Nomegestrol and chlormadinone - referral

Current status

European Commission final decision

Overview

New measures to minimise risk of meningioma with medicines containing nomegestrol or chlormadinone

On 1 September 2022, EMA’s human medicines committee (CHMP) endorsed the recommendation of the Pharmacovigilance Risk Assessment Committee (PRAC), which concluded that the benefits of medicines containing nomegestrol or chlormadinone outweigh the risks, provided new measures are taken to minimise the risk of meningioma.

A meningioma is a tumour of the membranes covering the brain and spinal cord. It is usually benign and is not considered to be a cancer, but due to their location in and around the brain and spinal cord meningiomas can in rare cases cause serious problems.

The CHMP recommended that medicines containing high-dose nomegestrol (3.75 – 5 mg) or high-dose chlormadinone (5 – 10 mg) should be used at the lowest effective dose and for the shortest duration possible, and only when other interventions are not appropriate. In addition, low- and high-dose nomegestrol- or chlormadinone-containing medicines must not be used by patients who have, or have had, meningioma.

As well as restricting the use of the high-dose medicines, the CHMP recommended that patients should be monitored for symptoms of meningioma, which can include change in vision, hearing loss or ringing in the ears, loss of smell, headaches, memory loss, seizures and weakness in arms or legs. If a patient is diagnosed with meningioma, treatment with these medicines must be permanently stopped. 

The product information for the high-dose medicines will also be updated to include meningioma as a rare side effect.

The recommendations follow a review by the PRAC of available data, including post-marketing safety data and results from two recent epidemiological studies.^1,2 These data showed that the risk of meningioma increases with increasing dose and duration of treatment. The CHMP endorsed the PRAC’s assessment of this risk.

The CHMP opinion was sent to the European Commission, which issued legally binding decisions valid across the EU between 28 October and 28 November 2022.

¹ Nguyen P, Hoisnard L, Neumann A, Zureik M, Weill A. Utilisation prolongée de l’acétate de chlormadinone et risque de méningiome intracrânien: une étude de cohorte à partir des données du SND. EPI-PHARE, 2021.

² Nguyen P, Hoisnard L, Neumann A, Zureik M, Weill A. Utilisation prolongée de l’acétate de nomégestrol et risque de méningiome intracrânien: une étude de cohorte à partir des données du SNDS. EPI-PHARE, 2021.    

Information for patients

• Meningiomas have been reported with the use of nomegestrol- or chlormadinone-containing medicines. 
• This risk, which is very low, is increased when the medicines are used at high doses (3.75 - 5 mg for nomegestrol and 5 - 10 mg for chlormadinone) and for prolonged periods of time. 
• EMA is therefore recommending that these medicines should only be used at the lowest effective dose and for the shortest duration possible. Higher doses (3.75 – 5 mg nomegestrol and 5 - 10 mg chlormadinone) should only be considered if other interventions are not possible.
• You should not use or be prescribed nomegestrol- or chlormadinone-containing medicines if you have a meningioma or have had one in the past.
• Contact your doctor immediately if you experience a change in vision (seeing double or blurriness), hearing loss or ringing in the ears, loss of smell, headaches that worsen with time, memory loss, seizures and weakness in your arms or legs.
• If you are diagnosed with a meningioma while using a nomegestrol- or chlormadinone-containing medicine, your doctor will stop your treatment with the medicine.
• The risk of meningioma may decrease after you stop treatment with a nomegestrol- or chlormadinone-containing medicine.

Information for healthcare professionals

• Meningiomas (single and multiple) have been reported with the use of nomegestrol- or chlormadinone-containing medicines, particularly at high doses and for prolonged time. The risk increases with increasing cumulative doses.
• The use of these medicines at high doses should be restricted to situations where other interventions are considered inappropriate, and they should be used at the lowest effective dose and for the shortest duration.
• Nomegestrol- or chlormadinone-containing medicines are contraindicated in patients with meningioma or a history of meningioma.
• Patients should be monitored for signs and symptoms of meningiomas in line with clinical practice. If a patient is diagnosed with meningioma, treatment with these medicines should be permanently stopped.
• Available evidence suggests that the risk of meningioma decreases after treatment discontinuation of the nomegestrol- or chlormadinone-containing medicine.

A direct healthcare professional communication (DHPC) has been sent to healthcare professionals prescribing, dispensing or administering the medicine. The DHPC has also been published on a dedicated page on the EMA website.

More about the medicines

Medicines containing nomegestrol acetate or chlormadinone acetate are available as tablets to be taken by mouth. They are available on their own or in combination with oestrogens to treat gynaecological disorders such as amenorrhoea (absence of menstrual periods) and other menstrual disorders, uterine bleeding, endometriosis (a condition in which tissue similar to the lining of the womb grows elsewhere in the body), breast tenderness, and as hormone replacement therapy or contraceptives (birth control). 

