"The U.S. Food and Drug Administration today approved Osphena (ospemifene) to treat women experiencing moderate to severe dyspareunia (pain during sexual intercourse), a symptom of vulvar and vaginal atrophy due to menopause.
Mechanism of Action
OSPHENA is an estrogen 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).
Following a single oral administration of OSPHENA 60 mg tablet in postmenopausal women under fasted condition, peak median serum concentrations was reached at approximately 2 hours (range: 1 to 8 hours) post-dose (see Figure 2). Mean ospemifene Cmax and AUC0-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, Cmax was reached at approximately 2.5 hours (range: 1 to 6 hours) post-dose. Mean ospemifene Cmax and AUC0-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 AUC0-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
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 Cmax and AUC0-inf by 2.3- and 1.7-fold, respectively, compared to fasted condition. Elimination half-life and time to maximum concentration (Tmax) were unchanged in the presence of food. In two food effect studies in healthy males using different ospemifene tablet formulations Cmax and AUC0-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].
OSPHENA is highly ( > 99 percent) bound to serum proteins. The apparent volume of distribution is 448 L.
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 9.16 L/hr using a population approach.
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 was excreted in feces and urine, respectively. Less than 0.2% of the ospemifene dose was excreted unchanged in urine.
Use In Specific Populations
The pharmacokinetics of ospemifene in pediatric patients has not been evaluated [see Use In Specific Populations].
No differences in ospemifene pharmacokinetics were detected with regard to age (range 40 to 80 years) [see Use in Specific Populations].
Race did not have clinically relevant effect on ospemifene pharmacokinetics.
In women with severe renal impairment (CrCL < 30 mL/min), the Cmax and AUC0-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].
In women with mild hepatic impairment (Child-Pugh Class A), the Cmax and AUC0-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 Cmax and AUC0-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 severe hepatic impairment on the pharmacokinetics of ospemifene has not been evaluated [see WARNINGS AND PRECAUTIONS, and Use in Specific Populations].
Ospemifene is metabolized primarily by CYP3A4 and CYP2C9. CYP2C19 and other pathways contribute to the metabolism of ospemifene. In order of decreasing potency, ospemifene was suggested to be a weak inhibitor for CYP2B6, CYP2C9, CYP2C19, CYP2C8, CYP2D6 and CYP3A4 in in vitro studies. Ospemifene is not a significant P-glycoprotein substrate in vitro; no in vivo transporter study was conducted.
Effect of Co-Administered Drugs on the Pharmacokinetics of Ospemifene
Fluconazole (CYP3A4/CYP2C9/CYP2C19 Inhibitor)
Fluconazole (a moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor) 400 mg was given on Day 1 followed by 200 mg on Days 2 to 5 under fasted condition. On Day 5 approximately one hour after fluconazole administration, ospemifene 60 mg was administered after breakfast (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Fluconazole 200 mg was taken for three additional days under fasted condition. Multiple doses of fluconazole in fourteen postmenopausal women increased the Cmax and AUC0-inf of ospemifene by 1.7- and 2.7-fold, respectively [see DRUG INTERACTIONS].
Rifampin (CYP3A4/CYP2C9/CYP2C19 Inducer)
Rifampin 600 mg was given once daily for 5 consecutive days (given at least one hour before or two hours after a meal) in the late afternoon. On Day 6 after an overnight fast, ospemifene 60 mg was administered in the morning after under fed condition (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Multiple doses of rifampin 600 mg in twelve postmenopausal women reduced Cmax and AUC0-inf of ospemifene by 51% and 58%, respectively. Rifampin and other inducers of CYP3A4 are expected to decrease the systemic exposure of ospemifene [see DRUG INTERACTIONS].
Ketoconazole (CYP3A4 Inhibitor)
Ketoconazole 400 mg was given once daily for 4 consecutive days after breakfast. On Day 5 after an overnight fast, ketoconazole 400 mg and ospemifene 60 mg were co-administered under fed condition (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Ketoconazole administration once daily continued for an additional 3 days (Days 6 to 8). Co-administration of a single 60 mg dose of ospemifene and multiple doses of ketoconazole in twelve postmenopausal women increased Cmax and AUC0-inf by 1.5- and 1.4-fold, respectively [see DRUG INTERACTIONS].
Omeprazole (CYP2C19 Inhibitor)
Omeprazole (a moderate CYP2C19 inhibitor) 40 mg was given for 5 days. On Day 5, approximately one hour after omeprazole administration, ospemifene 60 mg was administered after breakfast (two slices of bread with ham, cheese, a few slices of cucumber and/or tomatoes, and juice). Multiple doses of omeprazole in fourteen postmenopausal women increased Cmax and AUC0-inf by 1.20- and 1.17-fold, respectively.
