7.1,12.3) Do not use fluconazole concomitantly with OSPHENA. Fluconazole increases serum concentrations of OSPHENA (7.2, 12.3) Do not use rifampin concomitantly with OSPHENA. Rifampin decreases serum concentration of OSPHENA (7.2, 12.3) 7.1 Estrogens and estrogen agonist/antagonist OSPHENA should not be used concomitantly with estrogens and estrogen agonists/antagonists. The safety of concomitant use of OSPHENA with estrogens and estrogen agonists/antagonists has not been studied. 7.2 Fluconazole Fluconazole, a moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor, should not be used with OSPHENA. Fluconazole increases the systemic exposure of ospemifene by 2.7-fold. Administration of fluconazole with ospemifene may increase the risk of OSPHENA-related adverse reactions [see Clinical Pharmacology (12.3)]. 7.3 Rifampin 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 [see Clinical Pharmacology (12.3)]. 7.4 Ketoconazole 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 [see Clinical Pharmacology (12.3)]. 7.5 Warfarin Repeated administration of ospemifene had no effect on the pharmacokinetics of a single 10 mg dose of warfarin. No study was conducted with multiple doses of warfarin. The effect of ospemifene on clotting time such as the International Normalized Ratio (INR) or prothrombin time (PT) was not studied [see Clinical Pharmacology (12.3)]. 7.6 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 [see Clinical Pharmacology (12.3)]. 7.7 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.

Use In Specific Populations

Nursing Mothers: It is not known whether OSPHENA is excreted in human breast milk (8.3) 8.1 Pregnancy Teratogenic effects: Pregnancy Category X [see Contraindications (4)]. Risk Summary Based on animal data, OSPHENA is likely to increase the risk of adverse outcomes during pregnancy and labor. Adverse findings at maternally toxic doses included embryofetal lethality in rats and rabbits, and neonatal mortality and difficult labor in rats. The reproductive effects observed are consistent with and are considered to be related to estrogen receptor activity of OSPHENA. Animal Data The effects of OSPHENA on embryo-fetal development were studied in rats (0.1, 1 or 4 mg/kg/day) and rabbits (3, 10, or 30 mg/kg/day) when treated from implantation through organogenesis. In rabbits, there was an increase in the incidence of total resorptions at 30 mg/kg/day (10 times the human exposure based on surface area mg/m2). Drug-induced malformations were not observed in either rats or rabbits. The effects of OSPHENA on pre-and postnatal development were studied in pregnant rats (0.01, 0.05, and 0.25 mg/kg/day) treated from implantation through lactation. Pregnant rats given 0.05 or 0.25 mg/kg/day OSPHENA (0.8% to 4% the human exposure based on surface area mg/m2), 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. OSPHENA did not induce adverse effects in the surviving offspring of pregnant rats at drug exposures up to 4% the human exposure. 8.3 Nursing Mothers 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. 8.4 Pediatric Use OSPHENA is not indicated in children. Clinical studies have not been conducted in the pediatric population. 8.5 Geriatric Use Of the 1892 OSPHENA-treated women enrolled in the nine phase 2/3 trials of OSPHENA, >19 percent were 65 years of age or older. No clinically meaningful differences in safety or effectiveness were observed between these women and younger women less than 65 years of age. 8.6 Renal Impairment The pharmacokinetics of ospemifene in women with severe renal impairment (CrCL <30 mL/min) was similar to those in women with normal renal function [see Clinical Pharmacology (12.3)]. No dose adjustment of OSPHENA is required in women with renal impairment. 8.7 Hepatic Impairment 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 [see Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)]. No clinically important pharmacokinetic differences with OSPHENA were observed between women with mild to moderate hepatic impairment and healthy women [see Clinical Pharmacology (12.3)]. No dose adjustment of OSPHENA is required in women with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment.