Osphena Ospemifene 60 mg Tablet, Film Coated, 5-count — NDC 55494-580-55 (Billing 55494-0580-55)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action OSPHENA is an estrogen receptor agonist/antagonist with tissue selective effects. Its biological actions are mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism).

12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to OSPHENA nor her risk for adverse outcomes.

12.3Pharmacokinetics Absorption Following a single oral administration of OSPHENA 60 mg tablet in postmenopausal women under fasted condition, peak median serum concentration was reached at approximately 2 hours (range: 1 to 8 hours) post-dose (see Figure 2 ). Mean ospemifene C max and AUC 0-inf were 533 ng/mL and 4165 ng∙hr/mL, respectively. After a single oral administration of OSPHENA 60 mg tablet in postmenopausal women with a high fat/high calorie (860 kcal) meal, C max was reached at approximately 2.5 hours (range: 1 to 6 hours) post-dose.

Mean ospemifene C max and AUC 0-inf were 1198 ng/mL and 7521 ng∙hr/mL, respectively. The absolute bioavailability of ospemifene was not evaluated. Ospemifene exhibits less than dose-proportional pharmacokinetics from 25 to 200 mg with ospemifene capsule formulation.

Accumulation of ospemifene with respect to AUC 0-inf was approximately 2 after twelve weeks of daily administration. Steady-state was reached after nine days of ospemifene administration. Figure 2: Mean Serum Concentration Profile of Ospemifene Following a Single Oral Administration of OSPHENA 60 mg Tablet in Postmenopausal Women Under Fed (N=28) and Fasted (N=91) Conditions Figure 2 Food Effect In general, food increased the bioavailability of ospemifene by approximately 2-3 fold.

In a cross-study comparison, single dose OSPHENA 60 mg tablet administered with a high fat/high calorie meal (860 kcal) in postmenopausal women increased C max and AUC 0-inf by 2.3- and 1.7-fold, respectively, compared to fasted condition. Elimination half-life and time to maximum concentration (T max ) were unchanged in the presence of food. In two food effect studies in healthy males using different ospemifene tablet formulations, C max and AUC 0-inf increased by 2.3- and 1.8-fold, respectively, with a low fat/low calorie meal (300 kcal) and increased by 3.6- and 2.7-fold, respectively, with a high fat/high calorie meal (860 kcal), compared to fasted condition.

OSPHENA should be taken with food [see Dosage and Administration (2.1) ]. Distribution OSPHENA is highly (>99 percent) bound to serum proteins. The apparent volume of distribution is 448 L.

Metabolism In vitro experiments with human liver microsomes indicated that ospemifene primarily undergoes metabolism via CYP3A4, CYP2C9, and CYP2C19. The major metabolite was 4-hydroxyospemifene. The apparent total body clearance is

9.16L/hr using a population approach. Excretion The apparent terminal half-life of ospemifene in postmenopausal women is approximately 26 hours. Following an oral administration of ospemifene, approximately 75% and 7% of the dose were excreted in feces and urine, respectively.

Less than 0.2% of the ospemifene dose was excreted unchanged in urine. Use in Specific Populations Pediatric The pharmacokinetics of ospemifene in pediatric patients has not been evaluated [see Use in Specific Populations (8.4) ]. Geriatric No differences in ospemifene pharmacokinetics were detected with regard to age (range 40 to 80 years) [see Use in Specific Populations (8.5) ].

Race Race did not have a clinically relevant effect on ospemifene pharmacokinetics. Renal Impairment In women with severe renal impairment (CrCL <30 mL/min), the C max and AUC 0-inf for ospemifene following a single 60 mg dose administered with a high fat/high calorie meal were lower by 21% and higher by 20%, respectively [see Use in Specific Populations (8.6) ]. Hepatic Impairment In women with mild hepatic i… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action OSPHENA is an estrogen receptor agonist/antagonist with tissue selective effects. Its biological actions are mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism).

12.3Pharmacokinetics Absorption Following a single oral administration of OSPHENA 60 mg tablet in postmenopausal women under fasted condition, peak median serum concentration was reached at approximately 2 hours (range: 1 to 8 hours) post-dose (see Figure 2 ). Mean ospemifene C max and AUC 0-inf were 533 ng/mL and 4165 ng∙hr/mL, respectively. After a single oral administration of OSPHENA 60 mg tablet in postmenopausal women with a high fat/high calorie (860 kcal) meal, C max was reached at approximately 2.5 hours (range: 1 to 6 hours) post-dose.

