ELLAONE 30mg tablets medication leaflet

ellaOne 30 mg tablet

Each tablet contains 30 mg ulipristal acetate.

Each tablet contains 237 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1

Tablet

White to marble creamy, round curved tablet of 9 mm diameter engraved with “еllа” on both sides.

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

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 at any time during the menstrual cycle.

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

If a woman’s menstrual period is late or in case of symptoms of pregnancy, pregnancy should beexcluded before the tablet is administered.

No dose adjustment is necessary.

In the absence of specific studies, no alternate dose recommendations for ulipristal acetate can bemade.

In the absence of specific studies, ulipristal acetate is not recommended.

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

Adolescents:ulipristal acetate for emergency contraception is suitable for any woman of child bearing age,including adolescents. No differences in safety or efficacy have been shown compared to adult womenaged 18 and older (see section 5.1).

Oral use.

The tablet can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

ellaOne is for occasional use only. It should in no instance replace a regular contraceptive method. Inany case, women should be advised to adopt a regular method of contraception.

Ulipristal acetate is not intended for use during pregnancy and should not be taken by any womansuspected or known to be pregnant. However, it does not interrupt an existing pregnancy (see section4.6).

ellaOne does not prevent pregnancy in every case

In case the next menstrual period is more than 7 days late, if the menstrual period is abnormal incharacter or if there are symptoms suggestive of pregnancy or in case of doubt, a pregnancy testshould be performed. As with any pregnancy, the possibility of an ectopic pregnancy should beconsidered. It is important to know that the occurrence of uterine bleeding does not rule out ectopicpregnancy. Women who become pregnant after taking ulipristal acetate should contact their doctor(see section 4.6).

ulipristal acetate inhibits or postpones ovulation (see section 5.1). If ovulation has already occurred, itis no longer effective. The timing of ovulation cannot be predicted and therefore the tablet should betaken as soon as possible after unprotected intercourse.

No data are available on the efficacy of ulipristal acetate when taken more than 120 hours (5 days)after unprotected intercourse.

Limited and inconclusive data suggest that there may be reduced efficacy of ellaOne with increasingbody weight or body mass index (BMI) (see section 5.1). In all women, emergency contraceptionshould be taken as soon as possible after unprotected intercourse, regardless of the woman’s bodyweight or BMI.

After the tablet intake menstrual periods can sometimes occur a few days earlier or later than expected.

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 than20 days.

Concomitant use of ulipristal acetate and emergency contraception containing levonorgestrel is notrecommended (see section 4.5).

Contraception after ellaOne intake

Ulipristal acetate is an emergency contraceptive that decreases pregnancy risk after unprotectedintercourse but does not confer contraceptive protection for subsequent acts of intercourse. Therefore,after using emergency contraception, women should be advised to use a reliable barrier method untilher next menstrual period.

Although the use of ulipristal acetate for emergency contraception does not contraindicate thecontinued use of regular hormonal contraception, ellaOne may reduce its contraceptive action (seesection 4.5). Therefore, if a woman wishes to start or continue using hormonal contraception, she cando so after using ellaOne, however, she should be advised to use a reliable barrier method until thenext menstrual period.

Concomitant use of ellaOne with CYP3A4 inducers is not recommended due to interaction (e.g.barbiturates (including primidone and phenobarbital), phenytoin, fosphenytoin, carbamazepine,oxcarbazepine, herbal medicinal products containing Hypericum perforatum (St. John’s wort),rifampicin, rifabutin, griseofulvin, efavirenz, nevirapine and long term use of ritonavir).

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

This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take this medicine.

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Potential for other medicinal products to affect ulipristal acetate

Ulipristal acetate is metabolised by CYP3A4 in vitro.

