OSPHENA

1 Dosing Considerations The following situations may affect dosing of Osphena:  Concomitant use of ospemifene with estrogens, estrogen agonist/antagonist, fluconazole, rifampin, ketoconazole, highly protein-bound drugs and drugs known to inhibit CYP3A4 and CYP2C9 (see Drug Interactions, Drug-Drug Interactions section).

 Use of Osphena should be for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary.

 Osphena patients have significantly greater adherence and persistence compared with non-ring local estrogen therapies (LETs). 2 Recommended Dose and Dosage Adjustment One Osphena (ospemifene) 60 mg tablet with food once daily. No dose adjustment is required in women with any severity of renal impairment.

No dose adjustment is required with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment (see Warnings and Precautions section). Osphena should not be used in women with severe hepatic impairment (see Warnings and Precautions section).

Osphena is indicated for use in postmenopausal women. Osphena is not intended for use in children. Health Canada has not authorized an indication for pediatric use. 4 Administration Osphena (ospemifene) should be consistently taken orally with food, as the presence or absence of food may alter bioavailability.

5 Missed Dose In the event that a dose is missed, the next dose should be taken as soon as possible. If it is almost time for the next dose, the missed dose should be skipped and the next dose should be taken as planned. Doses should not be doubled to make up for a missed dose.

The prescribed dosing schedule should be continued.

1 Adverse Reaction Overview The following serious adverse reactions are discussed elsewhere in the Product Monograph:  Cardiovascular Disorders (see Warnings and Precautions, Cardiovascular section);  Malignant Neoplasms (see Warnings and Precautions, Carcinogenesis and Mutagenesis section); The most frequent adverse reactions that occurred in patients treated with Osphena 60 mg once daily in the 12-week double-blind, placebo-controlled clinical trials were hot flush, hyperhidrosis, muscle spasms and vaginal discharge (see Table 2).

Pooled analysis of hot flush treatment-emergent adverse events (TEAEs) found that the frequency of hot flushes declined after 4 weeks of ospemifene treatment. 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions.

The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating drug-related adverse events and for approximating rates.

The safety of Osphena has been assessed in ten (10) Phase II/III 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. Most women (n=1683) had a treatment period of at least 12 weeks, 432 had at least 52 weeks (1 year) of exposure.

The long-term safety in patients that had at least 52 weeks of exposure is similar to those listed in Table 2. 15 (1 case of thromboembolic stroke) and 0 per thousand women years, respectively in placebo. 15 (1 case of DVT) in placebo.

The incidence of pulmonary embolism was 0 per thousand women years in the Osphena 60 mg and placebo treatment groups. Table 2 below lists adverse reactions occurring more frequently in the Osphena 60 mg treatment group than in placebo and at a frequency ≥1%.

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General Carcinogenesis and Mutagenesis Endometrial Cancer:

Osphena (ospemifene tablets) is an estrogen receptor agonist/antagonist with tissue selective effects. In the endometrium, Osphena has weak 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. 5 per thousand women vs. 8 per thousand women for placebo. 3 per thousand women in the Osphena > 52 weeks treatment groups vs. 0 per thousand women for placebo. 9 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. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated. 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.

Osphena is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see Dosage Forms, Strengths, Composition and Packaging.

Osphena is contraindicated in women with any of the following conditions:  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 (MI)], or a history of these conditions  Severe hepatic impairment (see Warnings and Precautions section)  Women who are or may become pregnant.

Ospemifene 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 (see Warnings and Precautions, Special Populations section).  Hypersensitivity (for example, angioedema, urticaria, rash, pruritus) <OSPHENA>< ospemifene tablets > Product Monograph Page 5 of 33