Esmya: detailed information

Package leaflet: Information for the user

Esmya 5 mg tablets

Ulipristal acetate
Read this entire leaflet carefully before taking this medicine because it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful.
If you experience any adverse reactions, including those not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Contents of this leaflet

What Esmya is and what it is used for
What you need to know before taking Esmya
How to take Esmya
Possible side effects
How to store Esmya
Contents of the pack and other information

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 (also known as fibroids or myomas), which are benign tumours of the uterus.
Esmya is used in adult women (over 18 years of age) who have not yet reached menopause.
In some women, uterine fibroids can cause heavy menstrual bleeding ("periods"), pelvic pain (discomfort in the lower abdomen), and pressure on other organs.
This medicine works by modifying the activity of progesterone, a hormone naturally present in the body. It is used for the long-term treatment of fibroids to reduce their size, stop or reduce bleeding, and increase the number of red blood cells.

2. What you should know before taking Esmya

You should know that most women do not have menstrual bleeding (periods) during treatment and for several weeks afterwards.

Do not take Esmya

if you are allergic to ulipristal acetate or to any of the other ingredients of Esmya (listed in section 6);
if you have underlying liver disease;
if you are pregnant or breastfeeding;
if you have vaginal bleeding not caused by uterine fibroids;
if you have a tumour of the uterus, cervix (neck of the womb), ovaries or breast.

Warnings and precautions

Before starting treatment with Esmya, you will undergo blood tests to check liver function. Based on the results of these tests, your doctor will decide whether treatment with Esmya is suitable for you. These tests will be repeated every month for the first 2 treatment cycles. For subsequent treatment cycles, liver function will be checked once before each new treatment cycle and if you experience any of the symptoms described below. In addition, a further liver check must be carried out 2–4 weeks after stopping treatment.
If during treatment you notice any signs related to the liver, such as feeling unwell (nausea or vomiting), tiredness, severe fatigue, jaundice (yellowing of the eyes or skin), dark urine, itching or pain in the upper abdomen, stop taking Esmya and contact a doctor immediately. The doctor will check your liver function and decide whether you can continue treatment.
If you are taking a hormonal contraceptive (e.g. the oral contraceptive pill) (see "Other medicines and Esmya"), you must use a reliable alternative barrier method of contraception (such as a condom) while taking Esmya.
If you have liver or kidney disease, inform your doctor or pharmacist before taking Esmya.
If you suffer from severe asthma, Esmya may not be suitable for you. Discuss this with your doctor.

Treatment with Esmya generally causes a significant reduction in menstrual bleeding (periods) or may even stop it completely within the first 10 days of treatment. However, if you continue to experience excessive bleeding, inform your doctor.
Menstruation usually resumes within 4 weeks after stopping treatment with Esmya. The lining of the uterus may thicken or change as a result of treatment with Esmya. These changes disappear after treatment ends and menstruation resumes.

Children and adolescents
Children under 18 years of age must not take Esmya, as the safety and efficacy of ulipristal acetate in this age group have not been established.

Other medicines and Esmya
Inform your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
If you are taking any of the following medicines, inform your doctor or pharmacist, as these medicines may interact with Esmya:

Some medicines used to treat heart conditions (e.g. digoxin).
Some medicines used to prevent stroke and blood clots (e.g. dabigatran etexilate).
Some medicines used to treat epilepsy (e.g. phenytoin, fosphenytoin, phenobarbital, carbamazepine, oxcarbazepine, primidone).
Some medicines used to treat HIV infection (e.g. ritonavir, efavirenz, nevirapine).
Medicines used to treat certain bacterial infections (e.g. rifampicin, telithromycin, clarithromycin, erythromycin, rifabutin).
Some medicines used to treat fungal infections (e.g. ketoconazole (except shampoo), itraconazole).
Herbal remedies containing St. John’s wort (Hypericum perforatum), used for treating depression or anxiety.
Some medicines used to treat depression (e.g. nefazodone).
Some medicines used to treat high blood pressure (e.g. verapamil).

