Esmya 5mg tablets

  • Name:

    Esmya 5mg tablets

  • Company:
    info
  • Active Ingredients:

    Ulipristal acetate

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 31/07/18

files-icon(Click to Download)
Summary of Product Characteristics last updated on medicines.ie: 1/8/2018

Click on this link to Download PDF directly

Gedeon Richter (UK) Ltd

Gedeon Richter (UK) Ltd

Company Products

Medicine NameActive Ingredients
Medicine Name Bemfola 150 IU/0.25 ml solution for injection in a pre-filled pen Active Ingredients follitropin alfa
Medicine Name Bemfola 225 IU/0.375 ml solution for injection in a pre-filled pen Active Ingredients follitropin alfa
Medicine Name Bemfola 300 IU/0.50 ml solution for injection in a pre-filled pen Active Ingredients follitropin alfa
Medicine Name Bemfola 450 IU/0.75 ml solution for injection in a pre-filled pen Active Ingredients follitropin alfa
Medicine Name Bemfola 75 IU/0.125 ml solution for injection in a pre-filled pen Active Ingredients follitropin alfa
Medicine Name Esmya 5mg tablets Active Ingredients Ulipristal acetate
Medicine Name Ramonna 1500 microgram Tablet Active Ingredients Levonorgestrel
1 - 0 of 7 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 23 March 2020 Ed-HCP

Reasons for updating

  • Add New Doc

Free text change information supplied by the pharmaceutical company

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.

Updated on 1 August 2018 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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. 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

Updated on 31 July 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 4 - possible side effects
  • Change to section 4 - how to report a side effect
  • Change to section 6 - date of revision

Updated on 26 February 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 26 February 2018 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Updated 23.02.2018 to include the Date of Revision following publication of EC decision:

In Section 10 Date of Revision of the Text:
DD/MM/YYYY16/02/2018
On 8 February 2018, while the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)’s Article 20 review of Esmya 5mg tablets (ulipristal acetate) is ongoing, the EMA issued temporary measures which were published on their website on 9th February 2018: (see:http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Esmya/human_referral_prac_000070.jsp&mid=WC0b01ac05805c516f)

These temporary measures resulted in changes in the product information. The changes as agreed by the PRAC are as follows: 

In Section 4.2 Posology and Method of administration:

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).

In Section 4.4 Special warnings and precautions for use:
Hepatic impairment
There is no therapeutic experience with ulipristal acetate in patients with hepatic impariment. Hepatic impairment is expected to alter the elimination of ulipristal acetate, resulting in increased exposure (see section 5.2). This is considered not to be clinically relevant for patients with mildly impaired liver function. Ulipristal acetate is not recommended for use in patients with moderate or severe hepatic impairment unless the patient is closely monitored (see section 4.2). 

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

Updated on 23 February 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 23 February 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision

Updated on 19 February 2018 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

On 8 February 2018, while the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC)’s Article 20 review of Esmya 5mg tablets (ulipristal acetate) is ongoing, the EMA issued temporary measures which were published on their website on 9th February 2018:
(see:http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Esmya/human_referral_prac_000070.jsp&mid=WC0b01ac05805c516f)

These temporary measures resulted in changes in the product information. The changes as agreed by the PRAC are as follows:

In Section 4.2 Posology and Method of administration:
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 4.4and 5.2).

In Section 4.4 Special warnings and precautions for use:
Hepatic impairment
There is no therapeutic experience with ulipristal acetate in patients with hepatic impariment. Hepatic impairment is expected to alter the elimination of ulipristal acetate, resulting in increased exposure (see section 5.2). This is considered not to beclinically relevant for patients with mildly impaired liver function.Ulipristal acetate is not recommended for use in patients with moderate orsevere hepatic impairment unless the patient is closely monitored (see section4.2).
During the post-marketing experience, cases of liver injury and hepatic failure were reported. During treatment, 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.

