ellaOne 30 mg tablet

Each tablet contains 30 mg ulipristal acetate.

Excipients: each tablet contains 237 mg lactose monohydrate.

For a full list of excipients, see section 6.1

Tablet

White to off-white, round curved tablet engraved with code “еllа” on both faces

Emergency contraception within 120 hours (5 days) of unprotected sexual intercourse or contraceptive failure.

The treatment consists of one tablet to be taken orally as soon as possible, but no later than 120 hours (5 days) after unprotected intercourse or contraceptive failure.

The tablet can be taken with or without food.

If vomiting occurs within 3 hours of ellaOne intake, another tablet should be taken.

ellaOne can be taken at any moment during the menstrual cycle.

Pregnancy should be excluded before ellaOne is administered.

Renal or hepatic impairment: In the absence of specific studies, no specific dose recommendations for ellaOne can be made.

Severe hepatic impairment: In the absence of specific studies, ellaOne is not recommended.

Children and adolescents: A limited number of women under 18 years were included in clinical trials of ellaOne.

Hypersensitivity to the active substance or to any of the excipients.

Pregnancy.

Concomitant use with an emergency contraceptive containing levonorgestrel is not recommended (see section 4.5).

Use in women with severe asthma insufficiently controlled by oral glucocorticoid is not recommended.

Emergency contraception with ellaOne is an occasional method. It should in no instance replace a regular contraceptive method. In any case, women should be advised to adopt a regular method of contraception.

Although the use of ellaOne does not contraindicate the continued use of regular hormonal contraception, ellaOne may reduce its contraceptive action (see section 4.5). Therefore, after using emergency contraception, it is recommended that subsequent acts of intercourse be protected by a reliable barrier method until the next menstrual period starts.

Repeated administration of ellaOne within the same menstrual cycle is not advisable, as safety and efficacy of ellaOne after repeated administration within the same menstrual cycle has not been investigated.

Emergency contraception with ellaOne does not prevent pregnancy in every case. No data is available on the efficacy of ellaOne for women who have had unprotected intercourse more than 120 hours before ellaOne intake. In case of doubt, delay of more than 7 days in next menstrual period, abnormal bleeding at the expected date of menses, or symptoms of pregnancy, pregnancy should be excluded by a pregnancy test.

If pregnancy occurs after treatment with ellaOne, as for all pregnancies, the possibility of an ectopic pregnancy should be considered. Ectopic pregnancy may continue, despite the occurrence of uterine bleeding.

After ellaOne intake menstrual periods can sometimes occur earlier or later than expected by a few days. In approximately 7% of the women, menstrual periods occurred more than 7 days earlier than expected. In 18.5% of the women a delay of more than 7 days occurred, and in 4% the delay was greater than 20 days.

This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Concomitant use of ellaOne and the following active substances are not recommended due to potential for interaction: P-gp substrates (e.g. dabigatran etexilate, digoxin), CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St John's wort/Hypericum perforatum), medicinal products that increase gastric pH (e.g. proton pump inhibitors, antacids and H2-receptor antagonists), long term use of ritonavir, and emergency contraception containing levonorgestrel (see section 4.5).

• Potential for other medicinal products to affect ulipristal acetate:

No specific drug interaction studies have been performed in vivo.

Ulipristal acetate is metabolized by CYP3A4 in vitro. CYP3A4 inducers (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine, St John's wort/Hypericum perforatum) may therefore reduce plasma concentrations of ulipristal acetate and may result in decrease in efficacy. Concomitant use is therefore not recommended (see section 4.4).

The CYP3A4 inhibitor ritonavir can also have an inducing effect on CYP3A4 when ritonavir is used for a longer period. In such cases ritonavir might reduce plasma concentrations of ulipristal acetate. Concomitant use is therefore not recommended (see section 4.4). Enzyme induction wears off slowly and effects on the plasma concentrations of ulipristal acetate may occur even if a woman has stopped taking an enzyme inducer within the last 2-3 weeks.

Conversely, potent CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, telithromycin, clarithromycin, nefazodone) may increase exposure to ulipristal acetate. The clinical relevance is unknown.