Esmya is likely to reduce the effectiveness of some hormonal contraceptives. Hormonal contraceptives and progestins (e.g. norethisterone or levonorgestrel) are also likely to reduce the effectiveness of Esmya. Therefore, hormonal contraceptives are not recommended, and you must use a reliable alternative barrier method of contraception, such as a condom, during treatment with Esmya.

Esmya with food and drink
You should avoid drinking grapefruit juice during treatment with Esmya.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Do not take Esmya if you are pregnant. Treatment during pregnancy may affect its course (it is not known whether Esmya could harm the unborn child or cause miscarriage). If you become pregnant while taking Esmya, you must stop taking Esmya immediately and contact your doctor or pharmacist.
Esmya is likely to reduce the effectiveness of some hormonal contraceptives (see “Other medicines and Esmya”). Esmya is excreted in breast milk. You must therefore not breastfeed while taking Esmya.

Driving and using machines
Esmya may cause mild dizziness (see section 4 “Possible side effects”). If you experience these symptoms, do not drive and do not operate machinery.

3. How to take Esmya

Take this medicine exactly as your doctor has told you. If you are unsure, consult your doctor or pharmacist.
The recommended dose is one 5 mg tablet per day, taken in treatment cycles of up to a maximum of 3 months each. If your doctor has prescribed several 3-month treatment cycles with Esmya, you should start each new cycle as soon as possible during the second menstrual cycle following the completion of the previous treatment.
You should always start taking Esmya during the first week of the menstrual cycle.
The tablet should be swallowed with water and may be taken with or without food.

If you take more Esmya than you should
Experience with taking higher single doses of Esmya is limited. Serious harmful effects have not been reported following the concomitant intake of multiple doses of this medicine. However, if you take more Esmya than you should, it is recommended that you consult your doctor or pharmacist.

If you forget to take Esmya
If you forget a dose and it is less than 12 hours since you were supposed to take it, take it as soon as you remember. If more than 12 hours have passed, skip the missed dose and take the next tablet at your usual time. Do not take a double dose to make up for the forgotten tablet.

If you stop taking Esmya
Esmya must be taken daily during treatment cycles of up to a maximum of 3 months. During each treatment cycle, do not stop taking the tablets without consulting your doctor, even if you feel better, because symptoms may return later.

If you have any doubts about how to use this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
Stop using Esmya and contact a doctor immediately if you experience any of the following symptoms:

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

Very common side effects (may affect more than 1 in 10 people):

reduced or absent menstrual bleeding (amenorrhea)
thickening of the uterine lining (endometrial thickening)

Common side effects (may affect up to 1 in 10 people):

headache
dizziness
stomach discomfort, feeling unwell (nausea)
acne
muscle and bone pain (musculoskeletal pain)
fluid-filled sac in the ovary (ovarian cyst), breast tenderness/pain, lower abdominal (pelvic) pain
hot flushes
tiredness (fatigue)
weight gain

Uncommon side effects (may affect up to 1 in 100 people):

allergic reaction to the medicine
anxiety
mood swings
dizziness
dry mouth, constipation
hair loss, dry skin, increased sweating
back pain
urinary incontinence
uterine bleeding (uterine haemorrhage), vaginal discharge, abnormal vaginal bleeding, breast discomfort
swelling due to fluid retention (oedema)
extreme tiredness (asthenia)
increased blood cholesterol levels detected by blood tests, increased blood fats (triglycerides) detected by blood tests

Rare side effects (may affect up to 1 in 1,000 people):

nosebleeds
indigestion, bloating
rupture of a fluid-filled sac in the ovary (ovarian cyst rupture)
breast swelling

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system listed in Annex V.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Esmya

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and blister after
"Exp." The expiry date refers to the last day of that month.
Keep the blister in the outer packaging to protect the medicine from light.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Esmya contains

The active substance is ulipristal acetate. One tablet contains 5 mg of ulipristal acetate.
The other components are microcrystalline cellulose, mannitol, sodium croscarmellose, talc and magnesium stearate.