- CYP3A4 inducers

In vivo results show that the administration of ulipristal acetate with a strong CYP3A4 inducersuch as rifampicin markedly decreases Cmax and AUC of ulipristal acetate by 90% or more anddecreases ulipristal acetate half-life by 2.2-fold corresponding to an approximately 10-folddecrease of ulipristal acetate exposure. Concomitant use of ellaOne with CYP3A4 inducers (e.g.barbiturates (including primidone and phenobarbital), phenytoin, fosphenytoin, carbamazepine,oxcarbazepine, herbal medicines containing Hypericum perforatum (St. John’s wort),rifampicin, rifabutin, griseofulvin, efavirenz and nevirapine) therefore reduces plasmaconcentrations of ulipristal acetate and may result in a decreased efficacy of ellaOne. Forwomen who have used enzyme-inducing drugs in the past 4 weeks, ellaOne is not recommended(see section 4.4) and non-hormonal emergency contraception (i.e. a copper intrauterine device(Cu-IUD)) should be considered.

- CYP3A4 inhibitors

In vivo results show that administration of ulipristal acetate with a potent and a moderate

CYP3A4 inhibitor increased Cmax and AUC of ulipristal acetate with a maximum of 2- and5.9-fold, respectively. The effects of CYP3A4 inhibitors are unlikely to have any clinicalconsequences.

The CYP3A4 inhibitor ritonavir can also have an inducing effect on CYP3A4 when ritonavir isused for a longer period. In such cases ritonavir might reduce plasma concentrations of ulipristalacetate. Concomitant use is therefore not recommended (see section 4.4). Enzyme inductionwears off slowly and effects on the plasma concentrations of ulipristal acetate may occur even ifa woman has stopped taking an enzyme inducer in the past 4 weeks.

Medicinal products affecting gastric pH

Administration of ulipristal acetate (10 mg tablet) together with the proton pump inhibitoresomeprazole (20 mg daily for 6 days) resulted in approximately 65% lower mean Cmax, a delayed Tmax(from a median of 0.75 hours to 1.0 hours) and 13% higher mean AUC. The clinical relevance of thisinteraction for single dose administration of ulipristal acetate as emergency contraception is notknown.

Potential for ulipristal acetate to affect other medicinal products

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

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

- Concomitant use of ulipristal acetate and emergency contraception containing levonorgestrel isnot recommended (see section 4.4).

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 doseadministration induction of CYP1A2 and CYP3A4 by ulipristal acetate or its active metabolite is notlikely. Thus, administration of ulipristal acetate is unlikely to alter the clearance of medicinal productsthat are metabolised by these enzymes.

In vitro data indicate that ulipristal acetate may be an inhibitor of P-gp at clinically relevantconcentrations. Results in vivo with the P-gp substrate fexofenadine were inconclusive. The effects ofthe P-gp substrates are unlikely to have any clinical consequences.

PregnancyellaOne is not intended for use during pregnancy and should not be taken by any woman suspected orknown to be pregnant (see section 4.2).

Ulipristal acetate does not interrupt an existing pregnancy.

Pregnancy may occasionally occur after ulipristal acetate intake. Although no teratogenic potential hasbeen observed, animal data are insufficient with regard to reproduction toxicity (see section 5.3).

Limited human data regarding pregnancy exposure to ellaOne do not suggest any safety concern.

Nevertheless it is important that any pregnancy in a woman who has taken ellaOne be reported towww.hra-pregnancy-registry.com. The purpose of this web-based registry is to collect safetyinformation from women who have taken ellaOne during pregnancy or who become pregnant afterellaOne intake. All patient data collected will remain anonymous.

Ulipristal acetate is excreted in breast milk (see section 5.2). The effect on newborn/infants has notbeen studied. A risk to the breastfed child cannot be excluded. After intake of ulipristal acetate foremergency contraception, breast-feeding is not recommended for one week. During this time it isrecommended to express and discard the breast milk in order to stimulate lactation.

A rapid return of fertility is likely following treatment with ulipristal acetate for emergencycontraception. Women should be advised to use a reliable barrier method for all subsequent acts ofintercourse until the next menstrual period.

Ulipristal acetate has minor or moderate influence on the ability to drive or use machines: mild tomoderate dizziness is common after ellaOne intake, somnolence and blurred vision are uncommon;disturbance in attention has been rarely reported. The patient should be informed not to drive or usemachines if they are experiencing such symptoms (see section 4.8).

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

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

The adverse reactions reported in the phase III program of 2,637 women are provided in the tablebelow.

Adverse reactions listed below are classified according to frequency and system organ class using thefollowing convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to<1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated fromthe available data).

