Hepatic Impairment

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 eva luated [see Warnings and Precautions (5.3), Use in Specific Populations (8.7)].

Drug Interactions

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 (7.2)].

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 (7.3)].

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 (7.4)].

Omeprazole (CYP2C19 Inhibitor)

Omeprazole (a moderate CYP2C19 inhibitor) 40 mg was given for 5 days. On Day 5, approximately one hour after omeprazole admini