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Osphena

Generic Name: Ospemifene
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

Warning(s)

  • Has estrogen agonistic effects on endometrium.1 Increased risk of endometrial cancer in postmenopausal women with an intact uterus who use estrogens alone.1 (See GU Effects under Cautions.)

  • Increased risk of stroke and DVT observed in postmenopausal women receiving daily dosages of oral conjugated estrogens alone as part of Woman's Health Initiative (WHI) study.1 (See Contraindications and Cardiovascular Effects under Cautions.)

  • Prescribe for shortest duration consistent with treatment goals and risks for the individual woman.1

Introduction

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

Uses for Osphena

Dyspareunia

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

Slideshow: Flashback: FDA Drug Approvals 2013

Osphena 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 Osphena

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

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

Drug

Interaction

Comments

Antifungals, azoles (e.g., fluconazole, ketoconazole)

Increased ospemifene exposure; may increase risk of ospemifene-related adverse reactions1 12

Fluconazole: Avoid concomitant use1 12

Ketoconazole: Use concomitantly with caution12

Antimycobacterials, rifamycins (e.g., rifampin)

Rifampin: Decreased ospemifene exposure; may decrease efficacy of ospemifene1 12

Bupropion

No clinically important effects on bupropion pharmacokinetics1 11 12

Estrogen and estrogen agonist-antagonists

Safety of concomitant use not studied1

Avoid concomitant use1

Proton-pump Inhibitors (e.g., omeprazole)

Omeprazole: No clinically important effects on omeprazole pharmacokinetics; slight increase in ospemifene exposure1 11 12

Quinidine

No clinically important effects on ospemifene pharmacokinetics12

Warfarin

No clinically important effects on warfarin pharmacokinetics following single 10-mg dose of warfarin1 11

Effects on PT and INR not studied1

Osphena 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., Clcr <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.

Ospemifene

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

60 mg

Osphena

Shionogi

AHFS Drug Information. © Copyright, 1959-2014, Selected Revisions May 21, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Shionogi Inc. OSPHENA (ospemifene) prescribing information. Florham Park, NJ; 2013 Feb.

2. Goldstein SR, Bachmann GA, Koninckx PR et al. Ospemifene 12-month safety and efficacy in postmenopausal women with vulvar and vaginal atrophy. Climacteric. 2013; :. [PubMed 23984673]

3. . Management of symptomatic vulvovaginal atrophy: 2013 position statement of The North American Menopause Society. Menopause. 2013; 20:888-902; quiz 903-4. [PubMed 23985562]

4. Bachmann GA, Komi JO, Ospemifene Study Group. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause. 2010 May-Jun; 17:480-6. [PubMed 20032798]

5. Portman DJ, Bachmann GA, Simon JA et al. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause. 2013; 20:623-30. [PubMed 23361170]

6. Simon JA, Lin VH, Radovich C et al. One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. Menopause. 2013; 20:418-27. [PubMed 23096251]

7. Cui Y, Zong H, Yan H et al. The Efficacy and Safety of Ospemifene in Treating Dyspareunia Associated with Postmenopausal Vulvar and Vaginal Atrophy: A Systematic Review and Meta-Analysis. J Sex Med. 2013; :. [PubMed 24251418]

8. Koskimies P, Katila K, Lammintausta R et al. Oral bioavailability of ospemifene improves with food intake. Int J Clin Pharmacol Ther. 2013; 51:787-94. [PubMed 24040848]

9. Voipio SK, Komi J, Kangas L et al. Effects of ospemifene (FC-1271a) on uterine endometrium, vaginal maturation index, and hormonal status in healthy postmenopausal women. Maturitas. 2002; 43:207-14. [PubMed 12443837]

10. Tolonen A, Koskimies P, Turpeinen M et al. Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations. Drug Metabol Drug Interact. 2013; 28:153-61. [PubMed 23729558]

11. Turpeinen M, Uusitalo J, Lehtinen T et al. Effects of ospemifene on drug metabolism mediated by cytochrome P450 enzymes in humans in vitro and in vivo. Int J Mol Sci. 2013; 14:14064-75. [PubMed 23880855]

12. Lehtinen T, Tolonen A, Turpeinen M et al. Effects of cytochrome P450 inhibitors and inducers on the metabolism and pharmacokinetics of ospemifene. Biopharm Drug Dispos. 2013; 34:387-95. [PubMed 23852652]

13. Anderson GL, Limacher M, Assaf AR et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004; 291:1701-12. [PubMed 15082697]

14. Ylikorkala O, Cacciatore B, Halonen K et al. Effects of ospemifene, a novel SERM, on vascular markers and function in healthy, postmenopausal women. Menopause. 2003 Sep-Oct; 10:440-7. [PubMed 14501606]

15. Kangas L, Unkila M. Tissue selectivity of ospemifene: Pharmacologic profile and clinical implications. Steroids. 2013; 78:1273-80. [PubMed 24055829]

16. Maximov PY, Lee TM, Jordan VC. The discovery and development of selective estrogen receptor modulators (SERMs) for clinical practice. Curr Clin Pharmacol. 2013; 8:135-55. [PubMed 23062036]

17. Komi J, Lankinen KS, Härkönen P et al. Effects of ospemifene and raloxifene on hormonal status, lipids, genital tract, and tolerability in postmenopausal women. Menopause. 2005; 12:202-9.

18. Komi J, Heikkinen J, Rutanen EM et al. Effects of ospemifene, a novel SERM, on biochemical markers of bone turnover in healthy postmenopausal women. Gynecol Endocrinol. 2004; 18:152-8. [PubMed 15255284]

19. Kangas L, Härkönen P, Väänänen K et al. Effects of the Selective Estrogen Receptor Modulator Ospemifene on Bone in Rats. Horm Metab Res. 2013; :. [PubMed 24108389]

20. Koskimies P, Turunen J, Lammintausta R et al. Single-dose and steady-state pharmacokinetics of ospemifene, a selective estrogen receptor modulator, in postmenopausal women. Int J Clin Pharmacol Ther. 2013; 51:861-7. [PubMed 24075094]

21. Wurz GT, Soe LH, Degregorio MW. Ospemifene, vulvovaginal atrophy, and breast cancer. Maturitas. 2013; 74:220-5.

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