Description of the appearance of Esmya and package contents
Esmya is a white to off-white, round, biconvex tablet 7 mm in diameter, with the inscription “ES5”
imprinted on one side.
It is available in Al/PVC/PE/PVDC blisters in cardboard boxes containing 28, 30 and 84 tablets or in
Al/PVC/PVDC blisters in cardboard boxes containing 28 and 84 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Gedeon Richter Plc.
Gyömrői út 19-21.
1103 Budapest
Hungary
Manufacturer
Cenexi
17, rue de Pontoise
F-95520 Osny
France
Gedeon Richter Plc.
Gyömrői út 19-21.
1103 Budapest
Hungary
Other sources of information
More detailed information on this medicinal product is available on the European Medicines Agency
website: http://www.ema.europa.eu
ANNEX IV
SCIENTIFIC CONCLUSIONS
Scientific conclusions
Ulipristal acetate 5 mg (Esmya) was first authorised in all EU/EEA countries on 23 February 2012 via a centralised procedure. Since 2019, in several EU countries, generic medicines containing ulipristal acetate 5 mg have been authorised via national procedures under various brand names. The post-authorisation exposure to ulipristal acetate 5 mg is estimated at 960,414 patients overall up to 29 February 2020.
Ulipristal acetate was initially authorised in the EU for the preoperative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age, with a treatment cycle duration limited to 3 months due to the lack of long-term safety data beyond 3 months. In 2015, when long-term data became available, a second indication was approved to allow repeated intermittent treatment cycles in women for whom surgery was not planned.
In May 2018, the PRAC completed a review of the benefit-risk balance of Esmya under Article 20 of Regulation (EC) No 726/2004, initiated following reports of three cases of serious liver injury leading to liver transplantation. During the review, an additional case of acute liver failure associated with ulipristal acetate 5 mg was reported. Following the review and considering all available data, the PRAC recommended a series of measures to minimise the risk of serious liver injury associated with ulipristal acetate 5 mg, including restrictions to the indications. The PRAC recommendations were endorsed by the CHMP in May 2018. Currently, ulipristal acetate is approved in the EU/EEA for the following indications:

single treatment cycle for preoperative treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age;
intermittent treatment of moderate to severe symptoms of uterine fibroids in adult women of reproductive age who are not suitable candidates for surgery.
In December 2019, the EMA was informed of a new case of serious liver injury leading to liver transplantation following exposure to ulipristal acetate (the 5th case overall). The severity of the reported case, the causal relationship between ulipristal acetate 5 mg and acute liver failure, and its occurrence despite adherence to the implemented risk minimisation measures were considered major concerns, justifying a thorough assessment of the impact on the benefit-risk balance of ulipristal acetate and a further evaluation of the effectiveness of the implemented risk minimisation measures. On 5 March 2020, the European Commission (EC) initiated a procedure under Article 31 of Directive 2001/83/EC, requesting the Agency to evaluate these concerns and their impact on the benefit-risk balance of ulipristal acetate 5 mg and to issue an opinion on whether the marketing authorisation for ulipristal acetate 5 mg should be maintained, varied, suspended or revoked. Furthermore, the EC requested the Agency to issue an opinion on the need for interim measures. On 12 March 2020, after reviewing the available data, particularly the 5th overall case of serious liver injury leading to liver transplantation, the PRAC recommended, as an interim measure, the suspension of marketing authorisations for medicines containing ulipristal acetate 5 mg until a final decision could be reached. On 3 September 2020, the PRAC adopted a recommendation to revoke the marketing authorisations for the medicines concerned, which was subsequently reviewed by the CHMP under Article 107 duodecies of Directive 2001/83/EC.

