Ella (Page 3 of 5)

8.4 Pediatric Use

Safety and efficacy of ella have been established in women of reproductive age. The clinical trials of ella enrolled 41 females under age 18, and a post-marketing observational study evaluating effectiveness and safety of ella in adolescents enrolled 279 females under age 18, including 76 under age 16 years. In these studies, the safety and efficacy profile observed in adolescents aged 17 and younger was similar to that in adults. Use of ella before menarche is not indicated.

8.5 Geriatric Use

This product is not intended for use in postmenopausal women.

8.6 Race

While no formal studies have evaluated the effect of race, a cross-study comparison of two pharmacokinetic studies indicated that exposure in South Asians may exceed that in Caucasians and African Americans. However, no difference in efficacy and safety was observed for women of different races in clinical studies.

8.7 Hepatic Impairment

No studies have been conducted to evaluate the effect of hepatic disease on the disposition of ella.

8.8 Renal Impairment

No studies have been conducted to evaluate the effect of renal disease on the disposition of ella.

10 OVERDOSAGE

Experience with ulipristal acetate overdose is limited. In a clinical study, single doses equivalent to up to 4 times ella were administered to a limited number of subjects without any adverse reactions.

11 DESCRIPTION

The ella (ulipristal acetate) tablet for oral use contains 30 mg of a single active steroid ingredient, ulipristal acetate [17α-acetoxy-11β-(4-N,N-dimethylaminophenyl)-19-norpregna-4,9-diene-3,20-dione], a synthetic progesterone agonist/antagonist. The inactive ingredients are lactose monohydrate, povidone K-30, croscarmellose sodium and magnesium stearate.

Ulipristal acetate is a white to yellow crystalline powder which has a molecular weight of 475.6. The structural formula is:

Ulipristal acetate structural formula
(click image for full-size original)

C30 H37 NO4

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

When taken immediately before ovulation is to occur, ella postpones follicular rupture. The likely primary mechanism of action of ulipristal acetate for emergency contraception is therefore inhibition or delay of ovulation; however, alterations to the endometrium that may affect implantation may also contribute to efficacy.

12.2 Pharmacodynamics

Ulipristal acetate is a selective progesterone receptor modulator with antagonistic and partial agonistic effects (a progesterone agonist/antagonist) at the progesterone receptor. It binds the human progesterone receptor and prevents progesterone from occupying its receptor.

The pharmacodynamics of ulipristal acetate depends on the timing of administration in the menstrual cycle. Administration in the mid-follicular phase causes inhibition of folliculogenesis and reduction of estradiol concentration.

Pharmacodynamic data showed that administration of ella to 34 women in the late follicular phase postponed follicular rupture for at least 5 days in all (100%) of 8 subjects who took ella before the luteinizing hormone (LH) surge and 11 (79%) of 14 subjects who took ella immediately before ovulation (when LH has already started to rise). However, treatment was not effective in postponing follicular rupture when administered on the day of LH peak.

Dosing in the early luteal phase does not significantly delay endometrial maturation but decreases endometrial thickness by 0.6 ± 2.2 mm (mean ± SD).

Hormonal Contraceptives after ella intake:

When a combined oral contraceptive pill (COC) containing ethinyl estradiol 30 µg + levonorgestrel 150 µg was started the day after ella intake during the follicular phase, ella did not interfere with the COC’s ability to suppress ovarian activity, as assessed by measurement of follicle size via transvaginal ultrasound, combined with serum progesterone and estradiol levels: ovarian activity was suppressed in 61.5% (24/39) of subjects receiving ella plus COC and 62.2% (23/37) of subjects receiving a placebo plus the COC. The incidence of ovulation was similar between the group who received ella plus the COC [33.3% (13/39)] and the group who received a placebo plus the COC [32.4% (12/37)]. [see Warnings and Precautions (5.5) and Drug Interactions (7.3)].

The initiation of a desogestrel 75 µg “progestin-only pill” the day after ella intake during the follicular phase was associated with a higher incidence of ovulation in the six days following ella intake compared to an ella -only treatment group, and a relatively slower onset (3 to 4 days) of thickened cervical mucus compared to a group given desogestrel without prior ella intake (2 days), suggesting an effect of prior use of ella on the ability of desogestrel to inhibit mucus permeability. [See Warnings and Precautions (5.5) and Drug Interactions (7.1; 7.3)].

12.3 Pharmacokinetics

Absorption

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

Figure 1: Mean ((± SD) plasma concentration-time profile of ulipristal acetate and monodemethyl-ulipristal acetate following single dose administration of 30 mg ulipristal acetate
(click image for full-size original)
Table 2: Pharmacokinetic Parameter Values Following Administration of ella (ulipristal acetate) Tablet 30 mg to 20 Healthy Female Volunteers under Fasting Conditions
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)

1.00(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.

Distribution

Ulipristal acetate is highly bound (> 94%) to plasma proteins, including high density lipoprotein, alpha-l-acid glycoprotein, and albumin.

Metabolism

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.

Excretion

The terminal half-life of ulipristal acetate in plasma following a single 30 mg dose is estimated to 32.4 ± 6.3 hours.

Drug interactions

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.

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