In Section 10 Date of Revision of the Text:
08/12/2017
DD/MM/YYYY

Updated on 19 February 2018 PIL

Reasons for updating

  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 6 - date of revision

Updated on 21 December 2017 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Section 4.8 – addition of Adverse reactions during treatment course 1
Addition of:
Immune system disorders - Drug hypersensitivity* - Frequency Uncommon
Skin and subcutaneous tissue disorders – Angioedema – Frequency Not known

Addition of description:
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.

Change in Section 10 - Date of Revision of text
from 14/11/2016 to 08/12/2017

Updated on 18 December 2017 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 29 November 2016 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 9 - Date of first authorisation/renewal of the authorisation
  • Change to section 10 - Date of revision of the text
  • Correction of spelling/typing errors
  • Improved presentation of SPC

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

$0Tracked changes shown in redbelow wit specifics for each section as necessary:$0$04.2         Posology and method ofadministration$0$0Posology$0$0Thetreatment consists of one tablet of 5 mg to be taken orally once dailyfor treatment courses of up to 3 months each. Tablets may be taken with or without food.$0$0…….$0$0Method ofadministration$0$0Oral use. Tablets maybe taken with or without food should be swallowed with water.$0$04.4     Specialwarnings and precautions for use$0$0……..$0$0Contraception$0$0Concomitant use of progestagen‑only pills, a progestagen‑releasingintrauterine device orcombined oral contraceptive pills is not recommended (see section 4.5).Although a majority of women taking a therapeutic dose of ulipristal acetatehave anovulation, a non hormonal contraceptive method is recommended duringtreatment.$0$0Endometrialchanges$0$0.......$0$0Ifendometrial thickening is noted, which persists after return of menstruationsduring off‑treatment periods or beyond 3 months following the end of treatmentcourses, and/or an altered bleeding pattern is noted (see section "Bleeding pattern" belowbleedingpattern’), investigation including endometrial biopsyshould be performed in order to exclude other underlying conditions, includingendometrial malignancy.$0$0……………….$0$04.5Interaction with other medicinal products and other forms of interaction$0$0……………..$0$0Potentialfor ulipristal acetate to affect other medicinal products:$0$0Hormonalcontraceptives$0$0Ulipristalacetate may interfere with the action of hormonal contraceptive medicinal products(progestagen only, progestagen releasing devices or combined oral contraceptivepills) and progestagen administered for other reasons. Therefore concomitantadministration of medicinal products containing progestagen is not recommended(see sections 4.4 and 4.6). Medicinal products containing progestagenshould not be taken within 12 days after cessation of ulipristal acetatetreatment.$0$0……$0$0In 4.6, Breast feeding changed to Breastfeeding$0$04.6     Fertility, pregnancy and lactation$0$0……..$0$0Breastfeeding$0$0Available toxicological data in animalshave shown excretion of ulipristal acetate in milk (for details seesection 5.3). Ulipristal acetate is excreted in human milk. The effect on newborn/infants hasnot been studied. Arisk to thenewborns/infants cannot be excluded. Ulipristal acetate is contraindicated during breastfeeding (see sections 4.3 and 5.2).$0$0……$0$0In 4.8, formatting changes toensure '3 months' appears on one line in A4 printed SPC$0$04.8         Undesirable effects$0$0Summary ofthe safety profile$0$0..............$0$0Among these1,053 women, the safety of repeated intermittent treatment courses (eachlimited to 3 3 months) hasbeen evaluated in 551 women with uterine fibroids treated with 5 or10 mg ulipristal acetate in two phase III studies (including 446 womenexposed to four intermittent treatment courses of whom 53 were exposed to eightintermittent treatment courses) and demonstrated a similar safety profile tothat observed for one treatment course.