General summary of the PRAC’s scientific assessment
The efficacy of ulipristal acetate 5 mg in treating symptoms of uterine fibroids was demonstrated at the time of the initial marketing authorisation of Esmya. The clinical benefits of preoperative treatment are considered limited, as it is restricted to a single treatment cycle prior to surgery, and other short-term treatment alternatives exist. The benefits of ulipristal acetate are considered greater for the intermittent treatment indication, i.e., for patients not suitable candidates for surgery, as treatment alternatives for these patients are limited. Patients not suitable for surgery may include women who, for various reasons, present surgical risks, such as obesity, concomitant diseases, treatment with certain medications, or to preserve fertility. Therefore, ulipristal acetate 5 mg may provide clinically relevant benefits to women not suitable candidates for surgery, whose health and quality of life are affected by symptoms of uterine fibroids, particularly heavy bleeding.
In the previous review of Esmya under Article 20, the risk of drug-induced liver injury (DILI) associated with ulipristal acetate 5 mg was carefully examined. Following that review, “liver failure” was listed as an adverse reaction and drug-induced liver injury (DILI) as a significant identified risk of ulipristal acetate. Both approved indications were restricted, and several risk minimisation measures were implemented. Additionally, the marketing authorisation holder of Esmya was required to conduct several studies, including on the mechanism of ulipristal acetate-associated liver injury, to further characterise this risk. However, these studies did not further clarify the mechanism of liver injury associated with ulipristal acetate 5 mg, and based on available evidence, hepatotoxicity associated with ulipristal acetate is considered to be of an idiosyncratic nature, making it difficult to identify susceptible patients who would be at higher risk.
Since the previous review, Gedeon Richter observed a significant decline (over 50%) in patient exposure to Esmya. Between 1 March 2018 and 29 February 2020, 476 new cases were received within the SMQ liver disorders (serious and non-serious events); of these, 97 were serious, with 7 cases containing sufficient/partially sufficient information for causality assessment, including one case of serious liver injury leading to liver transplantation (the 5th case overall). In this case, no confounding factors were identified and other plausible causes were excluded; consequently, the causal relationship between ulipristal acetate and acute hepatitis leading to acute liver failure and liver transplantation was assessed as probable/highly probable, i.e., with a considerably higher degree of certainty.
It was also observed that progression to liver failure leading to liver transplantation could not be prevented. This case therefore confirms that the recommendations on liver monitoring included in the product information following the previous referral were not sufficient to prevent serious liver injury leading to liver transplantation in all patients.
In the context of the current review, marketing authorisation holders were asked to discuss the need and feasibility of any new risk minimisation measures to further mitigate the risk of serious hepatotoxicity, including changes to the product information, as well as proposals to monitor their effectiveness.
To further reduce the risk, the marketing authorisation holder of the originator medicine Esmya proposed to withdraw the preoperative indication, specifying that preoperative treatment could be replaced by the use of a GnRH agonist for short-term use. As highlighted by some experts consulted during this review, the reduction in fibroid volume achieved with ulipristal acetate 5 mg is not considered substantial, and therefore the use of this medicine in a preoperative setting does not significantly influence the positive outcome of a surgical procedure. Most experts also observed that alternatives exist for this indication in the preoperative phase. In light of the above and considering the risk of serious liver injury leading to liver transplantation due to ulipristal acetate 5 mg, the benefit-risk balance of ulipristal acetate 5 mg for the preoperative treatment of moderate to severe symptoms of uterine fibroids is considered unfavourable for this indication, which should therefore be removed.
To further reduce the risk, the marketing authorisation holder of Esmya also proposed restricting the target population for the intermittent treatment indication to patients not suitable candidates for hysterectomy. However, concerns were raised regarding the definition of this patient subset. Discussions within the expert group convened for this review revealed that the proposed description/definition of this subset is very broad (e.g., women with clear medical contraindications to surgery, women for whom other treatment options have proven ineffective, women wishing to preserve fertility, and women unwilling to undergo surgery). In clinical practice, depending on the interpretation of “patients unwilling to undergo surgery” or “patients not suitable candidates for surgery/hysterectomy”, this indication could apply to many patients, thereby weakening the restriction of the indication to “not suitable candidates for surgery/hysterectomy” as a risk minimisation measure. Experts also acknowledged that long-term data on the benefits of ulipristal acetate 5 mg beyond symptom relief, i.e., to avoid surgery/hysterectomy, are currently lacking.
Experts consulted during the review recommended the need to adequately communicate the benefits and risks of ulipristal acetate to patients, particularly the risk of liver injury, and stressed the importance of placing these benefits and risks in the context of the benefits and risks of all other available options. The PRAC considered the experts’ reflections that surgical treatment alternatives for moderate to severe symptoms of uterine fibroids are not without risk. However, the PRAC considered that a fair comparison between surgical and pharmacological treatments was difficult, as it would require including various short- and long-term outcomes of both treatments regarding health, preferably based on comparative studies. Surgical treatment may lead to immediate cure but may, in rare cases, carry a risk of short- or long-term sequelae, whereas pharmacological treatments mainly result in symptom relief but, in rare cases, may cause serious adverse events. Gedeon Richter, the marketing authorisation holder of Esmya, also recognised the need to assess the feasibility of ensuring equal opportunities for all patients to make an adequately informed decision, including adequate information sharing by the treating physician regarding the risks of treatment options and their consequences, and acknowledged that significant limitations may exist based on available communication tools and channels.
The PRAC considered that the proposed changes to the indications (i.e., removal of the preoperative indication and restriction of the intermittent indication to patients not suitable candidates for surgery/hysterectomy) could further reduce the number of patients exposed to ulipristal acetate 5 mg. However, as acknowledged by the marketing authorisation holder of Esmya, the patient group for which the therapy is suitable cannot be scientifically well-defined, making the decision to treat with ulipristal acetate 5 mg rather subjective. Furthermore, considering the idiosyncratic nature of the risk and the difficulty in predicting its occurrence (e.g., identifying relevant risk factors), the PRAC considered that the risk of serious liver injury would not be sufficiently reduced in patients still exposed. In addition, the consulted experts were unable to identify a population in which the risk could be predicted and therefore prevented. The PRAC also noted limitations in ensuring that adequate information is made available to all patients for informed decision-making and considered that no further risk minimisation measures could be implemented to avoid the risk of serious liver injury. In view of the above, the PRAC concluded that the benefit-risk balance of ulipristal acetate 5 mg was unfavourable as an intermittent treatment for moderate to severe symptoms of uterine fibroids.
Considering the severity and idiosyncratic nature of the risk of serious liver injury, the occurrence of liver failure despite implemented risk minimisation measures, the failure to identify further measures to avoid and reduce the risk, and the absence of a subgroup in which the benefit-risk balance of ulipristal acetate 5 mg could be positive, the PRAC concluded that this risk outweighs the benefits of ulipristal acetate 5 mg in all its indications. Since no future condition would result in a positive benefit-risk balance for these medicines, the PRAC recommended the revocation of marketing authorisations for medicines containing ulipristal acetate 5 mg.

