4.1. Therapeutic indications

Ulipristal acetate is indicated for intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women who have not reached menopause when uterine fibroid embolisation and/or surgical treatment options are not suitable or have failed.

4.2. Posology and method of administration

Esmya treatment is to be initiated and supervised by physicians experienced in the diagnosis and treatment of uterine fibroids.

Posology

The treatment consists of one tablet of 5 mg to be taken once daily for treatment courses of up to 3 months each. Tablets may be taken with or without food.

Treatments should only be initiated when menstruation has occurred:

- The first treatment course should start during the first week of menstruation.

- Re-treatment courses should start at the earliest during the first week of the second menstruation following the previous treatment course completion.

The treating physician should explain to the patient the requirement for treatment free intervals.

Repeated intermittent treatment has been studied up to 4 intermittent courses.

If a patient misses a dose, the patient should take ulipristal acetate as soon as possible. If the dose was missed by more than 12 hours, the patient should not take the missed dose and simply resume the usual dosing schedule.

Special population

Renal impairment

No dose adjustment is recommended in patients with mild or moderate renal impairment. In the absence of specific studies, ulipristal acetate is not recommended in patients with severe renal impairment unless the patient is closely monitored (see sections 4.4 and 5.2).

Paediatric population

There is no relevant use of ulipristal acetate in the paediatric population. The safety and efficacy of ulipristal acetate was only established in women of 18 years and older.

Method of administration

Oral use. Tablets should be swallowed with water.

4.3. Contraindications

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

Pregnancy and breastfeeding.

Genital bleeding of unknown aetiology or for reasons other than uterine fibroids.

Uterine, cervical, ovarian or breast cancer.

Underlying hepatic disorder.

4.4. Special warnings and precautions for use

Ulipristal acetate should only be prescribed after careful diagnosis. Pregnancy should be precluded prior to treatment. If pregnancy is suspected prior to initiation of a new treatment course, a pregnancy test should be performed.

Contraception

Concomitant use of progestagen-only pills, a progestagen-releasing intrauterine device or combined oral contraceptive pills is not recommended (see section 4.5). Although a majority of women taking a therapeutic dose of ulipristal acetate have anovulation, a non hormonal contraceptive method is recommended during treatment.

Endometrial changes

Ulipristal acetate has a specific pharmacodynamic action on the endometrium:

Changes in the histology of the endometrium may be observed in patients treated with ulipristal acetate. These changes are reversible after treatment cessation.

These histological changes are denoted as “Progesterone Receptor Modulator Associated Endometrial Changes” (PAEC) and should not be mistaken for endometrial hyperplasia (see sections 4.8 and 5.1).

In addition, reversible increase of the endometrium thickness may occur under treatment.

In case of repeated intermittent treatment, periodic monitoring of the endometrium is recommended. This includes annual ultrasound to be performed after resumption of menstruation during off-treatment period.

If endometrial thickening is noted, which persists after return of menstruations during off-treatment periods or beyond 3 months following the end of treatment courses, and/or an altered bleeding pattern is noted (see section "Bleeding pattern" below), investigation including endometrial biopsy should be performed in order to exclude other underlying conditions, including endometrial malignancy.

In case of hyperplasia (without atypia), monitoring as per usual clinical practice (e.g. a follow-up control 3 months later) would be recommended. In case of atypical hyperplasia, investigation and management as per usual clinical practice should be performed.

The treatment courses should each not exceed 3 months as the risk of adverse impact on the endometrium is unknown if treatment is continued without interruption.

Bleeding pattern

Patients should be informed that treatment with ulipristal acetate usually leads to a significant reduction in menstrual blood loss or amenorrhea within the first 10 days of treatment. Should the excessive bleeding persist, patients should notify their physician. Menstrual periods generally return within 4 weeks after the end of each treatment course.

If, during repeated intermittent treatment, after the initial reduction in bleeding or amenorrhea, an altered persistent or unexpected bleeding pattern occurs, such as inter-menstrual bleeding, investigation of the endometrium including endometrial biopsy should be performed in order to exclude other underlying conditions, including endometrial malignancy.

