On 13 March 2020, the European Medicines Agency’s (EMA’s) Pharmacovigilance Risk Assessment Committee (PRAC) has recommended that patients receiving fluorouracil given by injection or infusion and the related medicines capecitabine and tegafur, which are converted to fluorouracil in the body, should be tested for the lack of dihydropyrimidine dehydrogenase (DPD) before starting treatment.
The review concerns fluorouracil medicines as well as medicines containing capecitabine and tegafur (fluorouracil prodrugs). Fluorouracil and its prodrug medicines are used to treat various cancers. Medicines containing capecitabine and tegafur have been authorised through EMA and are marketed as Xeloda, Teysuno as well as various generic medicines containing capecitabine. Some tegafur and capecitabine containing medicines have also been authorised at national level.
For flucytosine, another medicine that gets converted to fluorouracil in the body, pre-treatment testing is not required, in order not to delay start of treatment of patients with severe yeast and fungal infections, including some forms of meningitis.
No pre-treatment testing is needed for patients treated with topical fluorouracil, applied to the skin to treat various skin conditions.
DPD deficiency causes fluorouracil to build up in the blood, which may lead to severe and life-threatening side effects such as neutropenia, neurotoxicity, severe diarrhoea and stomatitis. Up to 8% of the Caucasian population have low levels of a working DPD enzyme, and up to 0.5% completely lack the enzyme.
The PRAC assessed the available data and recommended the following measures to ensure the safe use of fluorouracil and fluorouracil-related medicines:
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 in the blood, or by checking for the presence of certain mutations 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.
The prescribing information for doctors and patients will be updated to include the above recommendations.
This review was initiated at the request of the French Medicines Agency, under Article 31 of Directive 2001/83/EC.
The PRAC recommendations will now be sent to the EMA Committee for Medicinal Products for Human Use, which will adopt the Agency’s opinion.