MedDRA Adverse reactions (frequency)

System organ class Common Uncommon Rare

Infections and Influenzainfestations

Immune system hypersensitivity reactionsdisorders including rash, urticaria,angioedema**

Metabolism and Appetite disordersnutrition disorders

Psychiatric disorders Mood disorders Emotional disorder Disorientation

Anxiety

Insomnia

Hyperactivity disorder

Libido changes

Nervous system Headache Somnolence Tremordisorders Dizziness Migraine Disturbance in attention

Dysgueusia

Eye disorders Visual disturbance Abnormal sensation in eye

Ocular hyperaemia

Photophobia

Ear and labyrinth Vertigodisorders

Respiratory, thoracic Dry throatand mediastinaldisorders

Gastrointestinal Nausea* Diarrhoeadisorders Abdominal pain* Dry mouth

Abdominal discomfort Dyspepsia

Vomiting* Flatulence

Skin and Acnesubcutaneous tissue Skin lesiondisorders Pruritus

Musculoskeletal and Myalgiaconnective tissue Back paindisorders

Reproductive system Dysmenorrhea Menorrhagia Genital pruritusand breast disorders Pelvic pain Vaginal discharge Dyspareunia

Breast tenderness Menstrual disorder Ruptured ovarian cyst

Metrorrhagia Vulvovaginal pain

Vaginitis Hypomenorrhea*

Hot flush

Premenstrual syndrome

General disorders Fatigue Chills Thirstand administration Malaisesite conditions Pyrexia

*Symptom which could also be related to an undiagnosed pregnancy (or related complications)

**Adverse reaction from spontaneous reporting

Adolescents: the safety profile observed in women less than 18 years old in studies and post-marketingis similar to the safety profile in adults during the phase III program (see section 4.2).

Post-marketing experience: the adverse reactions spontaneously reported in post-marketing experiencewere similar in nature and frequency to the safety profile described during the phase III program.

The majority of women (74.6%) in the phase III studies had their next menstrual period at theexpected time or within ± 7 days, while 6.8% experienced menses more than 7 days earlier thanexpected and 18.5% had a delay of more than 7 days beyond the anticipated onset of menses. Thedelay 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 amajority of cases (88.2%), this bleeding was reported as spotting. Among the women who receivedellaOne 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 onedose of ellaOne (73 women enrolled twice and 9 enrolled three times). There were no safety differencesin these subjects in terms of incidence and severity of adverse reactions, change in duration or volumeof menses or incidence of intermenstrual bleeding.

Reporting of suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Experience with ulipristal acetate overdose is limited. Single doses up to 200 mg have been used inwomen without safety concern. Such high doses were well-tolerated; however, these women had ashortened menstrual cycle (uterine bleeding occurring 2-3 days earlier than would be expected) and insome women, the duration of bleeding was prolonged, although not excessive in amount (spotting).

There are no antidotes and further treatment should be symptomatic.

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

Ulipristal acetate is an orally-active synthetic selective progesterone receptor modulator which acts viahigh-affinity binding to the human progesterone receptor. When used for emergency contraception themechanism of action is inhibition or delay of ovulation via suppression of the luteinising hormone(LH) surge. Pharmacodynamic data show that even when taken immediately before ovulation isscheduled to occur (when LH has already started to rise), ulipristal acetate is able to postponefollicular rupture for at least 5 days in 78.6% of cases (p<0.005 vs. levonorgestrel and vs. placebo)(see table).

Prevention of ovulation1,§

Placebo Levonorgestrel Ulipristal acetaten=50 n=48 n=34

Treatment before LH n=16 n=12 n=8surge 0.0% 25.0% 100%p<0.005*

Treatment after LH n=10 n=14 n=14surge but before LH peak 10.0% 14.3% 78.6%

NS† p<0.005*

Treatment after LH peak n=24 n=22 n=124.2% 9.1% 8.3%

NS† NS*1: Brache et al, Contraception 2013§: defined as presence of unruptured dominant follicle five days after late follicular-phase treatment

*: compared to levonorgestrel

NS: non statistically significant†: compared to placebo

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 observedeven after repeat administration at the daily dose of 10 mg. It has minimal affinity to the androgenreceptor and no affinity for the human estrogen or mineralocorticoid receptors.