Repeated intermittent treatment has been studied up to 4 intermittent treatment courses.

Renal impairment

Renal impairment is not expected to significantly alter the elimination of ulipristal acetate. In the absence of specific studies, ulipristal acetate is not recommended for patients with severe renal impairment unless the patient is closely monitored (see section 4.2).

Hepatic injury

During the post-marketing experience, cases of liver injury and hepatic failure, some requiring liver transplantation have been reported (see section 4.3).

Liver function tests must be performed before starting treatment. Treatment must not be initiated if transaminases (alanine transaminase (ALT) or aspartate aminotransferase (AST)) exceed 2 x ULN (isolated or in combination with bilirubin >2 x ULN).During treatment, liver function tests must be performed monthly during the first 2 treatment courses. For further treatment courses, liver function must be tested once before each new treatment course and when clinically indicated.If a patient during treatment shows signs or symptoms compatible with liver injury (fatigue, asthenia, nausea, vomiting, right hypochondrial pain, anorexia, jaundice), treatment should be stopped and the patient should be investigated immediately, and liver function tests performed.Patients who develop transaminase levels (ALT or AST) > 3 times the upper limit of normal during treatment should stop treatment and be closely monitored.In addition liver testing should be performed 2- 4 weeks after treatment has stopped.

Concomitant treatments

Co-administration of moderate (e.g. erythromycin, grapefruit juice, verapamil) or potent (e.g. ketoconazole, ritonavir, nefazodone, itraconazole, telithromycin, clarithromycin) CYP3A4 inhibitors and ulipristal acetate is not recommended (see section 4.5).

Concomitant use of ulipristal acetate and potent CYP3A4 inducers (e.g. rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, St John´s wort, efavirenz, nevirapine, long term use of ritonavir) is not recommended (see section 4.5).

Asthma patients

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

4.5. Interaction with other medicinal products and other forms of interaction

Potential for other medicinal products to affect ulipristal acetate:

Hormonal contraceptives

Ulipristal acetate has a steroid structure and acts as a selective progesterone receptor modulator with predominantly inhibitory effects on the progesterone receptor. Thus hormonal contraceptives and progestagens are likely to reduce ulipristal acetate efficacy by competitive action on the progesterone receptor. Therefore concomitant administration of medicinal products containing progestagen is not recommended (see section 4.4 and 4.6).

CYP3A4 inhibitors

Following administration of the moderate CYP3A4 inhibitor erythromycin propionate (500 mg twice daily for 9 days) to healthy female volunteers, Cmax and AUC of ulipristal acetate increased 1.2 and 2.9 fold, respectively; the AUC of the active metabolite of ulipristal acetate increased 1.5 fold while the Cmax of the active metabolite decreased (0.52 fold change).

Following administration of the potent CYP3A4 inhibitor ketoconazole (400 mg once daily for 7 days) to healthy female volunteers, Cmax and AUC of ulipristal acetate increased 2 and 5.9 fold, respectively; the AUC of the active metabolite of ulipristal acetate increased 2.4 fold while the Cmax of the active metabolite decreased (0.53 fold change).

No dose adjustment is considered necessary for administration of ulipristal acetate to patients receiving concomitant mild CYP3A4 inhibitors. Co-administration of moderate or potent CYP3A4 inhibitors and ulipristal acetate is not recommended (see section 4.4).

CYP3A4 inducers

Administration of the potent CYP3A4 inducer rifampicin (300 mg twice daily for 9 days) to healthy female volunteers markedly decreased Cmax and AUC of ulipristal acetate and its active metabolite by 90% or more and decreased ulipristal acetate half-life by 2.2-fold corresponding to an approximately 10-fold decrease of ulipristal acetate exposure. Concomitant use of ulipristal acetate and potent CYP3A4 inducers (e.g. rifampicin, rifabutin, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, primidone, St John´s wort, efavirenz, nevirapine, long term use of ritonavir) is not recommended (see section 4.4).