Reasons for the PRAC’s recommendation
Considering that:

the PRAC has examined the procedure under Article 31 of Directive 2001/83/EC arising from the evaluation of pharmacovigilance data for medicines containing ulipristal acetate 5 mg;
the PRAC has reviewed the information available to the committee regarding ulipristal acetate 5 mg and the risk of serious liver injury, including data provided in writing and orally by the marketing authorisation holders of ulipristal acetate 5 mg and the outcome of the consultation with the ad hoc expert group convened within this procedure;
the PRAC has reviewed all reported cases of serious liver injury in women treated with ulipristal acetate 5 mg for the treatment of fibroid symptoms, including the report of a new case of serious liver injury leading to liver transplantation (the 5th case overall), despite adherence to the agreed risk minimisation measures resulting from the previous referral under Article 20. The PRAC concluded that the causal association between ulipristal acetate 5 mg and serious liver injury was probable/highly probable and observed that progression to liver failure leading to liver transplantation could not be avoided;
the PRAC has analysed further proposals for risk minimisation and was unable to identify new measures ensuring effective risk reduction to an acceptable level. Considering its severity and idiosyncratic nature, the PRAC concluded that this risk outweighs the benefits of ulipristal acetate 5 mg in the treatment of fibroid symptoms. No patient subgroup was identified in which the benefits of ulipristal acetate 5 mg would outweigh the risks;
furthermore, the PRAC was unable to identify any conditions that, if met in the future, could result in a positive benefit-risk balance for these medicines. Consequently, the committee considers that the benefit-risk balance of medicines containing ulipristal acetate 5 mg for the treatment of fibroid symptoms is not favourable and recommends, under Article 116 of Directive 2001/83/EC, the revocation of marketing authorisations for all medicines containing ulipristal acetate 5 mg.