$0$0…………..$0$0In 5.1,reformatting the wording in different paragraphs for improved presentation ofinformation and spacing amends in tables 1 and 2 for N numbers; other trackedchanges below in red $0$05.1Pharmacodynamic properties$0$0Mechanism of action$0$0Ulipristal acetate exerts a direct effect on theendometrium.$0$0Ulipristalacetate exerts a direct action on fibroids reducing their size throughinhibition of cell proliferation and induction of apoptosis.$0$0Pharmacodynamic effects$0$0Endometrium$0$0Ulipristal acetate exerts a direct effect on theendometrium. When dailyadministration of a 5 mg dose is commenced during a menstrual cycle mostsubjects (including patients with myoma) will complete their first menstruationbut will not menstruate again until after treatment is stopped. When ulipristalacetate treatment is stopped, menstrual cycles generally resume within4 weeks.$0$0……………………..$0$0Fibroids$0$0Ulipristal acetate exerts a direct action onfibroids reducing their size through inhibition of cell proliferation andinduction of apoptosis.$0$0Pituitary$0$0A daily doseof ulipristal acetate 5 mg inhibits ovulation in the majority of patientsas indicated by progesterone levels maintained at around 0.3 ng/ml.$0$0………….$0$0Clinicalefficacy and safety$0$0Pre-operativeuse:$0$0The efficacyof fixed doses of ulipristal acetate 5 mg and 10 mg once daily wasevaluated in two Phase 3 randomised, double-blind, 13 week studiesrecruiting patients with very heavy menstrual bleeding associated with uterinefibroids. Study 1 was double-blind placebo controlled. Patients in thisstudy were required to be anaemic at Study entry (Hb < 10.2 g/dl) andall patients were to receive oral iron 80 mg Fe++ in addition to study drugmedicinal product.Study 2 contained the active comparator, leuprorelin 3.75 mg givenonce per month by intramuscular injection. In Study 2, a double‑dummymethod was used to maintain the blind. In both studies menstrual blood loss wasassessed using the Pictorial Bleeding Assessment Chart (PBAC). A PBAC >100within the first 8 days of menses is considered to represent excessivemenstrual blood loss.$0$0……$0$0Endometrial findings:$0$0In all PhaseIII studies including repeated intermittent treatment studies, a total of 7cases of hyperplasia were observed out of 789 patients with adequate biopsies(0.89%). The vast majority spontaneously reversed to normal endometrium afterresumption of menstruation during the off‑treatment period. The incidence ofhyperplasia did not increase with repeated treatment courses, including data on340 women who received up to 4 courses of ulipristal acetate 5 or 10 mg andlimited data of 43 women who received up to 8 courses of ulipristal acetate 10mg. The observed frequency is in line with control groups and prevalencereported in literature for symptomatic pre-menopausal women of this age group(mean of 40 years).$0$0Paediatricpopulation$0$0The European Medicines Agency has waived theobligation to submit the results of studies with Esmya in all subsets of thepaediatric population in leiomyoma of uterus (see section 4.2 forinformation on paediatric use).$0$0 $0$0In 5.2 Pharmacokinetic properties,  minorformatting change to bring text within section (Distrbution) on onepage for improved presentation of information in A4 printed SPC$0$09.       DATE OF FIRSTAUTHORISATION/RENEWAL OF THE AUTHORISATION$0$0Date offirst authorisation: 23 February 2012$0$0Date of latest renewal: 14 November 2016$0$010.DATE OF REVISION OF THE TEXT $0$014/11/2016$0$0Detailed information on this medicinal product isavailable on the website of the European Medicines Agency http://www.ema.europa.eu$0

Updated on 28 November 2016 PIL

Reasons for updating

  • Change to section 2 - use in children and adolescents
  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 6 - date of revision
  • Correction of spelling/typing errors
  • Improved presentation of PIL

