Osphena

1 INDICATIONS AND USAGE OSPHENA is indicated for: 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. ( 1.1 ) The treatment of moderate to severe vaginal dryness, a symptom of vulvar and vaginal atrophy, due to menopause. ( 1.2 ) 1.1 The Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause. 1.2 The Treatment of Moderate to Severe Vaginal Dryness, a Symptom of Vulvar and Vaginal Atrophy, due to Menopause.

2 DOSAGE AND ADMINISTRATION OSPHENA is an estrogen agonist/antagonist which has agonistic effects on the endometrium [see Warnings and Precautions (5.2) ]. Use OSPHENA for the shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate postmenopausal women periodically as clinically appropriate to determine if treatment is still necessary. One tablet taken orally once daily with food. ( 2.1 , 2.2 ) 2.1 Treatment of Moderate to Severe Dyspareunia, a Symptom of Vulvar and Vaginal Atrophy, Due to Menopause One 60 mg tablet taken orally with food once daily. 2.2 Treatment of Moderate to Severe Vaginal Dryness, a Symptom of Vulvar and Vaginal Atrophy, Due to Menopause One 60 mg tablet taken orally with food once daily.

5 WARNINGS AND PRECAUTIONS Venous Thromboembolism: Risk of DVT and PE ( 5.1 ) Known, suspected, or history of breast cancer ( 5.2 ) Severe Hepatic Impairment ( 5.3 , 8.7 , 12.3 ) 5.1 Cardiovascular Disorders Manage appropriately any 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). Stroke In the clinical trials for OSPHENA (duration of treatment up to 15 months), the incidence rates of thromboembolic and hemorrhagic stroke were 1.13 and 3.39 per thousand women years, respectively in OSPHENA 60 mg treatment group and 3.15 and 0 per thousand women years in placebo. Immediately discontinue OSPHENA if a thromboembolic or hemorrhagic stroke occurs or is suspected. The WHI estrogen-alone substudy reported a statistically significant increased risk of stroke 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 strokes per ten thousand women years, respectively). The increase in risk was demonstrated in year 1 and persisted. Coronary Heart Disease Two cases of myocardial infarction (MI) occurred in women receiving 60 mg of ospemifene in the OSPHENA clinical trials. The WHI estrogen-alone substudy reported no overall effect on coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving estrogen-alone compared to placebo. Venous Thromboembolism Two cases of DVT occurred in women receiving OSPHENA 60 mg in the OSPHENA clinical trials. Immediately discontinue OSPHENA if a VTE occurs or is suspected. If feasible, discontinue OSPHENA at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 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. 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 up to 52 weeks treatment groups at a rate of 101.4 per thousand women vs. 20.9 per thousand women for placebo. The incidence of any type of proliferative (weakly plus active plus disordered) endometrium was 26.3 per thousand women in the OSPHENA up to 52 weeks treatment groups vs. 0 per thousand women for placebo. Uterine polyps occurred at an incidence of 19.6 per thousand women in the OSPHENA up to 52 weeks treatment groups vs. 8.3 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 endome…

4 CONTRAINDICATIONS OSPHENA is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding. Estrogen-dependent neoplasia. Active DVT, PE, or a history of these conditions. Active arterial thromboembolic disease (for example, stroke and 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/m 2 . 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 ) 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 )

7 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 Do not use OSPHENA 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 Do not use OSPHENA concomitantly with fluconazole, a moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor. 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.

8.1 Pregnancy Risk Summary Not Recommended During Pregnancy OSPHENA is contraindicated in women who are or may become pregnant. 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 [see Contraindications (4) ]. 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data The effects of ospemifene 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 [Gestation Day (GD) 6-16 in the rat and GD6-18 in the rabbit. In rabbits, there was an increase in the incidence of total resorptions at 30 mg/kg/day (10 times the human exposure based on body surface area mg/m 2 )]. Drug-induced malformations were not observed in either rats or rabbits. The effects of ospemifene on pre- and postnatal development were studied in pregnant rats (0.01, 0.05, and 0.25 mg/kg/day) treated from implantation (GD6) through lactation (Lactation Day (LD) 21). Pregnant rats given 0.05 or 0.25 mg/kg/day ospemifene (0.8% to 4% the human exposure based on body surface area mg/m 2 ) 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. Ospemifene did not induce adverse effects in the surviving offspring of pregnant rats at drug exposures up to 4% the human exposure.

6 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) ] The most common adverse reactions (≥1 percent) with OSPHENA are: hot flush, vaginal discharge, muscle spasms, headache, hyperhidrosis, vaginal hemorrhage, night sweats. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Duchesnay 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 ten phase 2/3 trials (N=2209) with doses ranging from 5 to 90 mg per day. The duration of treatment in these studies ranged from 6 weeks to 15 months. The majority of women (N=1683) had treatment exposure up to 12 weeks; 847 had up to 52 weeks (1 year) of exposure. The incidence rates of thromboembolic and hemorrhagic stroke were 1.13 per thousand women years (1 reported case of thromboembolic stroke) and 3.39 per thousand women years (3 reported cases of hemorrhagic stroke), respectively in OSPHENA 60 mg treatment group and 3.15 (1 case of thromboembolic stroke) and 0 per thousand women years, respectively in placebo. There were 2 reported cases of DVT among the 1459 women in the OSPHENA 60 mg treatment group and 1 case of DVT among the 1136 women in the placebo group. Table 1 lists adverse reactions occurring more frequently in the OSPHENA 60 mg treatment group than in placebo and at a frequency ≥1% in the 12-week, double-blind, placebo-controlled clinical trials. Table 2 lists adverse reactions occurring more frequently in the OSPHENA 60 mg treatment group than in placebo and at a frequency ≥1% in all clinical trials up to 52-weeks. Table 1: Adverse Reactions Reported More Commonly in the OSPHENA Treatment Group (60 mg Once Daily) and at Frequency ≥1.0% in the 12 Week Double-Blind, Controlled Clinical Trials with OSPHENA vs. Placebo Ospemifene 60 mg (N=1459) % Placebo (N=1136) % Vascular Disorders Hot flush 6.5 2.6 Reproductive System and Breast Disorders Vaginal discharge 3.8 0.4 Musculoskeletal and Connective Tissue Disorders Muscle spasms 1.8 0.6 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 1.1 0.2 Table 2: Adverse Reactions Reported More Commonly in the OSPHENA Treatment Group (60 mg Once Daily) and at Frequency ≥1.0% in All Clinical Trials up to 52 Weeks (Safety Population) Ospemifene 60 mg All Trials (N=847) % Placebo (N=165) % Nervous System Disorders Headaches 2.8 2.4 Vascular Disorders Hot flush 12.2 4.2 Musculoskeletal and Connective Tissue Disorders Muscle spasms 4.5 2.4 Skin and Subcutaneous Tissue Disorders Hyperhidrosis 2.5 1.8 Night sweats 1.2 0.0 Reproductive System and Breast Disorders Vaginal discharge 6.0 0.6 Vaginal hemorrhage 1.3 0.0 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. Neoplasms Benign, Malignant and Unspecified (incl. cysts and polyps): endometrial hyperplasia, endometrial cancer Immune System Disorders: allergic conditions including hypersensitivity, angioedema Nervous System Disorders: headache Vascular Disorders: deep vein thrombosis, thrombosis, pulmonary embolism Skin and Subcutaneous Tissue Disorders: rash, rash erythematous, rash generalized, pruritus, urticaria