ECINQ

Ulipristal is a selective progesterone receptor modulator used for the purposes of emergency contraception (Ella) and for the treatment of uterine fibroids (Fibristal).

It is a derivative of 19-norprogesterone and has both antagonistic and partial agonist activity at the progesterone receptor.

It also binds to glucocorticoid receptor, however compared to mifepristone (a progesterone receptor antagonist), ulipristal is more tolerable and has lower glucocorticoid activity and better binding affinity.

Ulipristal is currently recommended as first line therapy for emergency contraception, due to improved efficacy and similar side effect profile as compared to the traditional use of levonorgestrel or the Yuzpe regimen.

The exact mechanism of action for ulipristal is still currently debated, though there is evidence that it functions by inhibiting ovulation.

A recent systematic review proclaimed that the majority of available evidence demonstrates an inhibitory effect on ovulation rather than a post-fertilization effect on the endometrium, which has been heavily debated due to ethical concerns related to abortion (Rosato et al, 2016).

Nevertheless, current and ongoing research into the agent's mechanism of action as an emergency contraceptive continue to provide potentially plausible evidence that ulipristal may, in fact, elicit activity on the endometrium that prevents embryo implantation 10, 11, 12.

Ulipristal is an emergency contraceptive indicated for prevention of pregnancy following unprotected intercourse or a known or suspected contraceptive failure. 13, 14 In Canada and Europe, this drug is indicated for within 120 hours (five days) of unprotected sexual intercourse or contraceptive failure. 14,

Ulipristal is a selective, reversible progestin receptor modulator and its tissue targets include the uterus, cervix, ovaries, and hypothalamus.

Ulipristal may act as an agonist or antagonist in the presence or absence of progesterone based on the tissue target.

If given mid-follicular phase, development of the follicle growth is delayed and estradiol concentrations decrease.

If given at the time when luteinizing hormone peaks, follicular rapture is delayed by several days.

If given early-luteal phase, a decrease in endometrial thickness can be observed.

Tmax, healthy subjects, single oral dose = 60-90 minutes Cmax, healthy subjects, single oral dose = 176 ± 89 ng/mL AUC(0-∞), healthy subjects, single oral dose = 556 ± 260 ng-h/mL.

Ulipristal is metabolized by

CYP3A4 and to a lesser extent by CYP1A2 into mono-demethylated (active) and di-methylated (inactive) metabolites.

Mean elimination half-life, single oral dose, healthy subject = 32.4 ± 6.3 hours.

Mean oral clearance, single oral dose, healthy subject (CL/F) = 76.8 ± 64.0 L/h.

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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.

Ella is contraindicated for use in the case of known or suspected pregnancy.

Known or suspected pregnancy.

Take one tablet orally as soon as possible, within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure.

Take with or without food.

Take at any time during the menstrual cycle.

After ella use, initiate or resume hormonal contraception no sooner than 5 days after the intake of ella and use a reliable barrier method until the next menstrual period.

If vomiting occurs within 3 hours of taking ella, consider repeating the dose. 2.1 Recommended Dosage and Administration Take one tablet of ella orally as soon as possible within 120 hours (5 days) after unprotected intercourse or a known or suspected contraceptive failure.

Take ella with or without food.

Take ella at any time during the menstrual cycle. 2.2 Recommendations Regarding Use with Hormonal Contraception After ella use, initiate or resume hormonal contraception no sooner than 5 days after the intake of ella and use a reliable barrier method until the next menstrual period.

For known or suspected failure of hormonal contraception refer to the hormonal contraceptive’s prescribing information for instructions on what to do. 2.3 Recommendation in Case of Gastrointestinal Disturbances If vomiting occurs within 3 hours of taking ella, consider repeating the dose.

Ella (ulipristal acetate) tablet, 30 mg is supplied in a PVC-PE-PVDC or PVC-PVDC-aluminum blister.

The tablet is a white to off-white, round, curved tablet marked with “ ella ” on both sides.

NDC 73302-456-01 (1 tablet unit of use package) Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) Keep the blister in the outer carton in order to protect from light.

Keep out of reach of children.

Ella is contraindicated for use during an existing or suspected pregnancy.

No signal of concern regarding pregnancy complications was found in postmarketing studies.

Isolated cases of major malformations in ella.

• exposed pregnancies were identified; however, the data are not sufficient to determine a risk for birth defects with inadvertent use of ella during pregnancy.

Miscarriage was reported in 14% of the known pregnancy outcomes; a rate that is similar to the U.S. background rate for miscarriage.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

In animal reproduction studies, no malformations were observed during repeated administration of ulipristal acetate to pregnant rats, rabbits and monkeys at daily drug exposures ⅓, ½, and 3 times respectively, the human exposure at a dose of 30 mg.

Data Human Data Ella pregnancy exposure data was collected in the U.S. and Europe from to 2015 and analyzed post-marketing using data from interventional clinical trials, observational studies and pharmacovigilance reports.

Known pregnancy outcomes were available for 462/784 pregnancies in which women received ella at doses of 30 mg or greater during the conception cycle or during pregnancy.

Data of pregnancies with known outcome were analyzed prospectively for 272 cases and retrospectively for 190 cases.

Pregnancy outcomes included 302 elective abortions (2 for fetal anomalies including with trisomy 21), 63 spontaneous abortions, and 13 ectopic pregnancies.

No maternal or fetal deaths were reported. 84 pregnancies continued until birth, with congenital anomalies reported in 5 infants, including 4 major malformations (2/4 with genetic syndromes).

Although these data do not allow estimation of the prevalence rate of congenital anomalies associated with inadvertent use of ella in pregnancy or determination of a causal relationship between reported anomalies and ella, they show that ella -exposed pregnancies were not associated with a pattern of increased risk of adverse outcomes.

Ulipristal acetate was administered repeatedly to pregnant rats and rabbits during the period of organogenesis.

Embryofetal loss was noted in all pregnant rats and in half of the pregnant rabbits following and 13 days of dosing, at daily drug exposures 1/3 and 1/2 the human exposure, respectively, based on body surface area (mg/m 2 ).

There were no malformations of the surviving fetuses in these studies.

Adverse effects were not observed in the offspring of pregnant rats administered ulipristal acetate during the period of organogenesis through lactation at drug exposures 1/24 the human exposure based on AUC.

Administration of ulipristal acetate to pregnant monkeys for 4 days during the first trimester caused pregnancy termination in 2/5 animals at daily drug exposures 3 times the human exposure based on body surface area.

There is no relevant use of ulipristal acetate for children of prepubertal age in the indication emergency contraception.

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 and younger was similar to that in adults.

Use of ella before menarche is not indicated.

This product is not intended for use in postmenopausal women.