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

Pregnancy rate (%) Odds ratio [95% CI] of

Randomised within 72h of unprotected intercourse or pregnancy risk, ulipristalcontrolled trial contraceptive failure2 acetate vs levonorgestrel2

* Ulipristal * Levonorgestrelacetate

HRA2914-507 0.91 1.68 0.50 [0.18-1.24](7/773) (13/773)

HRA2914-513 1.78 2.59 0.68 [0.35-1.31](15/844) (22/852)

Meta- analysis 1.36 2.15 0.58 [0.33-0.99](22/1617) ( 35/1625)2: Glasier et al, Lancet 2010

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

Limited and inconclusive data from clinical trials suggest a possible trend for a reduced contraceptiveefficacy of ulipristal acetate with high body weight or BMI (see section 4.4). The meta-analysis of thefour clinical studies conducted with ulipristral acetate presented below excluded women who hadfurther acts of unprotected intercourse.

BMI (kg/m2) Underweight Normal Overweight Obese0 - 18.5 18.5-25 25-30 30-

N total 128 1866 699 467

BMI (kg/m2) Underweight Normal Overweight Obese0 - 18.5 18.5-25 25-30 30-

N pregnancies 0 23 9 12

Pregnancy rate 0.00% 1.23% 1.29% 2.57%

Confidenceinterval 0.00 - 2.84 0.78 - 1.84 0.59 - 2.43 1.34 - 4.45

A post-marketing observational study evaluating efficacy and safety of ellaOne in adolescents aged 17and younger showed no difference in the safety and efficacy profile compared to adult women aged 18and older.

Following oral administration of a single 30 mg dose, ulipristal acetate is rapidly absorbed, with apeak plasma concentration of 176 ± 89 ng/ml occurring approximately 1 hour (0.5-2.0 h) afteringestion, and with an AUC0-∞ 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

AUC0-∞ compared with administration in the fasted state. Similar results were obtained for the activemono-demethylated metabolite.

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

Ulipristal acetate is a lipophilic compound and is distributed in breast milk, with a mean dailyexcretion of 13.35 µg [0-24 hours], 2.16 µg [24-48 hours], 1.06 µg [48-72 hours], 0.58 µg[72-96 hours], and 0.31 µg [96-120 hours].

In vitro data indicate that ulipristal acetate may be an inhibitor of BCRP (Breast Cancer Resistance

Protein) transporters at the intestinal level. The effects of ulipristal acetate on BCRP are unlikely tohave any clinical consequences.

Ulipristal acetate is not a substrate for either OATP1B1 or OATP1B3.

Biotransformation/elimination

Ulipristal acetate is extensively metabolised to mono-demethylated, di-demethylated and hydroxylatedmetabolites. The mono-demethylated metabolite is pharmacologically active. In vitro data indicatethat this is predominantly mediated by CYP3A4, and to a small extent by CYP1A2 and CYP2A6. Theterminal 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.

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

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

Information from reproductive toxicity studies is limited due to the absence of exposure measurementin these studies. Ulipristal acetate has an embryolethal effect in rats, rabbits (at repeated doses above 1mg/kg) and in monkeys. At these repeated doses, the safety for a human embryo is unknown. At doseswhich were low enough to maintain gestation in the animal species, no teratogenic effects wereobserved.

Carcinogenicity studies (in rats and mice) showed that ulipristal acetate is not carcinogenic.

Lactose monohydrate

Povidone

Croscarmellose sodium

Magnesium stearate

Not applicable

3 years

Store below 25°C. Store in the original package in order to protect from moisture. Keep the blister inthe outer carton in order to protect from light.

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

PVC-PVDC-Aluminium blister of 1 tablet.

Each carton contains one blister.

Not all pack sizes may be marketed.

No special requirements.

LABORATOIRE HRA PHARMA200 avenue de Paris92320 CHATILLON

France

EU/1/09/522/001

EU/1/09/522/002

Date of first authorisation: 15 May 2009

Date of latest renewal: 21 March 2014

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.