- Procedure started
- Under evaluation
- CHMP opinion
- European Commission final decision
In March 1999 Pharmacia & Upjohn submitted applications for Mutual Recognition of the Marketing Authorisation granted by the Competent Authority in Sweden, acting as Reference Member State, for Cyklo-f tablets. The Mutual Recognition procedure started on 03 April 1999. The Concerned Member States were Austria, Belgium, Denmark, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Portugal, Spain, and The Netherlands. The Concerned Member State, Germany considered that there were grounds for supposing that the authorisation of Cyklo-f may present a risk to public health and referred the matter to the CPMP under article 10 of Directive 75/319/EEC on 02 July 1999.
The public health risk raised by Germany related to the scientific basis of the dose recommendation, specifically the lack of clinical trials performed according to current standards confirming the recommended dose schedule.
The Marketing Authorisation Holder provided written responses on 6 September 1999 and on 15 December 1999.
Cyklo-f is supplied as white, capsular film coated tablets containing 500 mg of the active substance tranexamic acid, which is an anti-fibrinolytic, haemostatic agent acting by competitive inhibition of the activation of plasminogen to plasmin. This inhibition results in a stabilisation of formed fibrin which otherwise would have become lysed by plasmin.
Tranexamic acid has been marketed in many EU countries under the tradename Cyklokapron for more than three decades for the treatment of haemorrhage or risk of haemorrhage in increased fibrinolysis or fibrinogenolysis (including thrombolytic overdose) and for the treatment of menorrhagia. Cyklokapron tablets contain 500 mg tranexamic acid. The recommended dose of Cyklokapron for menorrhagia in the different European countries is 2-3 tablets 2-4 times daily for 3-4 days.
In order to support the CPMP evaluation of the matter of arbitration data from 6 clinical trials and postmarketing experience were submitted. The data indicated that 3 g tranexamic acid per day is the lowest clinically significant effective daily dose and that higher doses reduce the menstrual blood loss to a greater degree. The risk for experiencing gastrointestinal adverse events - although of mild nature - is increased at 6 g per day. Three days treatment would appear to be sufficient for most women, but for some it may be advantageous to extend the treatment to 4 days. Therefore, it seems justifiable to recommend 3 g per day as the normal dosage and, if needed, an increase to 4 g per day for 3-4 days.
Although most of the studies reviewed have not been performed according to current standards, the concordance in results justifies their use for the dose recommendation. Furthermore, the overall data accumulated over a period of more than three decades extensive human exposure to tranexamic acid do not indicate that Cyklo-f in the proposed indication and dose range would raise any major safety or efficacy CPMP/902/00 EMEA 2000 2/9 concerns. Therefore, although the submitted documentation is not according to the current standards, it supports a positive overall benefit/risk of Cyklo-f for menorrhagia at the recommended dose schedule.
The CPMP having considered the written responses provided by the Applicant, the Rapporteur/Co- Rapporteur's assessment reports and the comments from CPMP members was of the opinion that the public health risk issue raised by Germany should not prevent the granting of a marketing authorisation.
The CPMP adopted a positive opinion on 20 January 2000 recommending the granting of the Marketing Authorisation for Cyklo-f with amendments to the Summary of Product Characteristics (SPC) of the Reference Member State.
During the Standing Committee phase, the "Agence Francaise de Sécurite Sanitaire des Produits de Santé" informed the European Commission about a potential risk to public health with regard to the information in section 4.8 "Undesirable effects" of the SPC. This section included information on side-effects at 6 g daily dose, which is higher than the recommended 4 g maximum daily dose (as mentioned in section 4.2 "Posology and method of administration"). This information could be inadequately interpreted by prescribers who could consider 6 g as the maximum daily dose authorised instead of 4 g.
In a letter dated 14 April 2000, the Commission informed the EMEA that on the basis of the concern raised by France the Decision making process had been suspended and that the application was referred back to the EMEA for further consideration.
The CPMP agreed with the French Agency that the wording concerning the dose of 6 g as the maximum daily dose could be inadequately interpreted by the prescribing physicians, particularly with regard to the authorised maximum daily dose of 4 g. Therefore, the reference to side-effects at 6 g was deleted.
Since the positive risk/benefit ratio of Cyklo-f for the claimed indication and posology was maintained, the CPMP adopted a revised positive opinion on 25 May 2000 recommending the granting of the Marketing Authorisation for Cyklo-f with amendments to the SPC of the Reference Member State.
An overall summary of the scientific evaluation is provided, together the the amended SPC.
On the basis of the Opinion adopted by the CPMP the European Commission issued a Decision on 27 July 2000.
About this medicine
|International non-proprietary name (INN) or common name||
About this procedure
European Commission final decision
Article 29(4) referrals
This type of referral is triggered when there is a disagreement between Member States regarding a marketing authorisation application being evaluated in a mutual-recognition or decentralised procedure, on the grounds of a potential serious risk to public health.
Key dates and outcomes
|CHMP opinion date||
|EC decision date||
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.