Mean ospemifene C max and AUC 0-inf were 1198 ng/mL and 7521 ng∙hr/mL, respectively. The absolute bioavailability of ospemifene was not evaluated. Ospemifene exhibits less than dose-proportional pharmacokinetics from 25 to 200 mg with ospemifene capsule formulation.

Accumulation of ospemifene with respect to AUC 0-inf was approximately 2 after twelve weeks of daily administration. Steady-state was reached after nine days of ospemifene administration. Figure 2: Mean Serum Concentration Profile of Ospemifene Following a Single Oral Administration of OSPHENA 60 mg Tablet in Postmenopausal Women Under Fed (N=28) and Fasted (N=91) Conditions Figure 2 Food Effect In general, food increased the bioavailability of ospemifene by approximately 2-3 fold.

In a cross-study comparison, single dose OSPHENA 60 mg tablet administered with a high fat/high calorie meal (860 kcal) in postmenopausal women increased C max and AUC 0-inf by 2.3- and 1.7-fold, respectively, compared to fasted condition. Elimination half-life and time to maximum concentration (T max ) were unchanged in the presence of food. In two food effect studies in healthy males using different ospemifene tablet formulations, C max and AUC 0-inf increased by 2.3- and 1.8-fold, respectively, with a low fat/low calorie meal (300 kcal) and increased by 3.6- and 2.7-fold, respectively, with a high fat/high calorie meal (860 kcal), compared to fasted condition.

OSPHENA should be taken with food [see Dosage and Administration (2.1) ]. Distribution OSPHENA is highly (>99 percent) bound to serum proteins. The apparent volume of distribution is 448 L.

Metabolism In vitro experiments with human liver microsomes indicated that ospemifene primarily undergoes metabolism via CYP3A4, CYP2C9, and CYP2C19. The major metabolite was 4-hydroxyospemifene. The apparent total body clearance is

9.16L/hr using a population approach. Excretion The apparent terminal half-life of ospemifene in postmenopausal women is approximately 26 hours. Following an oral administration of ospemifene, approximately 75% and 7% of the dose were excreted in feces and urine, respectively.

Less than 0.2% of the ospemifene dose was excreted unchanged in urine. Use in Specific Populations Pediatric The pharmacokinetics of ospemifene in pediatric patients has not been evaluated [see Use in Specific Populations (8.4) ]. Geriatric No differences in ospemifene pharmacokinetics were detected with regard to age (range 40 to 80 years) [see Use in Specific Populations (8.5) ].

Race Race did not have a clinically relevant effect on ospemifene pharmacokinetics. Renal Impairment In women with severe renal impairment (CrCL <30 mL/min), the C max and AUC 0-inf for ospemifene following a single 60 mg dose administered with a high fat/high calorie meal were lower by 21% and higher by 20%, respectively [see Use in Specific Populations (8.6) ]. Hepatic Impairment In women with mild hepatic impairment (Child-Pugh Class A), the C max and AUC 0-inf for ospemifene following a single 60 mg dose administered with a high fat/high calorie meal were lower by 21% and 9.1%, respectively, compared to women with normal hepatic function.

In women with moderate hepatic impairment (Child-Pugh Class B), the C max and AUC 0-inf for ospemifene following a single 60 mg dose administered with a high fat/high calorie meal were higher by 1% and 29%, respectively, compared to women with normal hepatic function. The effect of… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to OSPHENA nor her risk for adverse outcomes.

14 CLINICAL STUDIES The effectiveness and safety of OSPHENA on moderate to severe symptoms of vulvar and vaginal atrophy in postmenopausal women were examined in four placebo-controlled clinical trials (three 12-week efficacy trials and one 52-week long-term safety trial). In the four placebo-controlled trials, a total of 1100 women received placebo and 1416 women received 60 mg OSPHENA. Trial 1 was a 12-week, randomized, double-blind, placebo-controlled, parallel-group trial that enrolled 826 generally healthy postmenopausal women between 41 to 81 years of age (mean 59 years of age) who at baseline had ≤5 percent superficial cells on a vaginal smear, a vaginal pH >5.0, and who identified at least one moderate to severe vaginal symptom that was considered the most bothersome to her (vaginal dryness, pain during intercourse [dyspareunia], or vaginal irritation/itching).