Concomitant administration of medicinal products that increase gastric pH (e.g. proton pump inhibitors, antacids and H2-receptor antagonists) may reduce plasma concentrations of ulipristal acetate and may result in decrease in efficacy. Concomitant use is therefore not recommended (see section 4.4).

• Potential for ulipristal acetate to affect other medicinal products:

P-glycoprotein transporters: In vitro data indicate that ulipristal may be an inhibitor of P-gp at clinically relevant concentrations. Thus, in the absence of clinical data, coadministration of ulipristal acetate and P-gp substrates (e.g. dabigatran etexilate, digoxin) is not recommended (see section 4.4).

Because ulipristal acetate binds the progesterone receptor with high affinity, it may interfere with the action of progestogen-containing medicinal products:

- Contraceptive action of combined hormonal contraceptives and progestogen-only contraception may be reduced

- Concomitant use of ulipristal acetate and emergency contraception containing levonorgestrel is not recommended (see section 4.4).

ellaOne is contra-indicated during an existing or suspected pregnancy (see section 4.3).

Extremely limited data are available on the health of the foetus/new-born in case a pregnancy is exposed to ulipristal acetate. Although no teratogenic potential was observed, animal data are insufficient with regard to reproduction toxicity (see section 5.3).

HRA Pharma maintains a pregnancy registry to monitor outcomes of pregnancy in women exposed to ellaOne. Patients and health care providers are encouraged to report any exposure to ellaOne by contacting the Marketing Authorisation Holder (see section 7).

It is unknown whether ulipristal acetate is excreted in human or animal breast milk. Ulipristal acetate is a lipophilic compound and may theoretically be excreted in breast milk. A risk to the breast-fed child cannot be excluded. After intake of ellaOne breastfeeding is not recommended for at least 36 hours.

No studies on the effect on the ability to drive and use machines have been performed.

ellaOne may have minor or moderate influence on the ability to drive or use machines: mild to moderate dizziness is common after ellaOne intake, somnolence and blurred vision are uncommon; disturbance in attention has been rarely reported.

The most commonly reported adverse reactions were headache, nausea, abdominal pain and dysmenorrhea.

Safety of ulipristal acetate has been evaluated in 4,718 women during the clinical development program.

The adverse reactions reported in the phase III program of 2,637 women are provided in the table below. The vast majority of adverse reactions were mild or moderate and resolved spontaneously.

Adverse reactions listed below are classified according to frequency and system organ class. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The majority of women (74.6%) in the phase III studies had their next menstrual period at the expected time or within ± 7 days, while 6.8% experienced menses more than 7 days earlier than expected and 18.5% had a delay of more than 7 days beyond the anticipated onset of menses. The delay was greater than 20 days in 4 % of the women.

A minority (8.7%) of women reported intermenstrual bleeding lasting an average of 2.4 days. In a majority of cases (88.2%), this bleeding was reported as spotting. Among the women who received ellaOne in the phase III studies, only 0.4% reported heavy intermenstrual bleeding.

In the phase III studies, 82 women entered a study more than once and therefore received more than one dose of ellaOne (73 women enrolled twice and 9 enrolled three times). There were no safety differences in these subjects in terms of incidence and severity of adverse events, change in duration or volume of menses or incidence of intermenstrual bleeding.

Experience with ulipristal acetate overdose is limited. Single doses up to 200 mg were administered to a limited number of subjects, and no severe or serious adverse reactions were reported.

Pharmacotherapeutic group:Sex hormones and modulators of the genital system, emergency contraceptives. ATC code: G03AD02.

Ulipristal acetate is an orally-active synthetic selective progesterone receptor modulator which acts via high-affinity binding to the human progesterone receptor. The primary mechanism of action is inhibition or delay of ovulation. Pharmacodynamic data show that even when taken immediately before ovulation is scheduled to occur, ulipristal acetate is able to postpone follicular rupture in some women.