Medicinal products affecting gastric pH

Administration of ulipristal acetate (10 mg tablet) together with the proton pump inhibitor esomeprazole (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. This effect of medicinal products that increase gastric pH is not expected to be of clinical relevance for daily administration of ulipristal acetate tablets.

Potential for ulipristal acetate to affect other medicinal products:

Hormonal contraceptives

Ulipristal acetate may interfere with the action of hormonal contraceptive medicinal products (progestagen only, progestagen releasing devices or combined oral contraceptive pills) and progestagen administered for other reasons. Therefore concomitant administration of medicinal products containing progestagen is not recommended (see sections 4.4 and 4.6). Medicinal products containing progestagen should not be taken within 12 days after cessation of ulipristal acetate treatment.

P-gp substrates

In vitro data indicate that ulipristal acetate may be an inhibitor of P-gp at clinically relevant concentrations in the gastrointestinal wall during absorption.

Simultaneous administration of ulipristal acetate and a P-gp substrate has not been studied and an interaction cannot be excluded. In vivo results show that ulipristal acetate (administered as a single 10 mg tablet) 1.5 hour before administration of the P-gP substrate fexofenadine (60 mg) has no clinically relevant effects on the pharmacokinetic of fexofenadine. It is therefore recommended that co-administration of ulipristal acetate and P-gp substrates (e.g. dabigatran etexilate, digoxin, fexofenadine) should be separated in time by at least 1.5 hours.

4.6. Fertility, pregnancy and lactation

Contraception in females

Ulipristal acetate is likely to adversely interact with progestagen-only pills, progestagen-releasing devices or combined oral contraceptive pills, therefore, concomitant use is not recommended. Although a majority of women taking a therapeutic dose of ulipristal acetate have anovulation, a non hormonal contraceptive method is recommended during treatment (see sections 4.4 and 4.5).

Pregnancy

Ulipristal acetate is contraindicated during pregnancy (see section 4.3).

There are no or limited amount of data from the use of ulipristal acetate in pregnant women.

Although no teratogenic potential was observed, animal data are insufficient with regard to reproduction toxicity (see section 5.3).

Breastfeeding

Available toxicological data in animals have shown excretion of ulipristal acetate in milk (for details see section 5.3). Ulipristal acetate is excreted in human milk. The effect on newborn/infants has not been studied. A risk to the newborns/infants cannot be excluded. Ulipristal acetate is contraindicated during breastfeeding (see sections 4.3 and 5.2).

Fertility

A majority of women taking a therapeutic dose of ulipristal acetate have anovulation, however, the level of fertility while taking multiple doses of ulipristal acetate has not been studied.

4.7. Effects on ability to drive and use machines

Ulipristal acetate may have minor influence on the ability to drive or use machines as mild dizziness has been observed after ulipristal acetate intake.

4.8. Undesirable effects

Summary of the safety profile

The safety of ulipristal acetate has been evaluated in 1,053 women with uterine fibroids treated with 5 mg or 10 mg ulipristal acetate during Phase III studies. The most common finding in clinical trials was amenorrhea (79.2%), which is considered as a desirable outcome for the patients (see section 4.4).

The most frequent adverse reaction was hot flush. The vast majority of adverse reactions were mild and moderate (95.0%), did not lead to discontinuation of the medicinal product (98.0%) and resolved spontaneously.

Among these 1,053 women, the safety of repeated intermittent treatment courses (each limited to 3 months) has been evaluated in 551 women with uterine fibroids treated with 5 or 10 mg ulipristal acetate in two phase III studies (including 446 women exposed to four intermittent treatment courses of whom 53 were exposed to eight intermittent treatment courses) and demonstrated a similar safety profile to that observed for one treatment course.

Tabulated list of adverse reactions

Based on pooled data from four phase III studies in patients with uterine fibroids treated for 3 months, the following adverse reactions have been reported. Adverse reactions listed below are classified according to frequency and system organ class. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as 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 from available data).