The medicines are marketed under several trade names including Belara, Lutenyl, Luteran, Naemis and Zoely and as generic medicines. With the exception of Zoely (nomegestrol acetate/estradiol), which is centrally authorised, all medicines reviewed during this procedure have been authorised via national procedures. Warnings about the risk of meningioma are already included in the product information for some of them, although the wording may differ across EU Member States. The CHMP recommendation will lead to alignment of the product information for these medicines across the EU.

More about the procedure

The review of products containing nomegestrol or chlormadinone was initiated at the request of France, under Article 31 of Directive 2001/83/EC.

The review was first carried out by the PRAC, the Committee responsible for the evaluation of safety issues for human medicines, which made a set of recommendations.

The PRAC recommendations were sent to the CHMP, responsible for questions concerning medicines for human use, which adopted the Agency’s opinion. The CHMP’s opinion was forwarded to the European Commission, which issued final legally binding decisions applicable in all EU Member States between 28 October and 28 November 2022.

New measures to minimise risk of meningioma with medicines containing nomegestrol or chlormadinone

Reference Number: EMA/684243/2022

Key facts

About this medicine

• Approved name:
  Nomegestrol and chlormadinone
• International non-proprietary name (INN) or common name:
  • nomegestrol
  • chlormadinone
• Associated names:
  Zoely

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-31/1510
• Type:
  Article 31 referrals

  This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

• Authorisation model:
  Centrally and nationally authorised products (mixed)
• Decision making model:
  PRAC-CHMP-EC

Key dates and outcomes

• Procedure start date:
  30/09/2021
• PRAC recommendation date:
  07/07/2022
• CHMP opinion date:
  01/09/2022
• EC decision date:
  28/11/2022
• Outcome:
  Risk minimisation measures

All documents

Procedure started

Nomegestrol and chlormadinone Article-31 referral - Notification

Nomegestrol and chlormadinone Article-31 referral - Timetable for the procedure

Reference Number: EMA/PRAC/522598/2021 – Rev. 2

Nomegestrol and chlormadinone Article-31 referral - PRAC list of questions

Reference Number: EMA/PRAC/522593/2021

Nomegestrol and chlormadinone Article-31 referral - Annex A and Annex I

Draft

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Nomegestrol and chlormadinone Article-31 referral - Medicines containing nomegestrol or chlormadinone: PRAC recommends new measures to minimise risk of meningioma

Reference Number: EMA/621250/2022

Opinion provided by Committee for Medicinal Products for human Use

Nomegestrol and chlormadinone Article-31 referral - Annex I (Zoely)

Nomegestrol and chlormadinone Article-31 referral - Annex III

New measures to minimise risk of meningioma with medicines containing nomegestrol or chlormadinone

Reference Number: EMA/684243/2022

European Commission final decision

Nomegestrol and chlormadinone Article-31 referral - Annex IV

Nomegestrol and chlormadinone Article-31 referral - Annex III

Nomegestrol and chlormadinone Article-31 referral - Annex II

Nomegestrol and chlormadinone Article-31 referral - Annex I

Nomegestrol and chlormadinone Article-31 referral - Assessment report

Reference Number: EMA/773938/2022

Nomegestrol and chlormadinone Article-31 referral - Divergent positions to CHMP opinion

Description of documents published

Please note that some of the listed documents apply only to certain procedures.

• Overview - lay-language summary of the stage of the procedure
• Notification – a letter from a Member State, the European Commission or the marketing authorisation holder requesting the initiation of the procedure
• Scientific background – further background information from the triggering Member State on the issues leading to the initiation of the procedure (if applicable)
• List of questions – questions agreed by the Committee requesting further information from the marketing authorisation holder(s) / applicant(s) to evaluate the issues identified
• Timetable for the procedure – agreed timeframe to respond to the list of questions, to assess the issues and to adopt a conclusion
• List of medicines concerned by the procedure – medicine(s) / active substance(s) concerned, and marketing authorisation holder(s) / applicant(s)
• List of questions to be addressed by the stakeholders – call for data to be submitted by stakeholders (e.g. healthcare professionals, patient organisations, individual patients) (if applicable)
• Stakeholder submission form – form to be used by stakeholders to submit data (if applicable)
• Scientific conclusions – scientific conclusions of the PRAC and/or CHMP and/or CMDh
• Assessment report – PRAC or CHMP assessment and conclusions on the issues investigated, including divergent positions (if applicable)
• Divergent positions – divergent positions of the CHMP or CMDh members for pharmacovigilance procedures (if applicable)
• Changes to the summary of product characteristics, labelling and package leaflet (amended sections or fully revised version) (if applicable)
• Condition(s) to the marketing authorisation(s) – condition(s) for the safe and effective use of the medicine(s) (if applicable)
• Condition for lifting the suspension – condition to be fulfilled for the suspension of the marketing authorisation(s) to be lifted (if applicable)
• Timetable for implementation of CMDh position – agreed timeframe to submit and finalise the variation(s) implementing the outcome of the procedure (if applicable)

Note that older documents may have different titles.