Ospemifene (Monograph)

Brand name: Osphena
Drug class: Estrogen Agonists-Antagonists
Chemical name: 2-[4-[(1Z)-4-Chloro-1,2-diphenyl-1-butenyl]phenoxy]-ethanol
Molecular formula: C₂₄H₂₃ClO₂
CAS number: 128607-22-7

Introduction

Tissue-selective, estrogen agonist-antagonist; triphenylethylene derivative.^{1 2 8 15 16}

Uses for Ospemifene

Dyspareunia

Treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, associated with menopause.^{1 3}

Ospemifene Dosage and Administration

General

• Has estrogen agonistic effects on endometrium; consider concomitant use of progestin therapy to reduce risk of endometrial cancer in postmenopausal women with an intact uterus.¹ (See GU Effects under Cautions.)

• Use for shortest duration consistent with treatment goals and risks for the individual woman.¹ Reevaluate patients periodically to determine if continued treatment is necessary.¹

Administration

Oral Administration

Administer orally with food.^{1 8}

Dosage

Adults

Dyspareunia

Oral

60 mg once daily.¹

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustments needed.¹

Severe hepatic impairment (Child-Pugh class C): Not studied; avoid use.¹ (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustments needed.¹

Cautions for Ospemifene

Contraindications

• Undiagnosed abnormal genital bleeding.¹

• Known or suspected estrogen-dependent neoplasia.¹

• Active DVT, PE, or history of these conditions.¹

• Active arterial thromboembolic disease (e.g., stroke, MI) or history of these conditions.¹

• Women who are or may become pregnant.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Warnings/Precautions

Warnings

Cardiovascular Effects

Increased risk of stroke and venous thromboembolism (VTE) observed in postmenopausal women receiving daily dosages of oral conjugated estrogen alone in Woman's Health Initiative (WHI) study.¹ Increased incidence of stroke and DVT also observed in women receiving ospemifene 60 mg daily compared with those receiving placebo.¹

Discontinue drug immediately if VTE, thromboembolic stroke, or hemorrhagic stroke occurs or is suspected.¹

Discontinue at least 4–6 weeks prior to surgery associated with increased risk of thromboembolism or during periods of prolonged immobilization, if possible.¹

Manage risk factors appropriately for cardiovascular disorders, arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, obesity), and/or VTE (e.g., personal or family history of VTE, obesity, systemic lupus erythematosus).¹

GU Effects

Increased risk of endometrial cancer reported in postmenopausal women with an intact uterus who use estrogen alone.^{1 9} Adding progestin to estrogen reduces risk of endometrial hyperplasia; other possible risks (e.g., breast cancer) associated with combined use of progestin and estrogen compared with estrogen therapy alone.¹ Concomitant use of progestin therapy with ospemifene not evaluated.¹

Endometrial cancer not reported in patients receiving ospemifene 60 mg daily (up to 52 weeks); one case of simple hyperplasia without atypia reported.^{1 2 4 5 6} Endometrial thickening, proliferative endometrium, and uterine polyps observed.¹

Clinical surveillance important for all women receiving ospemifene.¹ Rule out malignancy in postmenopausal women with undiagnosed persistent or recurrent abnormal genital bleeding.¹

Other Warnings/Precautions

Breast Cancer

Not adequately studied in women with breast cancer; do not use in women with known or suspected breast cancer or with history of breast cancer.¹

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; embryofetal deaths demonstrated in animals.¹ Reproductive effects consistent with estrogen-receptor activity of ospemifene.¹

If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹

Contraindicated in women who are or may become pregnant.¹

Specific Populations

Pregnancy

Category X.¹ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹

Pediatric Use

Not indicated in pediatric patients; not studied in this age group.¹

Geriatric Use

No substantial differences in safety and efficacy in women ≥65 years of age relative to younger women.¹

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustments needed.¹ (See Special Populations under Pharmacokinetics.)

