Following a single dose administration of ella in 20 women under fasting conditions, maximum plasma concentrations of ulipristal acetate and the active metabolite, monodemethyl-ulipristal acetate, were 176 and 69 ng/ml and were reached at 0.9 and 1 hour, respectively.
Figure 1: Mean (± SD) Plasma Concentration-time Profile of Ulipristal Acetate and Monodemethyl-ulipristal Acetate Following Single Dose Administration of 30 mg Ulipristal Acetate
|Mean (± SD)|
|Cmax (ng/ml)||AUC0-t (ng•hr/ml)||AUC0-∞ (ng•hr/ml)||tmax (hr)*||t1/2 (hr)|
|Ulipristal acetate||176 (89)||548 (259)||556 (260)||0.9 (0.5-2.0)||32 (6.3)|
|Monodemethyl-ulipristal acetate||69 (26)||240 (59)||246 (59)||0.9 (0.8-2.0)||27 (6.9)|
Cmax = maximum concentration
AUC0-t = area under the drug concentration curve from time 0 to time of last determinable concentration
AUC0-∞ = area under the drug concentration curve from time 0 to infinity
tmax = time to maximum concentration
t1/2 = elimination half-life * Median (range)
Effect of food: Administration of ella together with a high-fat breakfast resulted in approximately 40 — 45% lower mean Cmax , a delayed tmax (from a median of 0.75 hours to 3 hours) and 20 — 25% higher mean AUC0-∞ of ulipristal acetate and monodemethyl-ulipristal acetate compared with administration in the fasting state. These differences are not expected to impair the efficacy or safety of ella to a clinically significant extent; therefore, ella can be taken with or without food.
Ulipristal acetate is highly bound (> 94%) to plasma proteins, including high density lipoprotein, alpha-l-acid glycoprotein, and albumin.
Ulipristal acetate is metabolized to mono-demethylated and di-demethylated metabolites. In vitro data indicate that this is predominantly mediated by CYP3A4. The mono-demethylated metabolite is pharmacologically active.
The terminal half-life of ulipristal acetate in plasma following a single 30 mg dose is estimated to be 32.4 ± 6.3 hours.
CYP3A4 inducers: When a single 30 mg dose of ulipristal acetate was administered following administration of the strong CYP3A4 inducer, rifampin 600 mg once daily for 9 days, Cmax and AUC of ulipristal acetate decreased by 90% and 93% respectively. The Cmax and AUC of monodemethyl-ulipristal acetate decreased by 84% and 90% respectively [see Drug Interactions (7.1)].
CYP3A4 inhibitors: When a single 10 mg dose of ulipristal acetate was administered following administration of the strong CYP3A4 inhibitor, ketoconazole 400 mg once daily for 7 days, Cmax and AUC of ulipristal acetate increased by 2- and 5.9- fold, respectively. While the AUC of monodemethyl-ulipristal acetate increased by 2.4-fold, Cmax of monodemethyl-ulipristal acetate decreased by 47%. There was no in vivo drug-drug interaction study between ulipristal acetate 30 mg and CYP3A4 inhibitors [see Drug Interactions (7.1)].
In vitro studies demonstrated that ella does not induce or inhibit the activity of cytochrome P450 enzymes.
P-glycoprotein (P-gp) transporter: In vitro data indicate that ulipristal may be an inhibitor of P-gp at clinically relevant concentrations. When a single 60 mg dose of fexofenadine, a substrate of P-gp glycoprotein, was administered 1.5 hours after the administration of a single 10 mg dose of ulipristal acetate, there was no increase in Cmax or AUC of fexofenadine.
Breast Cancer Resistance Protein (BCRP) transporter: In vitro data indicate that ulipristal acetate may be an inhibitor of BCRP at the intestinal level.
The effects of ella on P-gp and BCRP transporters are unlikely to have any clinical consequences when considering ella ‘s single dose treatment regimen, although there was no in vivo drug interaction study between ulipristal acetate 30 mg (ella) and substrates of P-pg and BCRP transporters.
Carcinogenicity potential was evaluated in rats and mice.
Sprague Dawley rats were exposed to ulipristal acetate daily for 99-100 weeks at doses of 1, 3, or 10 mg/kg/day, representing exposures up to 31 times higher than exposures at the maximum recommended human dose (MRHD). There were no drug-related neoplasms in male rats. In female rats, potential treatment-related neoplastic findings were limited to adrenal cortical adenomas in the intermediate dose group (3 mg/kg/day). Despite the increase, this incidence of adrenal cortical adenomas in females may not be relevant to clinical use.
Tg.rasH2 transgenic mice were exposed to ulipristal acetate for 26 weeks at doses of 5, 45, or 130 mg/kg/day, representing exposures 100 times higher than exposures at the MRHD. There was no drug-related increase in neoplasm incidence in male or female mice.
Genotoxicity: Ulipristal acetate was not genotoxic in the Ames assay, in vitro mammalian assays utilizing mouse lymphoma cells and human peripheral blood lymphocytes , and in an in vivo micronucleus assay in mice.
Impairment of Fertility: Single oral doses of ulipristal acetate prevented ovulation in 50% of rats at 2 times the human exposure based on body surface area (mg/m2). Single doses of ulipristal acetate given on post-coital days 4 or 5 prevented pregnancy in 80-100% of rats and in 50% of rabbits when given on post-coital days 5 or 6 at drug exposures 4 and 12 times the human exposure based on body surface area. Lower doses administered for 4 days to rats and rabbits were also effective at preventing ovulation and pregnancy.
Two multicenter clinical studies evaluated the efficacy and safety of ella. An open-label study provided the primary data to support the efficacy and safety of ulipristal acetate for emergency contraception when taken 48 to 120 hours after unprotected intercourse. A single-blind comparative study provided the primary data to support the efficacy and safety of ulipristal acetate for emergency contraception when taken 0 to 72 hours after unprotected intercourse and provided supportive data for ulipristal acetate for emergency contraception when taken > 72 to 120 hours after unprotected intercourse. Women in both studies were required to have a negative pregnancy test prior to receiving emergency contraception. The primary efficacy analyses were performed on subjects less than 36 years of age who had a known pregnancy status after taking study medication.
|Open-Label Study 48 to 120 Hours *||Single-Blind Comparative Study 0 to 72 Hours *|
|N = 1,242||N = 844|
|Expected Pregnancy Rate **||5.5||5.6|
|Observed Pregnancy Rate **(95% confidence interval)||2.2(1.5, 3.2)||1.9(1.1, 3.1)|
* Time after unprotected intercourse when ella was taken
** Number of pregnancies per 100 women at risk for pregnancy
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