Esmya 5mg tablets

Updated guide following Article 31 referral procedure approval.

Updated guide following Article 31 referral procedure approval.

Updated patient card following Article 31 referral. 

1. What Esmya is and what it is used for

Esmya contains the active substance ulipristal acetate. It is used to treat moderate to severe symptoms of uterine fibroids (commonly known as myomas), which are non‑cancerous tumours of the uterus (womb).

Esmya is used in adult women (over 18 years of age) before they reach the menopause.

In some women, uterine fibroids may cause heavy menstrual bleeding (your ‘period’), pelvic pain (discomfort in the belly) and create pressure on other organs.

This medicine acts by modifying the activity of progesterone, a naturally occuring hormone in the body. It is used either before an operation of your fibroids or for long term treatment of your fibroids to reduce their size, to stop or reduce bleeding and to increase your red blood cell count.

4.       Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Stop using Esmya and immediately contact a doctor if you experience any of the following symptoms:

• swelling of face, tongue or throat; difficulty swallowing; hives and breathing difficulties. These are possible symptoms of angioedema (frequency not known).
• nausea or vomiting, severe tiredness, jaundice (yellowing of the eyes or skin), dark urine, itching or upper stomach ache. These symptoms may be signs of liver injury (frequency not known), which in a small number of cases led to liver transplantation. See also section 2 Warnings and precautions

6.         Contents of the pack and other information

This leaflet was last revised in January 2021

4.1      Therapeutic indications

Ulipristal acetate is indicated for one treatment course of pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.

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

4.4    Special warnings and precautions for use    -    Update to the wording under the subheading  'Hepatic Injury' 

Hepatic injury

During the post-marketing experience, cases of liver injury and hepatic failure, some requiring liver transplantation were 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.

4.8      Undesirable effects    -    Addition of the following paragraph under the subheading '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.

 10.      DATE OF REVISION OF THE TEXT

26/07/2018   11/01/2021    

This is a DHPC letter as approved by EMA and HPRA following EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)’s suggestion to suspend Esmya 5mg tablets (ulipristal acetate) during the ongoing Article 31 safety review.

Following EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)’s Article 20 review of Esmya 5mg tablets (ulipristal acetate) the EC have approved the below changes in the SmPC.

(see: http://ec.europa.eu/health/documents/community-register/html/h750.htm#top for more information)

4.1      Therapeutic indications

Ulipristal acetate is indicated for one treatment course of pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.

Ulipristal acetate is indicated for intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age who are not eligible for surgery.

1. 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.

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).

Hepatic impairment

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

4.3      Contraindications

Underlying hepatic disorder.

4.4      Special warnings and precautions for use

Hepatic impairment injury

Hepatic impairment is expected to alter the elimination of ulipristal acetate, resulting in increased exposure (see section 5.2).  

During the post-marketing experience, cases of liver injury and hepatic failure were reported. During treatment, l

Liver function tests should be performed at least monthly. In addition liver testing 2- 4 weeks after treatment has stopped is recommended . If a patient shows signs or symptoms compatible with liver injury (nausea, vomiting, right hypochondrial pain, anorexia, asthenia, jaundice, etc.), the patient should be investigated immediately, and liver function tests performed. Patients who develop transaminase levels > 2 times the upper limit of normal during treatment should stop treatment and be closely monitored.

During the post-marketing expereince, cases of liver injury and hepatic failure were 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.

In section 4.8 Undesirable effects - Hepatobiliary disorders added as a system organ class in the tabulated list of adverse reactions with Hepatic failure seen at a frequency not known (cannot be estimated from available data).

Moreover the following text was added in the:

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.

Section 10 DATE OF REVISION OF THE TEXT

26/07/2018 16/02/2018

Changes are shown as - additions in red, deletions crossed out

Section 4.1      Therapeutic indications (addition of indication)

Ulipristal acetate is indicated for pre-operative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.

Ulipristal acetate is indicated for intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age.

4.2         Posology and method of administration

 Posology

The treatment consists of one tablet of 5 mg to be taken orally once daily for treatment courses of up to 3 months each.

This 3-month treatment course can be repeated once.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 firstprevious treatment course completion.

Treatments should always be started during the first week of menstruation.

Due to the lack of long term safety data, the duration of treatment should not exceed two treatment courses of 3 months. 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.

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.

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 ‘bleeding pattern’), 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.

Endometrial changes

Ulipristal acetate has a specific pharmacodynamic action on the endometrium. Increase in thickness of the endometrium may occur. If the endometrial thickening persists beyond 3 months following the end of treatment and return of menstruations, this may need to be investigated as per usual clinical practice to exclude underlying conditions.

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). 

Only two treatment courses are recommended. The two treatment courses should each not exceed 3 months as the risk of adverse impact on the endometrium is unknown if treatment is continued.

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 will generally return within 4 weeks after the end of the treatment course.

4.8         Undesirable effects

Summary of the safety profile

The safety of ulipristal acetate has been evaluated in 602 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 (80.8 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 (935.60%), did not lead to discontinuation of the medicinal product (998.50%) and resolved spontaneously.

Among these 1,053 women, tThe safety of two repeated intermittent treatment courses (each limited to 3 months) has been evaluated in 131551 women with uterine fibroids treated with 5 or 10 mg ulipristal acetate in atwo phase III studyies (including 457 women exposed to four 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 three fourphase 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 (³1/10), common (³1/100 to <1/10), uncommon (³1/1,000 to <1/100), rare (³1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from available data).

* 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

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 this 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 9.8 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, open-label phase III clinical trial, the frequency was 45.3% and 5.8% for ulipristal acetate, respectively.

Headache
Mild or moderate severity headache was reported in 6 5.8% of patients.

5.1     Pharmacodynamic properties

Endometrium

About 5% of patients of reproductive age experiencing heavy menstrual bleeding have an endometrial thickness of greater than 16 mm. In about 10‑15% of patients treated with ulipristal acetate the endometrium may thicken (> 16 mm) during the first 3-month treatment course. In case of repeated treatment courses, endometrial thickening was less frequently observed (4.9% of patients after second treatment course and 3.5% after fourth treatment course). This thickening disappears after treatment is withdrawn and menstruation occurs. If endometrial thickness persists after return of menstruations during off-treatment periods or beyond the3 months following the end of treatment courses and return of menstruations then this , it may need to be investigated as per usual clinical practice to exclude other underlying conditions.

Ulipristal acetate does not affect serum levels of TSH, ACTH or prolactin during 3 months of treatment.

Clinical efficacy and safety

Pre-operative use:

The efficacy of fixed doses of ulipristal acetate 5 mg and 10 mg once daily was evaluated in two Phase 3 randomised, double-blind, 13 week studies recruiting patients with very heavy menstrual bleeding associated with uterine fibroids.....

Repeated intermittent use:

In a phase III study in 131 women with uterine fibroids receiving two intermittent 3-month treatment courses of ulipristal acetate 10 mg, amenorrhea was achieved at the end of the first treatment course in 79.5% of subjects. The second treatment course provided comparable results (88.5% of subjects). Myoma volume reduction (mean [median] change from screening) observed during the first treatment course (‑41.9% [-49.9%]) was maintained during the second one (-43.7% [-63.2%]).