CONTRAINDICATIONS

• Undiagnosed abnormal genital bleeding
• Known or suspected estrogen-dependent neoplasia
• Active deep vein thrombosis (DVT), pulmonary embolism (PE) or a history of these conditions
• Active arterial thromboembolic disease (e.g., stroke and myocardial infarction) or a history of these conditions
• Hypersensitivity (for example, angioedema, urticaria, rash, pruritus) to OSPHENA or any of its 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. 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.

WARNINGS AND PRECAUTIONS

Cardiovascular Disorders

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. Should thromboembolic or hemorrhagic stroke occur or be suspected, OSPHENA should be discontinued immediately.

In the OSPHENA clinical trials, two cases of myocardial infarctions (MI) occurred in women receiving 60 mg of ospemifene.

In the OSPHENA clinical trials, two cases of DVT occurred in women receiving OSPHENA 60 mg. 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.

Malignant Neoplasms

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 greatest risk appears to be associated with prolonged use and estrogen dose. 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 with OSPHENA therapy was not evaluated in the clinical trials.

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.

Severe Hepatic Impairment

OSPHENA should not be used in women with severe hepatic impairment.

In clinical trials, the more commonly reported adverse reactions in ≥1 percent of patients treated with OSPHENA 60 mg compared to placebo were:

1. In 12-week, double blind, placebo-controlled clinical trials were hot flush (6.5% vs. 2.6%), vaginal discharge (3.8% vs. 0.4%), muscle spasms (1.8% vs. 0.6%) and hyperhidrosis (1.1% vs. 0.2%)
2. In all clinical trials up to 52-weeks (safety population) were headaches (2.8% vs. 2.4%), hot flush (12.2% vs. 4.2%), muscle spasms (4.5% vs. 2.4%), hyperhidrosis (2.5% vs. 1.8%), night sweats (1.2% vs. 0.0%), vaginal discharge (6.00% vs. 0.6%) and vaginal hemorrhage (1.3% vs. 0.0%).

The following adverse reactions have been identified during post-approval use of ospemifene:

• Neoplasms Benign, Malignant and Unspecified (including 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

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 agonists/antagonists, fluconazole, ketoconazole or rifampin concomitantly with OSPHENA. Co-administration of OSPHENA with drugs that inhibit CYP3A4 and CYP2C9 may increase the risk of OSPHENA-related adverse reactions. OSPHENA is highly protein bound. Use cautiously with highly protein bound drugs as use with other highly protein-bound drugs may lead to increase exposure of that drug or ospemifene.

Please see Full Prescribing Information for OSPHENA (ospemifene) tablets, including Boxed Warning, regarding Endometrial Cancer and Cardiovascular Disorders, and Patient Information at osphena.com/hcp.