Detailed explanation by the CHMP of the scientific reasons for divergence from the PRAC’s recommendation
The CHMP considered the PRAC’s recommendation and supplementary information provided by marketing authorisation holders, as well as the outcome of the consultation with the ad hoc expert group convened within this procedure. Based on the aforementioned data, the CHMP did not agree with the general conclusions and reasons underlying the PRAC’s recommendation.

Points of divergence from the PRAC’s recommendation and scientific rationale for the CHMP’s position

Safety aspects
In 2018, within the context of the Article 20 review of Esmya, the risk of serious liver injury due to ulipristal acetate 5 mg was assessed, and both the PRAC and CHMP concluded that the medicine may carry a risk of serious liver injury. While uncertainty regarding causality remained, both committees acknowledged the very serious outcomes of the reported liver injury cases, and a series of risk minimisation measures for Esmya were implemented, including restriction of the indication, introduction of a contraindication in patients with underlying liver disease, recommendation to perform liver function tests before and during treatment, and the provision of educational material, including a patient alert card in every pack of ulipristal acetate 5 mg to adequately inform patients about potential risks of liver injury. With clear communication of the risk to patients and healthcare professionals, it was expected that any further cases of serious liver injury leading to liver damage would be reported.
An assessment of the effectiveness of the risk minimisation measures implemented in 2018 indicated that restriction of the population through limitation of the two indications led to a significant reduction in the number of treated patients to approximately 25–30% of the patient numbers before the Article 20 referral in 2018. The CHMP observed that the reporting rate of serious liver injury leading to liver transplantation remained unchanged, at 0.52/100,000 based on 4 cases among 765,000 patients exposed to ulipristal acetate 5 mg before the previous Article 20 procedure and at 0.51/100,000 based on 1 case among 194,614 patients exposed after the previous Article 20 procedure. It was also observed that these incidences are in line with a conservative background incidence of deaths/liver transplants of 0.55 cases per 100,000 inhabitants, as described by Ibañez in 2002.
The CHMP also highlighted that results from a limited number of patients who showed elevated liver function test results during treatment with ulipristal acetate 5 mg showed improvement or normalisation of liver function test (LFT) values after discontinuation of the medicine. Although these data are limited, they suggest that performing liver function tests is useful in preventing progression of liver damage. However, the CHMP recognised that the 5th case of serious liver injury reported in December 2019 had a probable/highly probable causal relationship with ulipristal acetate 5 mg, that this case occurred despite the implemented risk minimisation measures, and that progression to liver failure leading to liver transplantation could not be prevented.

Efficacy aspects

Preoperative treatment of moderate to severe symptoms of uterine fibroids
At the end of a single treatment cycle (3 months), 73.4% and 75.3% of patients in two different phase III studies reported amenorrhoea, and median fibroid volume was reduced by 21.2% and 35.6%, respectively, compared to baseline. The reduction in fibroid size, which could facilitate surgery, as well as the reduction in blood loss and anaemia, are considered clinically relevant. However, the clinical benefits of preoperative treatment are considered limited, and there is another short-term preoperative treatment alternative, namely the use of a GnRH agonist.
Intermittent treatment of moderate to severe symptoms of uterine fibroids
In a phase III study, at the end of the fourth treatment cycle, corresponding to approximately two years of treatment (four 3-month cycles with repeated treatment cycles initiated from the first week of the second menstruation after completion of the previous cycle), 69.6% of patients reported amenorrhoea, and median fibroid volume reduction from baseline was 71.8%. The benefits of ulipristal acetate 5 mg are considered greater in the intermittent treatment indication, i.e., for patients whose health and quality of life are affected by symptoms of uterine fibroids, particularly heavy bleeding, but who are not suitable candidates for surgery, as there are no other evident pharmacological treatment alternatives for these patients requiring longer-term treatment. Patients not suitable candidates for surgery may include women who, for various reasons, present surgical risks, e.g., due to obesity, increased risk of venous thrombosis, concomitant disease, or concomitant medication use. In addition, surgery may not be suitable for women who wish to preserve the possibility of pregnancy.

