Important Safety Information for Osphena®
WARNING: Endometrial Cancer and Cardiovascular Disorders
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 estrogen therapy. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. 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.
The Women’s Health Initiative (WHI) estrogen-alone sub study reported an increased risk of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg], relative to placebo. Osphena® 60 mg had thromboembolic and hemorrhagic stroke incidence rates of 0.72 and 1.45 per thousand women vs. 1.04 and 0 per thousand women for placebo and a DVT incidence rate of 1.45 vs. 1.04 per thousand women for placebo. Osphena® should be prescribed for the shortest duration consistent with treatment goals and risks for the individual woman.
- 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 (for example, stroke and myocardial infarction), or a history of these conditions
- Hypersensitivity (for example, angioedema, urticaria, rash, pruritus) to Osphena® or any of its ingredients
- 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.
Warnings and Precautions
In Osphena® clinical trials of up to 15 months, the incidence rates compared to placebo for thromboembolic and hemorrhagic stroke were 0.72 Osphena® 60 mg vs. 1.04 placebo and 1.45 Osphena® 60 mg vs. 0 placebo per thousand women. Should thromboembolic or hemorrhagic stroke occur or be suspected, Osphena® should be discontinued immediately. In clinical trials, a single MI occurred in a woman receiving Osphena® 60 mg.
Incidence rate of DVT was 1.45 Osphena® vs. 1.04 placebo per thousand women. Should a VTE occur or be suspected, Osphena® should be discontinued immediately. Osphena® should be discontinued at least 4 to 6 weeks before surgery with increased risk of thromboembolism or during periods of prolonged immobilization.
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogen therapy. The risk appears dependent on duration of treatment and estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. However, studies suggest a possible increased risk for breast cancer in patients receiving estrogen plus progestin therapy.
Osphena® is an estrogen agonist/antagonist with tissue selective effects. In the endometrium, Osphena® has agonistic effects. In Osphena® clinical trials, 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 5mm or greater was reported at a rate of 60.1 Osphena® vs. 21.2 placebo per 1000 women. Uterine polyps occurred at an incidence of 5.9 Osphena® vs. 1.8 placebo per 1000 women, and any type of proliferative endometrium (weakly plus active plus disordered) was 86.1 Osphena® vs. 13.3 placebo per 1000 women.
Osphena® 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.
Osphena® should not be used in women with severe hepatic impairment as it has not been studied.
In clinical trials the more commonly reported adverse reactions in ≥1 percent of patients treated with Osphena® 60 mg compared to placebo were: hot flush (7.5% vs. 2.6%), vaginal discharge (3.8% vs. 0.3%), muscle spasms (3.2% vs. 0.9%), hyperhidrosis (1.6% vs. 0.6%), and genital discharge (1.3% vs. 0.1%).
The following adverse reactions have been identified during post-approval use of ospemifene:
Immune System Disorders: allergic conditions including hypersensitivity, angioedema.
Nervous System Disorders: headache
Skin and Subcutaneous Tissue Disorders: rash, rash erythematous, rash generalized, pruritus, urticaria.
Drug interactions: Do not use estrogens or estrogen agonists/antagonists, fluconazole, 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.
Osphena® (ospemifene) is indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.