Treatment groups included 30 mg ospemifene (n=282), 60 mg ospemifene (n=276), and placebo (n=268). All women were assessed for improvement in the mean change from baseline to Week 12 for the co-primary efficacy variables of: most bothersome symptom (MBS) of vulvar and vaginal atrophy (defined as the individual moderate to severe symptom that was identified by the woman as most bothersome at baseline), percentage of vaginal superficial and vaginal parabasal cells on a vaginal smear, and vaginal pH. Following completion of 12-weeks, women with an intact uterus were allowed to enroll in a 40-week double-blind extension study, and women without an intact uterus were allowed to enroll in a 52-week open-label extension study.

Trial 2 was a 12-week, randomized, double-blind, placebo-controlled, parallel-group trial that enrolled 919 generally healthy postmenopausal women between 41 to 79 years of age (mean 59 years of age) who at baseline had ≤5 percent superficial cells on a vaginal smear, a vaginal pH >5.0, and who identified either moderate to severe vaginal dryness (dryness cohort) or moderate to severe dyspareunia (dyspareunia cohort) as most bothersome to her at baseline. Treatment groups included 60 mg ospemifene (n=463) and placebo (n=456).

Primary endpoints and study conduct were similar to those in Trial 1. Trial 3 was a 12-week, randomized, double-blind, placebo-controlled, parallel-group trial that enrolled 631 generally healthy postmenopausal women between 40 and 80 years of age (mean 60 years of age) who at baseline had ≤5 percent superficial cells on a vaginal smear, a vaginal pH >5.0, and had moderate to severe vaginal dryness as the self-reported most bothersome symptom of VVA. Treatment groups included 60 mg ospemifene (n=316) and placebo (n=315).

Primary endpoints and study conduct were similar to those in Trials 1 and 2. In Trial 3, 52 healthy postmenopausal women in the 60 mg ospemifene treatment group and 53 in placebo received treatment for up to 52-weeks. Trial 4 was a 52-week, randomized, double-blind, placebo-controlled, long-term safety trial that enrolled 426 generally healthy postmenopausal women between 49 to 79 years of age (mean 62 years of age) with an intact uterus.

Treatment groups included 60 mg ospemifene (n=363) and placebo (n=63). Effects on Dyspareunia in Postmenopausal Women In Trials 1 and 2, the modified intent-to-treat population of women treated with ospemifene when compared to placebo demonstrated a statistically significant improvement (least square mean change from baseline to Week 12) in the moderate to severe most bothersome symptom of dyspareunia (Trial 1, p=0.0012 and Trial 2, p<0.0001). See Table 3 .

A statistically significant increase in the proportion of superficial cells and a corresponding statistically significant decrease in the proportion of parabasal cells on a vaginal smear were also demonstrated (p<0.0001 for both trials). The mean reduction in vaginal pH between baseline and Week 12 was also statistically significant (p<0.0001 for both trials). Table 3: Week 12 Effects on Dyspareunia (the Woman's Self-Ide… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year carcinogenicity study in female mice, ospemifene was orally administered at 100, 400, or 1500 mg/kg/day. No evaluation for carcinogenicity was conducted in male mice. There was significant increase in adrenal subcapsular cell adenomas at 4 and 5 times the human exposure based on AUC, and adrenal cortical tumors at 5 times the human exposure.

In the ovary, an increase in sex cord/stromal tumors, tubulostromal tumors, granulosa cell tumors, and luteomas was also seen. These findings occurred at doses 2 to 5 times the human exposure based on AUC and are probably related to estrogenic/antiestrogenic effect of ospemifene in mice. In a 2-year carcinogenicity study in rats, ospemifene was orally administered at 10, 50, or 300 mg/kg/day.

A significant increase in thymomas was recorded for males and thymomas for females at all ospemifene dose levels, or 0.3 to 1.2 times the human exposure based on AUC. In the liver, an increase in hepatocellular tumors was recorded for females at all ospemifene dose levels. Mutagenesis Ospemifene was not genotoxic in vitro in the Ames test in strains of Salmonella typhimurium or at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells in the absence and in the presence of a metabolic activator system.

In in vivo testing, ospemifene was not genotoxic in a standard mouse bone marrow micronucleus test or in a determination of DNA adducts in the liver of rats. Impairment of Fertility The effect of ospemifene on fertility was not directly evaluated. In female rats and monkeys, decreases in ovarian and uterine weights, decreased corpora lutea number, increased ovarian cysts, uterine atrophy, and disrupted cycles were observed when given repeated daily oral doses.

In male rats, atrophy of the prostate and seminal vesicles was noted. The effects on reproductive organs observed in animals are consistent with the estrogen receptor activity of ospemifene and potential for impairment of fertility.