Leuprorelin-containing depot medicinal products - referral

Current status

CMDh final position

Overview

New measures to avoid handling errors with leuprorelin depot medicines

On 14 May 2020, EMA’s safety committee (PRAC) recommended measures to avoid handling errors in the preparation and administration of leuprorelin depot medicines.

A review by the PRAC found that handling errors resulted in some patients receiving insufficient amounts of their medicine. The errors reported included incorrect use of the needle or syringe, causing the medicine to leak from the syringe, and failure to inject leuprorelin properly.  

The Committee therefore recommended that only healthcare professionals familiar with the preparation steps for leuprorelin depot medicines should prepare and administer the medicines to patients. Patients should not prepare or inject these medicines themselves. 

The Committee also made recommendations for particular leuprorelin depot medicines. For the medicine Eligard, the product information is to be updated with warnings to strictly follow the instructions for preparation and administration and to monitor patients if a handling error occurs. In addition, the company marketing Eligard must replace the current device used to administer the medicine with one that is easier to handle. The regulatory application for this modification should be submitted by October 2021.

For another medicine, Lutrate Depot, the PRAC recommended that instructions for handling the medicine be revised to make them easier to follow and its packaging changed so the instructions are easier to find.

Depot formulations of leuprorelin are used to treat prostate cancer, breast cancer, certain conditions that affect the female reproductive system, and early puberty. Several formulations require complex steps to prepare the injection.

The PRAC recommendations were adopted by the CMDh¹ by consensus and will be implemented directly at national level.

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¹ The CMDh is a medicines regulatory body representing the European Union (EU) Member States, Iceland, Liechtenstein and Norway.

Information for patients

• Errors in using leuprorelin depot medicines (which are designed to work over a long period) may make treatment less effective.
• These medicines should only be prepared and given by a doctor or nurse with experience in using them. You should not prepare or inject these medicines yourself.
• If you have concerns about your treatment, please discuss these with your doctor or pharmacist.

Information for healthcare professionals

• Leuprorelin depot medicines should only be prepared and given by healthcare professionals who are familiar with the procedures. Patients should not inject the medicine themselves.
• These recommendations follow a review of reports of handling errors with depot formulations of leuprorelin medicines, which could result in underdosing and a lack of efficacy.
• Handling errors are related to the complexity of the reconstitution process, which involves multiple steps for some leuprorelin depot formulations. Reported handling errors include incorrect use of syringe or needle (causing the medicine to leak from the syringe), inadequate reconstitution, and incorrect injection of the leuprorelin implant.
• For Eligard, used to treat advanced hormone-dependent prostate cancer, warnings will be included in the summary of product characteristics to inform healthcare professionals about cases of handling errors and to remind them to strictly follow the instructions for preparation and administration of the medicine. In case of suspected or known handling error with the medicine, patients should be monitored appropriately.
• The company that markets Eligard has been asked to modify the device to reduce the high number of preparation steps. The regulatory application for this modification should be submitted within 18 months.
• Instructions for handling Lutrate Depot will be revised to make them easier to follow and the packaging will be changed to facilitate access to these instructions.

A direct healthcare professional communication (DHPC) will be sent in due course to healthcare professionals prescribing, dispensing or administering the medicine. The DHPC will also be published on theDirect healthcare professional communications page.

More about the medicines

Depot formulations of leuprorelin medicines are given by injection under the skin or into a muscle and they release the active substance gradually over 1 to 6 months. These medicines are used to treat prostate cancer, breast cancer, conditions that affect the female reproductive system (endometriosis and uterine fibroids), and early puberty. They include implants as well as powders and solvents for the preparation of injections.

Leuprorelin medicines are also available as daily injections but this formulation is not included in the review as there have been no reports of handling errors with daily use injections.

Leuprorelin medicines have been authorised via national procedures. They are marketed in many EU countries and are available under several brand names, including Eligard, Eliprogel, Enantone, Ginecrin, Lupron, Lutrate, Politrate and Procren.

More about the procedure

The review of leuprorelin depot medicines was initiated at the request of Germany, under Article 31 of Directive 2001/83/EC.

The review was first carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which issued a set of recommendations.

As all leuprorelin medicines are authorised nationally, the PRAC recommendations were sent to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which  adopted the recommendations by consensus on 24 June 2020. The CMDh is a body representing EU Member States as well as Iceland, Liechtenstein and Norway. It is responsible for ensuring harmonised safety standards for medicines authorised via national procedures.

