ospemifene (Rx)

1-10%

Hot flush (7.5%)

Vaginal discharge (3.8%)

Muscle spasms (3.2%)

Hyperhidrosis (1.6%)

Genital discharge (1.3%)

Postmarketing reports

Hypersensitivity

Angioedema

Rash

Rash, erythematous

Generalized rash

Pruritus

Urticaria

Neoplasms: Benign, malignant and unspecified, endometrial hyperplasia, endometrial cancer

Vascular disorders: Deep vein thrombosis, thrombosis, pulmonary embolism

Contraindications

Undiagnosed abnormal genital bleeding

Known or suspected estrogen-dependent neoplasia

History of, or active DVT or PE

History of, or active arterial thromboembolic disease (eg, stroke, MI)

Known or suspected pregnancy or women who may become pregnant

Documented hypersensitivity to drug or ingredients

Cautions

Manage risk factors for cardiovascular disorders, arterial vascular disease (eg, hypertension, DM, smoking, hypercholesterolemia, obesity), and/or venous thromboembolism to reduce risk for progression to serious disease

Increased risk for endometrial hyperplasia (see Black Box Warnings)

Has not been studied in women with breast cancer; do not use with known or suspected breast cancer or history of breast cancer

Do not use with severe hepatic impairment (not studied)

Ospemifene is primarily metabolized by CYP3A4 and CYP2C9; CYP2C19 also contributes to its metabolism; avoid moderate-to-strong inhibitors of these isoenzymes as they may increase risk of adverse effects

May initiate or increase occurrence of hot flashes in some women

Pregnancy

Contraindicated in women who are or may become pregnant; if a woman becomes pregnant while taking this drug, she should be apprised of the potential hazard to a fetus

Based on animal data, ospemifene is likely to increase risk for 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

Reproductive effects observed are consistent with, and are considered to be related to ospemifene’s estrogen receptor activity

Lactation

Unknown if excreted in human breast milk

Do not breastfeed

Animal studies

• Excreted in rat milk and detected at concentrations higher than that in maternal plasma

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Estrogen agonist/antagonist with tissue selective effects; its biological actions are mediated through binding to estrogen receptors resulting in activation of estrogenic pathways in some tissues and blockade in others

Absorption

Peak plasma time: 2 hr (fasted); 2.5 hr (high fat/high calorie meal)

Peak plasma concentration: 533 ng/mL (fasted); 1198 ng/mL (high fat/high calorie meal)

AUC: 4165 ng•h/mL (fasted); 7521 ng•h/mL (high fat/high calorie meal)

Distribution

Protein bound: >99%

Vd: 448 L

Metabolism

Metabolized by CYP3A4, CYP2C9, and CYP2C19

Elimination

Half-life: 26 hr

Total body clearance: 9.16 L/hr

Excretion: 75% feces, 7% urine

Oral Administration

Take with food; food increases bioavailability by ~2-3 fold