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

Procedure started
Under evaluation
PRAC recommendation
CHMP opinion
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.

Treatment with fluorouracil, capecitabine or tegafur

Before starting cancer treatment with fluorouracil given by injection or infusion (drip), capecitabine or tegafur, your doctor should do a test to check whether you have a working DPD enzyme.
If you have a known complete lack of DPD, you will not be given these treatments as they will increase the risk of severe and life-threatening side effects.
If you have a partial DPD deficiency, your doctor may start treatment at low doses, which can be increased if there are no serious side effects.
If you know that you have a partial DPD deficiency or if you have a family member who has partial or complete DPD deficiency, talk to your doctor or pharmacist before taking these medicines.
If you are using fluorouracil applied to the skin for conditions such as actinic keratosis and warts you do not need a DPD test, as the level of fluorouracil absorbed through the skin into the body is very low.
If you have any questions about your treatment or about DPD testing, talk to your doctor or pharmacist.

Treatment with flucytosine

Flucytosine is a medicine related to fluorouracil that is used to treat severe yeast and fungal infections, including some forms of meningitis (inflammation of the membranes that surround the brain and spinal cord).
As flucytosine may have to be given urgently, pre-treatment DPD testing (which may take up to one week) is not required in order to avoid any delay in starting therapy.
If you have a known complete DPD deficiency you must not be given flucytosine, due to the risk of life-threatening side effects.
In case of side effects, your doctor may consider stopping treatment with flucytosine. Your doctor may also consider testing DPD activity, since the risk of severe side effects is higher in patients with a low DPD activity.
If you have any questions about your treatment or about DPD testing, speak to your doctor.

Fluorouracil, capecitabine and tegafur

Patients with partial or complete DPD deficiency are at increased risk of severe toxicity during treatment with fluoropyrimidines (fluorouracil, capecitabine, tegafur). Phenotype and/or genotype testing is therefore recommended before starting treatment with fluoropyrimidines.
Treatment with fluorouracil, capecitabine or tegafur-containing medicines is contraindicated in patients with known complete DPD deficiency.
A reduced starting dose should be considered in patients with identified partial DPD deficiency.
Therapeutic drug monitoring of fluorouracil may improve clinical outcomes in patients receiving continuous fluorouracil infusions.

Flucytosine

Pre-treatment testing for DPD deficiency is not required, in order to avoid delay in starting treatment with flucytosine.
Treatment with flucytosine is contraindicated in patients with known complete DPD deficiency due to the risk of life-threatening toxicity.
In case of drug toxicity, consideration should be given to stopping treatment with flucytosine. Determination of DPD activity may be considered where drug toxicity is confirmed or suspected.

Two direct healthcare professional communications (one DHPC for fluorouracil, capecitabine and tegafur, and a separate one for flucytosine) will be sent in due course to healthcare professionals prescribing, dispensing or administering the medicines. The DHPCs will also be published on a dedicated page on the EMA website.

The review concerns fluorouracil medicines given by injection or applied to the skin as well as medicines containing capecitabine and tegafur taken by mouth (so-called fluorouracil prodrugs), which are converted to fluorouracil in the body. It also includes the antifungal medicine flucytosine which is given by injection or by mouth and some of which is converted into fluorouracil in the body.

Fluorouracil given by injection or infusion and its prodrug medicines are used to treat various cancers. They work by interfering with enzymes involved in making new DNA, thereby blocking the growth of cancer cells.

Fluorouracil applied to the skin is used for various skin conditions such as actinic keratosis and dermal warts.

Capecitabine has been authorised through EMA with the brand name Xeloda as well as various generic medicines. A medicine containing tegafur has been authorised through EMA with the brand name Teysuno.

Some tegafur- and capecitabine-containing medicines have also been authorised at national level, as have all fluorouracil and flucytosine medicines.

The review was initiated March 2019 at the request of the French Medicines Agency (ANSM), 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 made a set of recommendations.

The PRAC recommendations were sent to the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which adopted the Agency’s opinion. The CHMP opinion was forwarded to the European Commission, which issued final legally binding decisions for the medicines concerned between 3 July and 7 July 2020 that are applicable in all EU Member States.

Fluorouracil and fluorouracil related substances Article 31 referral - EMA recommendations on DPD testing prior to treatment with fluorouracil, capecitabine, tegafur and flucytosine

Reference Number: EMA/367286/2020

English (EN) (170.01 KB - PDF)

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

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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.
Authorisation model: Centrally and nationally authorised products (mixed)
Decision making model: PRAC-CHMP-EC

Key dates and outcomes

Procedure start date: 15/03/2019
PRAC recommendation date: 12/03/2020
CHMP opinion date: 30/04/2020
EC decision date: 07/07/2020
Outcome: Variation

All documents

Procedure started

Fluorouracil and fluorouracil related substances Article 31 referral - Notification

English (EN) (461.39 KB - PDF)

First published: 15/03/2019

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Fluorouracil and fluorouracil related substances Article 31 referral - Annex I

Reference Number: EMA/176877/2019 Rev. 1

English (EN) (394.2 KB - PDF)

First published: 15/03/2019Last updated: 21/07/2020

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Fluorouracil and fluorouracil related substances Article 31 referral - Timetable for the procedure

Reference Number: EMA/PRAC/165647/2019 Rev.4

English (EN) (123.95 KB - PDF)

First published: 15/03/2019Last updated: 11/12/2019

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Fluorouracil and fluorouracil related substances Article 31 referral - PRAC List of questions

Reference Number: EMA/PRAC/165648/2019

English (EN) (84 KB - PDF)

First published: 15/03/2019

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Opinion provided by Committee for Medicinal Products for human Use

Fluorouracil and fluorouracil related substances Article 31 referral - Annex III

Reference Number: EMA/CHMP/171789/2020

English (EN) (198.08 KB - PDF)

First published: 30/04/2020

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European Commission final decision

Fluorouracil and fluorouracil related substances Article 31 referral - Annex I

English (EN) (394.2 KB - PDF)

First published: 23/07/2020

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Fluorouracil and fluorouracil related substances Article 31 referral - Annex III

English (EN) (194.87 KB - PDF)

First published: 23/07/2020

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Fluorouracil and fluorouracil related substances Article 31 referral - Annex II

English (EN) (202.1 KB - PDF)

First published: 23/07/2020

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Fluorouracil and fluorouracil related substances Article 31 referral - Assessment report

AdoptedReference Number: EMA/274404/2020

English (EN) (989.63 KB - PDF)

First published: 15/07/2020

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Fluorouracil and fluorouracil related substances Article 31 referral - EMA recommendations on DPD testing prior to treatment with fluorouracil, capecitabine, tegafur and flucytosine

Reference Number: EMA/367286/2020

English (EN) (170.01 KB - PDF)

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

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Other languages (22)

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.

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

Current status

Overview

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

Key facts

About this medicine

About this procedure

Key dates and outcomes

All documents

Procedure started

Opinion provided by Committee for Medicinal Products for human Use

European Commission final decision

News

Topics

How useful do you find this page?

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

Current status

Overview

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

Information for patients

Information for healthcare professionals

More about the medicine

More about the procedure

Key facts

About this medicine

About this procedure

Key dates and outcomes

All documents

Procedure started

Opinion provided by Committee for Medicinal Products for human Use

European Commission final decision

News

Related content

Direct healthcare professional communications (DHPC)

Topics

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