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) (updated)


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

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    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 - Annex I (PDF/394.2 KB) (new)


    First published: 23/07/2020

  • List item

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


    First published: 23/07/2020

  • List item

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


    First published: 23/07/2020

  • List item

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

    Adopted

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

  • Document description

    • Annex I - List of the medicines affected by the referral
    • Annex II - Scientific conclusions of the CHMP or CMDh
    • Annex III - Changes to the summary of product characteristics, labelling or package leaflet - available when the CHMP or CMDh recommends changes to the product information. Also includes conditions for lifting of suspensions, if applicable
    • Annex IV - Conditions of the marketing authorisation - available when the CHMP or CMDh recommends other measures to be taken for the marketing authorisation such as safety measures or additional studies
    • Notification - A letter from a Member State, the European Commission or a marketing-authorisation holder requesting the initiation of a referral procedure
    • Rationale for triggering - Background provided by the party triggering the referral explaining the issues leading to the initiation of the procedure
    • PRAC list of questions - Questions agreed by the PRAC requesting further information to evaluate the issues identified
    • PRAC timetable - Timeframe agreed by the PRAC to receive information, assess the issues and adopt a recommendation
    • PRAC / CHMP or CMDh assessment report - The assessment and conclusions of the PRAC and CHMP or CMDh on the issues investigated

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