System Organ Class

Adverse reactions during treatment course 1

Very common

Common

Uncommon

Rare

Frequency

Not known

Immune system disorders

Drug hypersensitivity*

Psychiatric disorders

Anxiety

Emotional disorder

Nervous system disorders

Headache*

Dizziness

Ear and labyrinth disorders

Vertigo

Respiratory, thoracic and mediastinal disorders

Epistaxis

Gastrointestinal disorders

Abdominal pain

Nausea

Dry mouth

Constipation

Dyspepsia

Flatulence

Hepatobiliary disorders

Hepatic failure*

Skin and subcutaneous tissue disorders

Acne

Alopecia**

Dry skin

Hyperhidrosis

Angioedema

Musculoskeletal and connective tissue disorders

Musculoskeletal pain

Back pain

Renal and urinary disorders

Urinary incontinence

Reproductive system and breast disorders

Amenorrhea

Endometrial thickening*

Hot flush*

Pelvic pain

Ovarian cyst*

Breast tenderness/pain

Uterine haemorrhage*

Metrorrhagia

Genital discharge

Breast discomfort

Ovarian cyst ruptured*

Breast swelling

General disorders and administration site conditions

Fatigue

Oedema

Asthenia

Investigations

Weight increased

Blood cholesterol increased

Blood triglycerides increased

* see section "Description of selected adverse reactions"

** The verbatim term “mild hair loss” was coded to the term “alopecia”

When comparing repeated treatment courses, overall adverse reactions rate was less frequent in subsequent treatment courses than during the first one and each adverse reaction was less frequent or remained in the same frequency category (except for dyspepsia which was classified as uncommon in treatment course 3 based on one patient occurence).

Description of selected adverse reactions

Hepatic failure

During the post-marketing experience, cases of hepatic failure have been reported. In a small number of these cases, liver transplantation was required. The frequency of occurrence of hepatic failure and patient risk factors are unknown.

Endometrial thickening

In 10-15% of patients, thickening of the endometrium (> 16 mm by ultrasound or MRI at end of treatment) was observed with ulipristal acetate by the end of the first 3-month treatment course. In subsequent treatment courses, endometrial thickening was less frequently observed (4.9% and 3.5% of patients by the end of second and fourth treatment course, respectively). The endometrial thickening reverses when treatment is stopped and menstrual periods resume.

In addition, reversible changes to the endometrium are denoted PAEC and are different from endometrial hyperplasia. If hysterectomy or endometrial biopsy specimens are sent for histology, then the pathologist should be informed that the patient has taken ulipristal acetate (see sections 4.4 and 5.1).

Hot flush

Hot flushes were reported by 8.1% of patients but the rates varied across trials. In the active comparator controlled study the rates were 24% (10.5% moderate or severe) for ulipristal acetate and 60.4% (39.6% moderate or severe) for leuprorelin-treated patients. In the placebo-controlled study, the rate of hot flushes was 1.0% for ulipristal acetate and 0% for placebo. In the first 3-month treament course of the two long term Phase III trials, the frequency was 5.3% and 5.8% for ulipristal acetate, respectively.

Drug hypersensitivity

Drug hypersensitivity symptoms such as generalised oedema, pruritus, rash, swelling face or urticaria were reported by 0.4% of patients in Phase III trials.

Headache

Mild or moderate severity headache was reported in 5.8% of patients.

Ovarian cyst

Functional ovarian cysts were observed during and after treatment in 1.0% of patients and in most of the cases spontaneously disappeared within a few weeks.

Uterine haemorrhage

Patients with heavy menstrual bleeding due to uterine fibroids are at risk of excessive bleeding, which may require surgical intervention. A few cases have been reported during ulipristal acetate treatment or within 2-3 months after ulipristal acetate treatment was stopped.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the MHRA Yellow Card Scheme (www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Experience with ulipristal acetate overdose is limited.

Single doses up to 200 mg and daily doses of 50 mg for 10 consecutive days were administered to a limited number of subjects, and no severe or serious adverse reactions were reported.