Effect of Ospemifene on the Pharmacokinetics of the Co-Administered Drug
Ospemifene 60 mg was given after a light breakfast (two slices of bread with ham and cheese and juice) once daily for 12 days in sixteen postmenopausal women who were determined to be rapid metabolizers of CYP2C9 (CYP2C9*1/*1 or CYP2C9*1/*2). On Day 8, a single dose of warfarin 10 mg and vitamin K 10 mg were administered one hour after a light breakfast. The geometric mean ratio (90% CI) for S-warfarin with and without ospemifene for Cmax and AUC0-inf were 0.97 (0.92-1.02) and 0.96 (0.91-1.02), respectively. Multiple doses of ospemifene did not significantly affect the pharmacokinetics of a single dose of warfarin. No study was conducted with multiple doses of warfarin.
Ospemifene 60 mg was administered once daily for 7 days after a light meal in the late afternoon in fourteen postmenopausal women. On Day 8 after an overnight fast, a single 20 mg dose of omeprazole was administered in the morning of at least 10 hrs; ospemifene was not given on Day 8. The geometric mean ratios for the metabolic index (omeprazole/5-hydroxyomeprazole) at the concentration at the 3 hr time point and for AUC0-8hr was 0.97 with and without ospemifene. It is unclear if ospemifene will affect the pharmacokinetics of drugs metabolized by CYP2C19 due to the significant time gap between ospemifene and omeprazole administration.
Ospemifene 60 mg was administered once daily for seven consecutive days after the evening meal in sixteen postmenopausal women (not homozygous for CYP2B6*6). On the Day 8 after overnight fast, a single 150 mg dose of sustained release bupropion was administered in morning under fasted condition. The geometric mean ratio (90% CI) for bupropion with and without ospemifene for Cmax and AUC0-inf were 0.82 (0.75-0.91) and 0.81 (0.77-0.86), respectively. The geometric mean ratio (90% CI) for hydroxybupropion, an active metabolite formed via CYP2B6, with and without ospemifene for Cmax and AUC0-inf were 1.16 (1.09-1.24) and 0.98 (0.921.04), respectively.
The effectiveness and safety of OSPHENA on moderate to severe symptoms of vulvar and vaginal atrophy in postmenopausal women were examined in three placebo-controlled clinical trials (two 12-week efficacy trials and one 52-week long-term safety trial). In the three placebo-controlled trials, a total of 787 women received placebo and 1102 women received 60 mg OSPHENA.
The first clinical trial was a 12-week, randomized, double-blind, placebo-controlled, parallel-group study 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 OSPHENA (n=282), 60 mg OSPHENA (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.
The second clinical trial was a 12-week, randomized, double-blind, placebo-controlled, parallel-group study 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 OSPHENA (n=463) and placebo (n=456). Primary endpoints and study conduct were similar to those in Trial 1.
The third clinical trial was a 52-week, randomized, double-blind, placebo-controlled, long-term safety study 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 OSPHENA (n=363) and placebo (n=63).
Effects on Dyspareunia
In the 1st and 2nd clinical trial, the modified intent-to-treat population of women treated with OSPHENA 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 (MBS) of dyspareunia (1st trial p=0.0012, 2nd trial p < 0.0001). See Table 2. 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 was also demonstrated (p < 0.0001 for both). The mean reduction in vaginal pH between baseline and Week 12 was also statistically significant (p < 0.0001).
Table 2: Week 12 Effects on Dyspareunia (the Woman's
Self-Identified Most Bothersome Moderate to Severe Symptom of Vulvar and
Vaginal Atrophy at Baseline). Mean Change in Severity at Week 12 with Last Observation
Carried Forward (LOCF), Modified Intent-to-Treat Populationa
|1st Clinical Trial Results|
|Most Bothersome Moderate to Severe Symptom at Baseline||OSPHENA 60 mg
|Baseline Mean (SD)||2.7 (0.44)||2.7 (0.45)|
|LS Mean Change from Baseline (SE)||-1.39 (0.11)||-0.89 (0.11)|
|p-value vs. placebo||0.0012||---|
|2nd Clinical Trial Results|
|Most Bothersome Moderate to Severe Symptom at Baseline||OSPHENA 60 mg (N=301)||Placebo (N=297)|
|Baseline Mean (SD)||2.7 (0.47)||2.7 (0.47)|
|LS Mean Change from Baseline (SE)||-1.55 (0.06)||-1.29 (0.07)|
|p-value vs. placebo||< 0.0001||---|
|a The modified intent-to-treat population (mITT) included
only women in the ITT population who at baseline met the inclusion criteria of
≤ 5 percent superficial cells on a vaginal smear, a vaginal pH > 5.0,
and who identified moderate or severe dyspareunia as her most bothersome
Definitions: LOCF = last observation carried forward; SD = standard deviation; SE = standard error; LS = least square
Last reviewed on RxList: 3/18/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Osphena Information
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