Fluorouracil and fluorouracil related substances (capecitabine, tegafur and flucytosine) containing medicinal products

  • Procedure started
  • Under evaluation
  • PRAC recommendation
  • CHMP opinion
  • European Commission final decision
Current status:
European Commission final decision

Overview

EMA recommendations on DPD testing prior to treatment with fluorouracil, capecitabine, tegafur and flucytosine

On 30 April 2020, EMA recommended that patients should be tested for the lack of the enzyme dihydropyrimidine dehydrogenase (DPD) before starting cancer treatment with fluorouracil given by injection or infusion (drip) or with the related medicines, capecitabine and tegafur.

As treatment for severe fungal infections with flucytosine (another medicine related to fluorouracil) should not be delayed, testing patients for DPD deficiency before they start treatment is not required.

Patients who completely lack DPD must not be given any fluorouracil medicines. For patients with partial deficiency, the doctor may consider starting cancer treatment at lower doses than normal or stoppingflucytosine treatment if severe side effects occur.

These recommendations do not apply to fluorouracil medicines used on the skin for conditions such as actinic keratosis and warts, as only very low levels of the medicine are absorbed through the skin.

A significant proportion of the general population ha s a deficiency of DPD,1 which is needed to break down fluorouracil and the related medicines capecitabine, tegafur and flucytosine. As a result, following treatment with these medicines, fluorouracil can build up in their blood, leading to severe and life-threatening side effects such as neutropenia (low levels of neutrophils, a type of white blood cells needed to fight infection), neurotoxicity (damage to the nervous system), severe diarrhoea and stomatitis (inflammation of the lining of the mouth).

Patients can be tested for DPD deficiency by measuring the level of uracil (a substance broken down by DPD) in the blood, or by checking for the presence of certain mutations (changes) in the gene for DPD. Relevant clinical guidelines should be taken into consideration.


1Up to 9% of the Caucasian population have low levels of a working DPD enzyme, and up to 0.5% completely lack the enzyme.

Key facts

About this medicine
Approved name
Fluorouracil and fluorouracil related substances (capecitabine, tegafur and flucytosine) containing medicinal products
International non-proprietary name (INN) or common name
  • capecitabine
  • fluorouracil
  • tegafur
  • flucytosine
Associated names
  • Xeloda
  • Teysuno
  • Capecitabine Accord
  • Capecitabine Medac
  • Capecitabine Teva
  • Ecansya (previously Capecitabine Krka)
About this procedure
Current status
European Commission final decision
Reference number
EMEA/H/A-31/1481
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.

Decision making model
PRAC-CHMP-EC
Authorisation model
Centrally and nationally authorised products (mixed)
Key dates and outcomes
Procedure start date
15/03/2019
PRAC recommendation date
12/03/2020
CHMP opinion/CMDh position date
30/04/2020
EC decision date
07/07/2020
Outcome
Variation

All documents

Procedure started

  • List item

    Fluorouracil and fluorouracil related substances Article 31 referral - Notification (PDF/461.39 KB)


    First published: 15/03/2019

  • List item

    Fluorouracil and fluorouracil related substances Article 31 referral - Annex I (PDF/394.2 KB)


    First published: 15/03/2019
    Last updated: 21/07/2020
    EMA/176877/2019 Rev. 1

  • List item

    Fluorouracil and fluorouracil related substances Article 31 referral - Timetable for the procedure (PDF/123.95 KB)


    First published: 15/03/2019
    Last updated: 11/12/2019
    EMA/PRAC/165647/2019 Rev.4

  • List item

    Fluorouracil and fluorouracil related substances Article 31 referral - PRAC List of questions (PDF/84 KB)


    First published: 15/03/2019
    EMA/PRAC/165648/2019

  • Opinion provided by Committee for Medicinal Products for Human Use

    European Commission final decision

  • List item

    Fluorouracil and fluorouracil related substances Article 31 referral - EMA recommendations on DPD testing prior to treatment with fluorouracil, capecitabine, tegafur and flucytosine (PDF/170.01 KB)


    First published: 30/04/2020
    Last updated: 08/10/2020
    EMA/367286/2020

  • List item

    Fluorouracil and fluorouracil related substances Article 31 referral - Annex I (PDF/394.2 KB)


    First published: 23/07/2020

  • List item

    Fluorouracil and fluorouracil related substances Article 31 referral - Annex III (PDF/194.87 KB)


    First published: 23/07/2020

  • List item

    Fluorouracil and fluorouracil related substances Article 31 referral - Annex II (PDF/202.1 KB)


    First published: 23/07/2020

  • List item

    Fluorouracil and fluorouracil related substances Article 31 referral - Assessment report (PDF/989.63 KB)

    Adopted

    First published: 15/07/2020
    EMA/274404/2020

  • 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.

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