The PRAC recommendations will now be implemented by EU Member States, Iceland, Lichtenstein, Norway and the United Kingdom¹.

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¹ As of 1 February 2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period.

Leuprorelin-containing depot medicines Article-31 referral - New measures to avoid handling errors with leuprorelin depot medicines

Reference Number: EMA/330921/2020

Key facts

About this medicine

• Approved name:
  Leuprorelin-containing depot medicinal products
• International non-proprietary name (INN) or common name:
  leuprorelin
• Associated names:
  • Daronda
  • Depo-Eligard
  • Eligard
  • Eligard Depot
  • Eligard Mensua
  • Eligard Semestral
  • Eligard Trimestral
  • Elityran 1 Month Depot (Dps)
  • Elityran 3 Month Depot (Dps)
  • Enanton Depot Dual
  • Enanton Depot Set
  • Enantone
  • Enantone L.P
  • Enantone Lp
  • Enantone Monats-Depot
  • Ginecrin Depot
  • Klebrocid 3-Monats-Depot
  • Klebrocid Depot Zweikammerspritze
  • Leptoprol
  • Lerin
  • Leugon
  • Leuprex 3
  • Leuprol
  • Leuprolin Ratiopharm
  • Leuprone 1-Monatsdepot
  • Leuprone 3-Monatsdepot
  • Leuprorelin 1-Month Depot Gp-Pharm
  • Leuprorelin Hexal
  • Leuprorelin Sandoz
  • Leuprorelina Gp-Pharm
  • Leupro-Sandoz 1-Monats-Depot
  • Leupro-Sandoz 3-Monats-Depot
  • Leuprorelina Trimestral Sandoz
  • Leuprostin
  • Leuproreline Sandoz
  • Lucrin
  • Lucrin Depot
  • Lucrin Pds Depot
  • Lucrin Pds Depot 1 Maand
  • Lucrin Pds Depot 3 Maanden
  • Lucrin Pds Depot 6 Maanden
  • Lupron Depo
  • Lutrate 1 Month Depot
  • Lutrate 3 Month Depot
  • Lutrate Depo
  • Lutrate Depot
  • Lutrate Depot Trimestral
  • Politrate
  • Politrate Depot
  • Procren Depot
  • Procren Depot Pds
  • Procrin Mensual
  • Procrin Semestral
  • Procrin Trimestral
  • Prostap 3 Dcs
  • Prostap 6 Dcs
  • Prostap Sr Dcs
  • Prostaplant
  • Sixantone
  • Trenantone
  • Trenantone-Gyn
  • Zeulide
  • Елигард
  • Лутрат Депо

About this procedure

• Current status:
  CMDh final position
• Reference number:
  EMEA/H/A-31/1486
• 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:
  Nationally authorised product(s)
• Decision making model:
  PRAC-CMDh

Key dates and outcomes

• PRAC recommendation date:
  14/05/2020
• CHMP opinion date:
  24/06/2020

All documents

Procedure started

Leuprorelin-containing depot medicines Article-31 referral - Review of handling errors with depot formulations of leuprorelin medicines started

Reference Number: EMA/316598/2019

Leuprorelin-containing depot medicines Article-31 referral - Notification

Leuprorelin-containing depot medicines Article-31 referral - List of questions

Reference Number: EMA/PRAC/317692/2019

Leuprorelin-containing depot medicines Article-31 referral - Timetable for the procedure

Reference Number: EMA/PRAC/317693/2019 Rev 2

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Leuprorelin-containing depot medicines Article-31 referral - PRAC recommends new measures to avoid handling errors

Reference Number: EMA/250923/2020 Rev.

Position provided by CMDh

Leuprorelin-containing depot medicines Article-31 referral - Annex IV

Leuprorelin-containing depot medicines Article-31 referral - Annex II

Adopted

Leuprorelin-containing depot medicines Article-31 referral - Public assessment report to PRAC recommendation

AdoptedReference Number: EMA/397961/2020

Leuprorelin-containing depot medicines Article-31 referral - Timetable for the implementation of the CMDh position (Annex V)

Leuprorelin-containing depot medicines Article-31 referral - Annex III

Leuprorelin-containing depot medicines Article-31 referral - Annex I

Leuprorelin-containing depot medicines Article-31 referral - New measures to avoid handling errors with leuprorelin depot medicines

Reference Number: EMA/330921/2020

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.