1. Osphena® (ospemifene) Stefanie L Drahuschak University of Pittsburgh PharmD Candidate 2014

2. Indications Osphena® is an estrogen agonist/antagonist indicated for the treatment of moderate to severe dyspareunia (painful intercourse), a symptom of vulvar and vaginal atrophy due to menopause

3. Mechanism of Action Osphena® is an estrogen agonist/antagonist with tissue selective effects. Biological actions are mediated through binding to estrogen receptors, resulting in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism)

4. Contraindictions Undiagnosed abnormal genital bleeding Known or suspected estrogen-dependent neoplasia Active DVT, pulmonary embolism, or a hx of these conditions Active arterial thromboembolic disease (stroke, MI) or a hx of these diseases Women who are or may become pregnant

5. Pharmacokinetics Absorption ▫Peak median serum concentrations reached at ~2 hours (range: 1-8 hours) ▫Steady state reached after 9 days of continuous ospemifene administration ▫Food increases the bioavailability by ~2-3 fold

6. Pharmacokinetics Distribution ▫Highly bound to serum proteins (~99%) ▫Apparent Vd is 448 L Metabolism ▫Primarily undergoes metabolism via CYP3A4, 2C9, and 2C19 ▫Major metabolite is 6-hydroxyospemifene

7. Pharmacokinetics Excretion ▫Terminal t 1/2 in postmenopausal women is approximately 26 hours ▫Following PO administration  ~75% excreted in feces, ~7% excreted in urine  Less than 0.02% excreted unchanged in urine

8. Drug Interactions Strong CYP3A4/2C9/2C19 inhibitors and inducers ▫Fluconazole, rifampin, ketoconazole, omeprazole Estrogens and estrogen agonists/antagonists Highly protein-bound drugs ▫Ospemifene is more than 99% protein bound and may affect protein binding of other drugs

9. Dosing For the treatment of moderate to severe painful intercourse caused by vulvar and vaginal atrophy due to menopause  60 mg PO once daily with food

10. Use in Special Populations Pregnancy ▫Category X ▫Is likely to increase adverse outcomes during pregnancy and labor Lactation ▫Unknown whether ospemifene is excreted in milk ▫Was found in rat milk at higher concentrations than in maternal plasma

11. Use in Special Populations Pediatrics ▫Was not studied in pediatrics and is not indicated for use in children Geriatrics ▫>19% of patients enrolled in clinical trials were 65 yo or older ▫No clinically significant differences in safety were observed

12. Use in Special Population Renal Impairment ▫PKs in women with severe renal impairment (CrCl < 30 mL/min) was similar to women with normal renal function ▫No dose adjustment necessary Hepatic Impairment ▫Has not been studied in women with severe hepatic impairment (Child-Pugh Class C)-should not be used ▫No dose adjustment required for mild-moderated hepatic impairment

13. Availability 60 mg tablets White to off-white, oval, film-coated tablets containing 60 mg of ospemifene; an imprint of “60” on one side of tablet

14. Clinical Studies Efficacy and safety were examined in 3 placebo- controlled clinical trials (two 12-week efficacy trials and one 52-week long-term safety trial) A total of 787 women received placebo and 1102 women received 60 mg Osphena In the 1 st and 2 nd clinical trials, modified intent-to- treat population treated with Osphena when compared to placebo demonstrated a statistically significant improvement in moderate-severe most bothersome symptoms (MBS) of dyspareunia (1 st trial p=0.0012; 2 nd trial p<0.0001)

15. References 1) Osphena® [package insert]. Florham Park, NJ: Shionogi, Inc; 2013. 2) Portman DJ, Bachmann GA, Simon JA. Ospemifene, a novel selective estrogen receptor modulator for treating dyspareunia associated with postmenopausal vulvar and vaginal atrophy. Menopause. 2013;20(6):623- 30. 3) 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(4):418-27. 4) Bachmann GA, Komi JO. Ospemifene effectively treats vulvovaginal atrophy in postmenopausal women: results from a pivotal phase 3 study. Menopause. 2013;17(3):480-86.