Ulipristal acetate also has high affinity for the glucocorticoid receptor and in vivo, in animals, antiglucocorticoid effects have been observed. However, in humans, no such effect has been observed even after repeat administration at the daily dose of 10 mg. It has minimal affinity to the androgen receptor and no affinity for the human estrogen or mineralocorticoid receptors.

Results from two independent randomized controlled trials (see Table) showed the efficacy of ulipristal acetate to be non-inferior to that of levonorgestrel in women who presented for emergency contraception between 0 and 72 hours after unprotected intercourse or contraceptive failure. When the data from the two trials were combined via meta-analysis, the risk of pregnancy with ulipristal acetate was significantly reduced compared to levonorgestrel (p=0.046).

1 – Glasier et al, Lancet 2010

Two trials provide efficacy data on ellaOne used up to 120 hours after unprotected intercourse. In an open-label clinical trial, which enrolled women who presented for emergency contraception and were treated with ulipristal acetate between 48 and 120 hours after unprotected intercourse, a pregnancy rate of 2.1% (26/1241) was observed. In addition, the second comparative trial described above also provides data on 100 women treated with ulipristal acetate from 72 to 120 hours after unprotected intercourse, in whom no pregnancies were observed.

Absorption

Following oral administration of a single 30 mg dose, ulipristal acetate is rapidly absorbed, with a peak plasma concentration of 176 ± 89 ng/ml occurring approximately 1 hour (0.5-2.0 h) after ingestion, and with an AUC_0- of 556 ± 260 ng.h/ml.

Administration of ulipristal acetate together with a high-fat breakfast resulted in approximately 45% lower mean Cmax, a delayed Tmax (from a median of 0.75 hours to 3 hours) and 25% higher mean AUC_0- compared with administration in the fasted state. Similar results were obtained for the active mono-demethylated metabolite.

The absorption of ulipristal acetate is pH-dependent and may be reduced in situations where gastric pH is increased irrespective of cause.

Distribution

Ulipristal acetate is highly bound (>98%) to plasma proteins, including albumin, alpha-l-acid glycoprotein, and high density lipoprotein.

Metabolism/elimination

Ulipristal acetate is extensively metabolized to mono-demethylated, di-demethylated and hydroxylated metabolites. The mono-demethylated metabolite is pharmacologically active. In vitro data indicate that this is predominantly mediated by CYP3A4, and to a small extent by CYP1A2 and CYP2D6. The terminal half-life of ulipristal acetate in plasma following a single 30 mg dose is estimated to 32.4 ± 6.3 hours, with a mean oral clearance (CL/F) of 76.8 ± 64.0 L/h.

Special populations

No pharmacokinetic studies with ulipristal acetate have been performed in females with impaired renal or hepatic function.

Interactions

In vitro data indicate that ulipristal acetate and its active metabolite do not significantly inhibit CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4, at clinically relevant concentrations. After single dose administration induction of CYP1A2 and CYP3A4 by ulipristal or its active metabolite is not likely. Thus, administration of ulipristal acetate is unlikely to alter the clearance of medicinal products that are metabolised by these enzymes.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and genotoxicity. Most findings in general toxicity studies were related to its mechanism of action as a modulator of progesterone and glucocorticoid receptors, with antiprogesterone activity observed at exposures similar to therapeutic levels.

Reproduction toxicity data are insufficient due to lack of human and animal pharmacokinetic data. Due to its mechanism of action, ulipristal acetate has an embryolethal effect in rats, rabbits (at repeated doses above 1 mg/kg) and in monkeys. The safety for a human embryo is unknown. At doses which were low enough to maintain gestation in the animal species, no teratogenic potential was observed.

Carcinogenicity studies with ulipristal acetate have not been conducted.

Lactose monohydrate

Povidone K30

Croscarmellose sodium

Magnesium stearate

Not applicable

3 years

Keep the blister in the outer carton in order to protect from light.

PVC-PE-PVDC-Aluminium blister of 1 tablet.

The carton contains one blister of one tablet.

No special requirements

Laboratoire HRA Pharma

15, rue Béranger

F-75003 Paris

France

EU/1/09/522/001

15/05/2009

10/11/2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu/.