Benefit-risk balance
The CHMP observed that the 5th case of serious liver injury reported with ulipristal acetate 5 mg had a probable/highly probable causal relationship with the medicine and acknowledged that this case occurred despite the implemented risk minimisation measures and that progression to liver failure leading to liver transplantation could not be avoided. However, the CHMP noted that the incidence of serious liver injury leading to liver transplantation with ulipristal acetate 5 mg is in line with a conservative background incidence of deaths/liver transplants.
The CHMP also considered the proposal by the marketing authorisation holder of Esmya to withdraw the preoperative indication to limit exposure to ulipristal acetate and further minimise risk. The indication of a single preoperative treatment cycle reflects a situation where surgery is planned; however, the reduction in fibroid size and reduction in blood loss and anaemia are considered clinically relevant. Nevertheless, the CHMP observed that some experts consulted during this review highlighted that the reduction in fibroid volume with ulipristal acetate 5 mg was not considered substantial, and therefore the use of this product in a preoperative setting does not significantly influence the positive outcome of surgery. The CHMP also noted that experts highlighted the existence of alternatives for this indication in the preoperative phase. In view of the above and considering the risk of serious liver injury leading to liver transplantation with ulipristal acetate 5 mg, the CHMP agreed with the PRAC that ulipristal acetate 5 mg should no longer be used for the preoperative treatment of moderate to severe symptoms of uterine fibroids and that this indication should therefore be removed.
The CHMP noted that the PRAC also considered the benefit-risk balance of ulipristal acetate 5 mg to be negative for the intermittent treatment of moderate to severe symptoms of uterine fibroids. However, the CHMP considered that the benefits of ulipristal acetate 5 mg in the intermittent treatment indication remain relevant for a subgroup of women with moderate to severe symptoms of uterine fibroids when uterine fibroid embolisation and/or surgical treatment options are unsuitable or have proven ineffective, as treatment alternatives for these patients are very limited.
Experts consulted during an ad hoc expert group meeting agreed that, when considering ulipristal acetate 5 mg as an intermittent treatment, it is very important to consider the risks associated with alternative options (hysterectomy and less invasive alternative surgical treatments, such as abdominal myomectomy or intraoperative conversion to hysterectomy). An important aspect to consider is that each surgical option carries its own risk, e.g., mortality rates following hysterectomy range from 1 in 500 to 1 in 3,000; while major complications such as haemorrhage and intestinal perforation occur at a frequency of 1 in 100. Fibroid recurrence after myomectomy is common and may require additional treatment (American College of Obstetricians and Gynaecologists, 2008). Abdominal myomectomy also carries substantial risks regarding fertility, including a 3–4% risk of intraoperative conversion to hysterectomy and frequent postoperative intrauterine adhesions. The rates of major complications following embolisation are similar to those following surgery, but embolisation is associated with a higher risk of minor complications and the need for further surgical intervention (usually hysterectomy). The expert group specified that it is also important to consider the patient population who do not wish to undergo surgery, such as younger patients for whom refusing hysterectomy would preserve the possibility of pregnancy. In this context, most experts consulted during the ad hoc expert group meeting emphasised the need for ulipristal acetate 5 mg as an option for the intermittent treatment of moderate to severe symptoms of uterine fibroids. It was also observed that experts stressed the importance of a detailed risk analysis and careful individual case review before making any treatment decision, and that patient counselling should be central to the decision-making process. The patient representative present at the meeting shared this view, highlighting the importance of choice and informed individual decision-making considering all available options. The CHMP agreed that the decision on whether surgery, including hysterectomy, is the best option must be made at the level of the treating physician and patient within an informed decision-making process. The CHMP also considered that, provided the benefits and risks of ulipristal acetate 5 mg and other available therapeutic options are adequately communicated to both healthcare professionals and patients, ulipristal acetate 5 mg should remain available for the 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 unsuitable or have proven ineffective. To further minimise risks and improve communication regarding risks associated with ulipristal acetate 5 mg, the CHMP recommended updating the product information to reflect that liver transplantation was required in some cases of liver injury. The CHMP also recommended updating educational material for both prescribers and patients to increase awareness of the risk of serious liver injury and to reinforce the need to inform patients about the risks and benefits of available treatment options to enable informed decision-making.

