Other safety alerts
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| European Union: New testing and treatment recommendations for fluorouracil, capecitabine, tegafur and flucytosine |
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The European Medicines Agency (EMA) announced that EMA’s safety committee, Pharmacovigilance Risk Assessment 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 (up to 8% of the Caucasian population have low levels of a working DPD enzyme, and up to 0.5% completely lack the enzyme), 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
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.
Please refer to the following website in EMA for details:
http://www.ema.europa.eu/en/medicines/../fluorouracil-fluorouracil-related-substances-capecitabine-tegafur-flucytosine-containing-medicinal
In Hong Kong, there are 4 registered pharmaceutical products containing fluorouracil, 24 products containing capecitabine and 4 products containing tegafur. All products are prescription-only medicines. There is no registered pharmaceutical product containing flucytosine. So far, the Department of Health (DH) has received 90 cases of adverse drug reaction related to fluorouracil, 51 cases related to capecitabine and 1 case related to tegafur. The DH has not received any case of adverse drug reaction related to flucytosine. Related news was previously issued by the EMA and was posted on Drug Office’s website on 18 Mar 2019. Letters to inform local healthcare professionals of EMA’s announcement on starting review on screening patients before treatment with fluorouracil, capecitabine, tegafur and flucytosine were issued by the DH on 18 Mar 2019. In light of the above EMA’s announcement, the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Saturday, Mar 14, 2020
Issued at HKT 12:00
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