Severe hepatic impairment (Child-Pugh class C): Not studied; do not use in such patients.¹

Renal Impairment

Dosage adjustment not required.¹

Common Adverse Effects

Hot flush, vaginal discharge, genital discharge, muscle spasms, hyperhidrosis.¹

Drug Interactions

Metabolized mainly in the liver by CYP isoenzymes 3A4 and 2C9; other CYP isoenzymes (2C19, 2B6) also involved in metabolism.^{1 10 11 12}

Weak inhibitor of CYP2B6, 2C9, 2C19, 2C8, 2D6, and 3A4 in vitro.^{1 11}

Not a clinically important substrate for P-glycoprotein (P-gp) transport system in vitro.¹

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors (potent or moderate) of CYP3A4, 2C9, and/or 2C19: Possible pharmacokinetic interaction (increased plasma concentrations and AUC of ospemifene).^{1 10 11 12} Concomitant use with drugs that inhibit both CYP3A4 and 2C9 may increase risk of ospemifene-related adverse reactions.¹

Inducers (potent or moderate) of CYP3A4, 2C9, and/or 2C19: Possible pharmacokinetic interaction (decreased plasma concentrations and AUC of ospemifene).¹ Concomitant use may decrease efficacy of ospemifene.¹

Substrates of CYP2B6, 2C9, 2C19, 2C8, 2D6, and 3A4: Clinically important pharmacokinetic interactions unlikely.^{1 11}

Protein-bound Drugs

Concomitant use with other highly protein-bound drugs may lead to increased exposure of ospemifene or the other drug.¹

Specific Drugs

Ospemifene Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability not evaluated; rapidly absorbed following oral administration.^{1 20}

Peak serum concentrations attained approximately 2.5 hours following administration of a single 60-mg dose with high-fat, high-calorie meal.¹

Food

Administration with food increases bioavailability twofold to threefold.¹

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B) does not substantially alter peak concentration and AUC.¹ Pharmacokinetics not studied in patients with severe hepatic impairment (Child-Pugh class C).¹ (See Hepatic Impairment under Cautions.)

Severe renal impairment (i.e., Cl_cr <30 mL/minute) does not substantially alter peak concentration and AUC.¹

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

>99%.¹

Elimination

Metabolism

Metabolized mainly in the liver by CYP isoenzymes 3A4 and 2C9; other isoenzymes (CYP2C19 and 2B6) also involved in metabolism.^{1 10 11 12} Major metabolite is 4-hydroxyospemifene.^{1 10 11 12}

Elimination Route

Excreted in feces (75%) and urine (7%).^{1 20}

Half-life

Approximately 26 hours.¹

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).¹

Actions

• Tissue-selective, estrogen agonist-antagonist;^{1 2} also referred to as a selective estrogen receptor modulator (SERM).^{3 4 7 14 15}

• Binds to estrogen receptor (ER)α and ERβ; stronger binding occurs at ERα receptor.¹⁶

• Activates estrogenic pathways in some tissues and blocks estrogenic pathways in other tissues.¹

• Exhibits strong estrogenic effects on vaginal epithelium (e.g., improvements in maturation index, vaginal pH, symptoms of menopause [e.g., dyspareunia, vaginal dryness]).^{2 4 5 9 15 17}

• In animal studies, estrogenic effects on bone observed.¹⁹ In healthy postmenopausal women, reduced biochemical markers of bone turnover observed.^{15 18} Further studies needed to evaluate effects on bone mineral density (BMD) and fracture risk.¹⁵

• No substantial effects on serum lipoprotein concentrations (i.e., total, LDL-, or HDL-cholesterol; triglycerides).^{14 17}

• Weak estrogenic effects on endometrial tissue;^{8 9 15} slight dose-related mean increase in endometrial thickness, but no cases of endometrial cancer observed.^{2 6 7 15} (See GU Effects under Cautions.)

• Preclinical data show possible antiestrogenic activity in several breast cancer models; such effects not assessed in clinical trials.^{3 15 16 21} (See Breast Cancer under Cautions.)

Advice to Patients

• Importance of instructing patients to read the manufacturer's patient information prior to initiation of therapy and each time the prescription is refilled.¹

• Importance of advising patients that ospemifene may initiate or increase occurrence of hot flushes in some women.¹

• Importance of reporting any unusual vaginal bleeding to a clinician as soon as possible.¹

• Importance of informing a clinician of any current or previous occurrence of cancer, VTE, stroke, or MI.¹

• Importance of informing a clinician of any impending surgery or prolonged bed rest.¹

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹ Advise pregnant women of risk to fetus.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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