Updated on 8 May 2016 SmPC

Reasons for updating

  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

$0$0In section 4.8 (undesirable effects), Summary of the safety profile, an amend and additional text with regards to safety database numbers has been undertaken as below$0$0$0$0$0$0''Amongthese 1,053 women, the safety of repeated intermittent treatment courses (eachlimited to 3 months) has been evaluated in 551 women with uterine fibroidstreated with 5 or 10 mg ulipristal acetate in two phase III studies $0$0(including 457 446 women exposed to four intermittent treatment courses of whom 53 wereexposed to eight intermittent treatment courses) and demonstrated a similarsafety profile to that observed for one treatment course.''$0$0$0$0$0$0$0In section 5.1 (Pharmacoidynamic properties), under Endometrial findings, additional text added as below:$0$0$0$0$0$0''The incidence of hyperplasia did not increasewith repeated treatment courses, including data on 340 women who received up to4 courses of ulipristal acetate 5 or 10 mg and limited data of 43 women whoreceived up to 8 courses of ulipristal acetate 10 mg.'' $0

Updated on 8 June 2015 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.5 - Nature and contents of container
  • Change to section 8 - MA number
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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).

 

 

System Organ Class

Adverse reactions during treatment course 1

Very common

 

Common

 

Uncommon

 

Rare

 

Psychiatric disorders

 

 

Anxiety

Emotional disorder

 

Nervous system disorders

 

Headache*

Dizziness

 

Ear and labyrinth disorders

 

Vertigo

 

 

Respiratory, thoracic and mediastinal disorders

 

 

Epistaxis

 

Epistaxis

 

Gastrointestinal disorders

 

Abdominal pain

Nausea

Dyspepsia

Dry mouth

Flatulence

Constipation

Dyspepsia

Flatulence

Skin and subcutaneous tissue disorders

 

Acne

Hyperhidrosis

Alopecia**

Dry skin

Hyperhidrosis

 

Musculoskeletal and connective tissue disorders

 

Musculoskeletal pain

Back pain

 

Renal and urinary disorders

 

 

Urinary incontinence

 

Reproductive system and breast disorders

Amenorrhea

Endometrial thickening*

 

Uterine haemorrhage*

Hot flush*

Pelvic pain

Ovarian cyst*

Breast tenderness/pain

Uterine haemorrhage*

Metrorrhagia

Ovarian cyst ruptured

Genital discharge

Breast swelling

Breast discomfort

Ovarian cyst ruptured*

Breast swelling

 

General disorders and administration site conditions

 

Oedema
Fatigue

Oedema

Asthenia

 

Investigations

 

Weight increased Blood cholesterol increased

Blood cholesterol increased

Blood triglycerides increased Weight 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

 

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%]).

In view of studies 1 and 2 results, it is expected that similarly to the 10 mg dose the efficacy of the 5 mg dose in the first treatment course will be maintained in the second treatment course.

Although the number of patients that completed the four treatment courses of 3 months is limited, i.e. 99 patients, the safety data are sufficient to support one additional 3-month treatment course in a pre-operative setting.

The efficacy of repeated treatment courses fixed doses of ulipristal acetate 5 mg or 10 mg once daily was evaluated in two Phase 3 studies assessing up to 4 intermittent 3-month treatment courses in patients with heavy menstrual bleeding associated with uterine fibroids. Study 3 was on open-label study assessing ulipristal acetate 10 mg, where each of the 3-month treatment was followed by 10 days of double-blind treatment with progestin or placebo. Study 4 was a randomized, double-blind clinical study assessing ulipristal acetate 5 or 10 mg.

 

Studies 3 and 4 showed efficacy in controlling uterine fibroid symptoms (e.g. uterine bleeding) and reducing fibroid size after 2 and 4 courses.

In study 3, treatment efficacy has been shown over > 18 months of repeated intermittent treatment (4 courses of 10 mg once daily), 89.7% of patients were in amenorrhea at the end of the treatment course 4.

In study 4, 61.9% and 72.7% of patients were in amenorrhea at the end of both treatment course 1 and 2 combined (5 mg dose and 10 mg dose, respectively, p=0.032); 48.7 % and 60.5 % were in amenorrhea at the end of all four treatment courses combined (5 mg dose and 10 mg dose, respectively, p=0.027). At the end of treatment course 4, 158 (69.6%) subjects and 164 (74.5%) subjects were assessed as being in amenorrhea, in the 5 mg dose and 10 mg dose respectively (p=0.290).

