Cyproterone- and ethinylestradiol-containing medicines - referral

Current status

European Commission final decision

Overview

Benefits of Diane 35 and its generics outweigh risks in certain patient groups

On 29 May 2013, the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) endorsed by majority (26:1) the recommendation of the European Medicines Agency's Pharmacovigilance Risk Assessment Committee (PRAC), which concluded that the benefits of Diane 35 (cyproterone acetate 2 mg / ethinylestradiol 35 micrograms) and its generics outweigh the risks, provided that several measures are taken to minimise the risk of thromboembolism (formation of blood clots in blood vessels). These medicines should be used solely in the treatment of moderate to severe acne related to androgen sensitivity or hirsutism (excessive unwanted growth of hair in women) in women of reproductive age. Furthermore, Diane 35 and generics should only be used for the treatment of acne when alternative treatments, such as topical therapy and antibiotic treatment, have failed.

Since Diane 35 and its generics act as hormonal contraceptives, women should not take these medicines in combination with other hormonal contraceptives. Concomitant use of Diane 35 and its generics with another hormonal contraceptive will expose women to a higher dose of oestrogen and increase the risk of thromboembolism.

The risk of thromboembolism occurring with these medicines is low and well known. However, to minimise this risk, further measures should be implemented in addition to the updated product information. These include providing educational materials to prescribers and patients highlighting the risks of thromboembolism, for example a prescriber checklist to ensure that the risks, together with the signs and symptoms, are discussed with the patient.

These recommendations were endorsed by the CMDh, a body representing European Union (EU) Member States. Because the CMDh took this position by majority it was sent to the European Commission, which endorsed it and adopted a final legally binding decision on 25 July 2013.

The review of Diane 35 and its generics was triggered by the French medicines agency, the National Agency for the Safety of Medicine and Health Products (ANSM), following its decision to suspend Diane 35 and its generics in France within three months. The French decision followed a national review of the medicine by ANSM. This review highlighted serious thromboembolic events and extensive off-label use of these medicines as a contraceptive only.

Despite the PRAC recommendation ANSM proceeded with the suspension of the marketing authorisation of these medicines in France. However, the subsequent European Commission decision to maintain the marketing authorisation with the agreed risk-minimisation measures, including changes to the information to prescribers and patients, is to be implemented in all EU Member States

Information to patients

Diane 35 and its generics should only be used to treat moderate to severe acne (related to sensitivity to hormones called androgens) or hirsutism in women of child-bearing age. However, when used for acne, they should only be used if other treatments, such as those applied to the skin and antibiotics, have failed.

• If you are using these medicines for other conditions you should make a non-urgent appointment with your doctor to review your treatment.
• You should not stop taking these medicines before speaking to your doctor. Diane 35 and its generics act also as hormonal contraceptives and stopping them means that you will have to use another form of contraception to prevent unwanted pregnancies.
• You should always read the package leaflet and be aware that there is a low risk of blood clots with these medicines. The risk of blood clots in the veins with these medicines is 1.5 to 2 times higher than for combined oral contraceptives (COCs) containing levonorgestrel and may be similar to the risk with contraceptives containing gestodene, desogestrel or drospirenone.
• You should be aware that there are factors that can increase the risk of blood clots in blood vessels, such as increasing age, smoking, obesity and prolonged immobility. You should immediately report any relevant symptoms to your doctor, such as pain and swelling in the legs, or breathlessness and a sharp pain in the chest.
• If you have any questions you should speak to your doctor or pharmacist.

Information to healthcare professionals

Healthcare professionals should follow these recommendations:

• Diane 35 and its generics should only be used for the treatment of moderate to severe acne related to androgen-sensitivity (with or without seborrhoea) or hirsutism, in women of reproductive age.
• For the treatment of acne, these medicines should only be used after topical therapy or systemic antibiotic treatment has failed.
• Since Diane 35 and its generics act also as hormonal contraceptives, they should not be used in combination with other hormonal contraceptives.
• Doctors should review patients on Diane 35 and generics in line with these recommendations at their next scheduled appointment
• Doctors should discuss with their patients the risk of thromboembolism and risk factors such as increasing age, smoking, obesity and prolonged immobility.
• Healthcare professionals were sent a letter with further details.

These recommendations are based on a review of all available data on the risk of thromboembolism as well as the benefits of Diane 35 and its generics:

• The review confirmed the rare and known risk of thromboembolism with Diane 35 and its generics. Observational studies have shown that the risk of venous thromboembolism (VTE) with these medicines is 1.5 to 2 times higher than for combined oral contraceptives containing levonorgestrel and may be similar to the risk with contraceptives containing gestodene, desogestrel or drospirenone. Data on the risk of arterial thromboembolism (ATE) with Diane and its generics are sparse and indicate that this risk is lower than for VTE.
• The review also showed that the excess risk of VTE is highest during the first year of use of Diane 35 and its generics or when restarting or switching from an oral hormonal contraceptive to Diane 35 and its generics after a pill-free interval of at least one month.
• In terms of effectiveness, the available data support the use of Diane 35 and its generics in the treatment of moderate to severe acne related to androgen sensitivity or hirsutism, in women of reproductive age. The efficacy in moderate and severe acne with or without seborrhoea or hirsutism has been demonstrated in more than 30 clinical trials.
• In the treatment of alopecia androgenetica and acne without androgenic features, the data on efficacy is limited.

More about the medicine

Medicines containing cyproterone acetate 2 mg and ethinylestradiol 35 micrograms have been approved via national procedures and are available on prescription under various trade names in all EU Member States except Cyprus. Diane 35 was first authorised in 1985. These medicines work by blocking the effects of a class of hormones called androgens. Cyproterone also supresses ovulation and therefore has a contraceptive effect.

