PRAC provides new recommendations on testing and treatment with fluorouracil, capecitabine, tegafur and flucytosine

The EMA Pharmacovigilance Risk Assessment Committee (PRAC) recommends that patients be tested for the absence of an enzyme called dihydropyrimidine dehydrogenase (DPD) before starting cancer treatment with medicinal products containing fluorouracil administered by injection or infusion (drip), and with the related medicinal products capecitabine and tegafur, which are converted to fluorouracil in the body.

Since the treatment of severe fungal infections with flucytosine (other medicinal products related to fluorouracil) should not be delayed, testing patients for DPD deficiency before the start of treatment is not required.

Testing before treatment is not required for patients who received topical fluorouracil (applied to the skin for the treatment of various skin conditions).

A lack of the active DPD enzyme, which is needed to break down fluorouracil, leads to accumulation of fluorouracil in the blood. This can lead to severe and life-threatening side effects such as neutropenia, neurotoxicity, severe diarrhea, and stomatitis.

PRAC assessed the available data and the following measures were recommended to ensure the safe use of fluorouracil and concomitant medicinal products:

Fluorouracil, capecitabine and tegafur

Testing patients for DPD deficiency is recommended before starting treatment with fluorouracil administered by injection or infusion, and with the concomitant medicinal products capecitabine and tegafur. This can be done by measuring the level of uracil (a substance broken down by DPD) in the blood, or by testing for certain mutations (changes) in the DPD gene that are associated with an increased risk of severe, life-threatening side effects.

Relevant clinical recommendations should be taken into account.

Patients with known complete DPD deficiency should not be given fluorouracil or use capecitabine or tegafur, because the complete absence of active DPD leads to a higher risk of serious adverse effects.

Patients with partial DPD deficiency also have an increased risk of severe adverse effects. In the event of adverse effects, the treating physician should consider discontinuing treatment with flucytosine. DPD activity testing should be performed, since the risk of serious adverse effects is higher in patients with low DPD activity.

The prescribing information for doctors and patients will be updated, including the above-mentioned recommendations.

Pre-treatment testing or dose adjustment based on DPD activity is not required for patients using topical fluorouracil because the level of fluorouracil entering the body through the skin is extremely low, and no safety issues with topical use of fluorouracil are expected in patients with partial or complete DPD deficiency.

Flucytosine

Flucytosine is used to treat severe yeast and fungal infections, including some forms of meningitis. To avoid delay in starting therapy, prior testing for DPD deficiency is not required.

Flucytosine should not be administered to patients with known complete DPD deficiency due to the risk of life-threatening adverse effects.

Patients with partial DPD deficiency also have an increased risk of severe side effects. In the event of side effects, the treating physician should consider discontinuing flucytosine. DPD activity testing may also be considered, since the risk of serious side effects is higher in patients with low DPD activity.

The prescribing information for doctors and patients will be updated, including the above-mentioned recommendations.

More about medicines

The review concerns fluorouracil products administered by injection or applied to the skin, as well as medicinal products containing capecitabine and tegafur taken orally (fluorouracil-related medicinal products), which are converted to fluorouracil in the body. It also includes the antifungal medicinal product flucytosine, administered by injection or by mouth, part of which is converted to fluorouracil in the body.

Fluorouracil, administered by injection or infusion, and its related medicinal products are used to treat various oncological diseases. By interfering with the enzymes involved in creating new DNA, they thereby block the growth of cancer cells.

Fluorouracil applied to the skin is used for various skin conditions, such as actinic keratosis and cutaneous condylomas.

Medicinal products containing capecitabine and tegafur were authorized through the EMA and are marketed as Xeloda, Teysuno, as well as various generic medicinal products containing capecitabine.

Some medicinal products containing tegafur and capecitabine, as well as all flucytosine and fluorouracil products, have also been authorized at the national level.

This review was initiated at the request of the French Medicines Agency (ANSM) in accordance with Article 31 of Directive 2001/83/EC.

The review was carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), which is responsible for assessing safety issues of medicinal products for human use and which provided recommendations. The PRAC recommendations will now be sent to the Committee for Medicinal Products for Human Use (CHMP), which is responsible for questions concerning medicinal products for human use and which will adopt the Agency's opinion.