 

Table 2: Results of primary and selected secondary efficacy assessments in long term Phase III studies

Parameter

After treatment course 2

(two times 3 months of treatment)

After treatment course 4

(four times 3 months of treatment)

 

Study 3a

Study 4

Study 3

Study 4

Patients starting treatment course 2 or 4

10 mg/day

N=132

5 mg/day

N= 213

10 mg/day

N=207

10 mg/day

N=107

5 mg/day

N=178

10 mg/day

N=176

Patients in amenorrheab,c

N=131

N = 205

N = 197

N=107

N =227

N =220

116

(88.5%)

152

(74.1%)

162

(82.2%)

96

(89.7%)

158 (69.6%)

164 (74.5%)

Patients with controlled bleedingb,c, d

NA

N=199

N=191

NA

N= 202

N=192

175 (87.9%)

168 (88.0%)

148 (73.3%)

144 (75.0%)

Median change in myoma volume from baseline

-63.2%

-54.1%

-58.0%

-72.1%

-71.8%

-72.7%

a Treatment course 2 assessment corresponds to Treatment course 2 plus one menstrual bleeding.

b Patients with missing values were exluded from the analysis.

c N and % include withdrawn patients

d Controlled bleeding was defined as no episodes of heavy bleeding and a maximum of 8 days of bleeding (not including days of spotting) during the last 2 months of a treatment course.

 

Endometrial findings:

In all Phase III studies including repeated intermittent treatment studies, a total of 7 cases of hyperplasia were observed out of 789 patients with adequate biopsies (0.89%). The vast majority spontaneously reversed to normal endometrium after resumption of menstruation during the off-treatment period. The incidence of hyperplasia did not increase with repeated treatment courses. The observed frequency is in line with control groups and prevalence reported in literature for symptomatic pre-menopausal women of this age group (mean of 40 years).


Endometrial findings:

In all Phase III studies including repeated intermittent treatment studies, a total of 7 cases of hyperplasia were observed out of 789 patients with adequate biopsies (0.89%). The vast majority spontaneously reversed to normal endometrium after resumption of menstruation during the off-treatment period. The incidence of hyperplasia did not increase with repeated treatment courses. The observed frequency is in line with control groups and prevalence reported in literature for symptomatic pre-menopausal women of this age group (mean of 40 years).


5.2     Pharmacokinetic properties (additions in red)

Absorption

Following oral administration of a single dose of 5 or 10 mg, ulipristal acetate is rapidly absorbed, with a Cmax of 23.5 ± 14.2 ng/ml and 50.0 ± 34.4 ng/ml occurring approximately 1 h after ingestion, and with an AUC0-∞ of 61.3 ± 31.7 ng.h/ml and 134.0 ± 83.8 ng.h/ml, respectively. Ulipristal acetate is rapidly transformed into a pharmacologically active metabolite with a Cmax of 9.0 ± 4.4 ng/ml and 20.6 ± 10.9 ng/ml also occurring approximately 1 h after ingestion, and with an AUC0-∞ of 26.0 ± 12.0 ng.h/ml and 63.6 ± 30.1 ng.h/ml respectively.


6.5         Nature and contents of container (addition in red)

Alu/PVC/PE/PVDC or Alu/PVC/PVDC blister.

Pack of 28, 30 and 84 tablets.

Not all pack sizes may be marketed.

 

8.         MARKETING AUTHORISATION NUMBER(S) (additions in red)

 

EU/1/12/750/001

EU/1/12/750/002

EU/1/12/750/003

EU/1/12/750/004

EU/1/12/750/005

 

10.     DATE OF REVISION OF THE TEXT (new date)

 

27/05/2015

 

Updated on 8 June 2015 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision
  • Change to dosage and administration
  • Changes to therapeutic indications

Updated on 24 March 2014 SmPC

Reasons for updating

  • New SPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

None provided

Updated on 11 March 2014 PIL

Reasons for updating

  • New PIL for new product