More about the procedure

The review of Diane 35 and its generics was initiated in February 2013 at the request of France, under Article 107i of Directive 2001/83/EC, also known as the urgent Union procedure.

A review of these data was first conducted by the PRAC. The PRAC's recommendations were sent to the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh), which adopted a final position. The CMDh is a medicines regulatory body representing the EU Member States. Its main responsibility is to resolve disagreements between Member States involved in mutual recognition or decentralised procedures, to ensure that patients have the same level of protection, no matter where they are in the EU.

As the CMDh position was adopted by majority vote and not by consensus, the CMDh position was sent to the European Commission, which endorsed a legally binding decision throughout the EU on 25 July 2013.

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Benefits of Diane 35 and its generics outweigh risks in certain patient groups

Reference Number: EMA/318380/2013

Key facts

About this medicine

• Approved name:
  Cyproterone- and ethinylestradiol-containing medicines
• International non-proprietary name (INN) or common name:
  • cyproterone
  • ethinyl estradiol
• Associated names:
  • Acnemine
  • Acneson
  • Chloe
  • Clairette
  • Cyprest
  • Cyprodiol
  • Diane 35
  • Dianette
  • Feminil
  • Minerva
  • Zyrona

About this procedure

• Current status:
  European Commission final decision
• Reference number:
  EMEA/H/A-107i/1357
• Type:
  Article 107i procedures

  This type of procedure is triggered when a Member State or the European Commission consider that urgent action is necessary because of a safety issue. Situations that fall under this procedure include consideration for suspension or revocation of the marketing authorisation for a medicine, the prohibition of supply of a medicine or major changes to the marketing authorisation such as deletion of indications, reduction of the recommended dose or new contraindications. The procedure is also applicable in case of a safety issue with a class of medicines.

• Authorisation model:
  Nationally authorised product(s)
• Decision making model:
  PRAC-CMDh

Key dates and outcomes

• Procedure start date:
  07/02/2013
• PRAC recommendation date:
  16/05/2013
• CHMP opinion date:
  29/05/2013
• EC decision date:
  25/07/2013
• Outcome:
  Risk minimisation measures

Data submission

The Agency invites all stakeholders (e.g. healthcare professionals, patients' organisations, the general public) to submit data relevant to this procedure. This is in accordance with Article 107j(1) of Directive 2001/83/EC.

The following requirements apply for data to be considered:

• Submissions must be accompanied by the submission form below, with all fields completed. The form must be used with Adobe Reader X+ or Adobe Acrobat X+:

  Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Stakeholder's submission form

• Data submitted should make reference to the Pharmacovigilance Risk Assessment Committee (PRAC) questions:

  Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - PRAC list of questions to be addressed by stakeholders

• The submission of all data should take place by 11 March 2013.

Submitting data

Send the completed form electronically to the stakeholders' submission inbox ([e-mail]). Specify the name of the medicine in the subject line of the e-mail.

The size of the submission file should not exceed 25 MB. If your attempt to send your data package to the dedicated e-mail address is unsuccessful, please use alternative submission means.

It is of the utmost importance that data are provided promptly, to avoid undermining the safety review. Due to the urgent nature of the procedure, you are strongly advised to submit your data in English.

Protection of personal data

Personal data submitted are subject to data-protection rules as established by Regulation (EC) 45/2001. They will be treated in accordance with the specific privacy statement for public consultations.

Treatment and publication of data

Data submitted will be received and recorded by the Agency.

The Agency will prepare a list of all submissions received, which will be published as an annex to the PRAC assessment report for transparency purposes and public awareness.

Please note that all data submitted in the context of this procedure may be shared and disclosed in the public domain.

All documents

Procedure started

Cryopterone / ethinylestradiol-containing medicines: Article-107i procedure - Rationale for the triggering of procedure under Article 107i of Directive 2001/83/EC on cyproterone / ethinylestradiol (2 mg / 0.035 mg) prese...

Reference Number: EMEA/H/A-107i/1357

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Annex I

AdoptedReference Number: EMA/84655/2013

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Stakeholder's submission form

AdoptedReference Number: EMA/639499/2012

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Timetable for the procedure

AdoptedReference Number: EMA/PRAC/69142/2013 Rev.1

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - PRAC list of questions to be addressed by stakeholders

AdoptedReference Number: EMA/PRAC/78185/2013

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - PRAC list of questions

AdoptedReference Number: EMA/PRAC/69149/2013

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Notification

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Start of review of Diane 35 and other medicines containing cyproterone acetate 2 mg and ethinylestradiol 35 micrograms

AdoptedReference Number: EMA/76602/2013

Recommendation provided by Pharmacovigilance Risk Assessment Committee

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - PRAC assessment report

AdoptedReference Number: EMA/339116/2013

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - PRAC recommendations on Diane 35: Questions and answers

Reference Number: EMA/280182/2013

Position provided by CMDh

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Divergent positions to CMDh position

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Annex IV

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Annex III

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Annex I

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Annex II

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Benefits of Diane 35 and its generics outweigh risks in certain patient groups - PRAC recommendation endorsed by CMDh

Reference Number: EMA/318380/2013

European Commission final decision

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Benefits of Diane 35 and its generics outweigh risks in certain patient groups

Reference Number: EMA/318380/2013

Cyproterone / ethinylestradiol-containing medicines: Article-107i procedure - Benefits of Diane 35 and its generics outweigh risks in certain patient groups

Reference Number: EMA/318380/2013

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.