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:
Recommendation provided by Pharmacovigilance Risk Assessment Committee


New testing and treatment recommendations for fluorouracil, capecitabine, tegafur and flucytosine

EMA’s safety committee (PRAC) has recommended that patients should be tested for the lack of an enzyme called dihydropyrimidine dehydrogenase (DPD) before starting cancer treatment with medicines containing fluorouracil given by injection or infusion (drip) and the related medicines capecitabine and tegafur, which are converted to fluorouracil in the body.

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.

No pre-treatment testing is needed for patients treated with topical fluorouracil (applied to the skin to treat various skin conditions).

Lack of a working DPD enzyme,1 which is needed to break down fluorouracil, causes fluorouracil to build up in the blood. This may lead 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 body’s nervous system), severe diarrhoea and stomatitis (inflammation of the lining of the mouth).

The PRAC assessed the available data and recommended the following measures to ensure the safe use of fluorouracil and fluorouracil-related medicines:

Fluorouracil, capecitabine and tegafur

Testing of patients for DPD deficiency is recommended before starting treatment with fluorouracil injection or infusion, capecitabine and tegafur. This can be done 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 which are associated with an increased risk of severe side effects. Relevant clinical guidelines should be taken into consideration.

Patients with a known complete DPD deficiency must not be given fluorouracil injection or infusion, capecitabine or tegafur, as a complete lack of working DPD puts them at higher risk of severe and life-threatening side effects.

For patients with a partial DPD deficiency, a reduced starting dose of these medicines should be considered; since the effectiveness of a reduced dose has not been established, following doses may be increased if there are no serious side effects. Regular monitoring of fluorouracil blood levels in patients receiving fluorouracil by continuous infusion could improve treatment outcome.

Pre-treatment testing or dose adjustments based on DPD activity are not needed for patients using topical fluorouracil. This is because the level of fluorouracil absorbed through the skin into the body is extremely low, and the safety of topical fluorouracil is not expected to change in patients with partial or complete DPD deficiency.


Flucytosine 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). To avoid any delay in starting therapy, pre-treatment testing for DPD deficiency is not required.

Patients with a known complete DPD deficiency must not be given flucytosine, due to the risk of life-threatening side effects.

Patients with a partial DPD deficiency are also at increased risk of severe side effects. In case of side effects, the treating doctor should consider stopping treatment with flucytosine. Testing of DPD activity may also be considered, since the risk of severe side effects is higher in patients with a low DPD activity.

The prescribing information for doctors and patients will be updated to include the above recommendations.

1Up to 8% 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
Recommendation provided by Pharmacovigilance Risk Assessment Committee
Reference number
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
Authorisation model
Centrally and nationally authorised products (mixed)
Key dates and outcomes
Procedure start date
PRAC recommendation date

All documents

Procedure started

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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