Summary of the new recommended measures

Changes to the product information
The CHMP considered that changes to sections 4.1, 4.4 and 4.8 of the product characteristics summary were necessary to minimise the risk of serious liver injury associated with ulipristal acetate 5 mg.
The indication has been restricted to 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 unsuitable or have proven ineffective.
The indication for a single preoperative treatment cycle has been removed, as ulipristal acetate 5 mg should no longer be used for this indication.
Furthermore, the section on warnings and precautions in the product information (section 4.4) and the description of the adverse reaction of liver failure in section 4.8 have been modified to include the fact that liver transplantation was required in some cases of liver injury and liver failure reported with ulipristal acetate 5 mg.
The package leaflet has been amended accordingly.

Additional risk minimisation measures
Marketing authorisation holders must implement a risk management system described in a revised risk management plan with the following modifications.
The CHMP considered that the existing prescriber guide should be modified to reflect the revised indication and the fact that liver transplantation was required in some cases of liver injury and liver failure reported with ulipristal acetate 5 mg, as well as to highlight that the frequency of liver failure and risk factors for patients are unknown.
Prescribers must also inform patients about the risks and benefits of available treatment options to enable informed decision-making.
It was also considered that the existing patient alert card should be modified to clarify that liver transplantation was required in a small number of cases.

Direct communication to healthcare professionals and communication programme
The committee adopted the wording of a direct healthcare professional communication (DHPC) to inform healthcare professionals of the outcome of this review, including the restricted indication for ulipristal acetate, to provide basic information on the risk of serious liver injury, and to advise informing patients about possible signs and symptoms of liver injury, as well as the risks and benefits of all available alternatives to enable informed decision-making. The committee also agreed on a communication programme.

Reasons for the CHMP’s opinion and divergence from the PRAC’s recommendation
Considering that:

the CHMP took into account the PRAC’s recommendation on ulipristal acetate 5 mg and all data provided by marketing authorisation holders of ulipristal acetate 5 mg;
the CHMP observed that the causal association between ulipristal acetate 5 mg and the 5th case of serious liver injury leading to liver transplantation was assessed as probable/highly probable, and acknowledged that progression to liver failure leading to liver transplantation could not be prevented, despite adherence to the agreed risk minimisation measures resulting from the previous Article 20 referral;
the CHMP agreed that the risk of serious liver injury outweighs the benefits of ulipristal acetate as a single preoperative treatment cycle for moderate to severe symptoms of uterine fibroids in adult women of reproductive age, and therefore this indication should be removed in agreement with marketing authorisation holders;
the CHMP, however, considered that the benefit-risk balance of ulipristal acetate for the intermittent treatment indication is favourable exclusively in a subgroup of women with moderate to severe symptoms of uterine fibroids who have not reached menopause and for whom uterine fibroid embolisation and/or surgical treatment options are unsuitable or have proven ineffective, provided that risks are adequately communicated to patients and prescribers through appropriate wording in the product information and educational material to ensure informed treatment decisions, in addition to the risk minimisation measures already implemented as a result of the previous review. Consequently, the CHMP considers that the benefit-risk balance of medicines containing ulipristal acetate 5 mg remains favourable, subject to the changes to the product information and additional risk minimisation measures described above. Therefore, the CHMP recommends a variation to the terms of the marketing authorisations for medicines containing ulipristal acetate 5 mg.