ADR that result in revision of patient information
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| European Union: EMA recommendations on DPD testing prior to treatment with fluorouracil, capecitabine, tegafur and flucytosine |
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European Medicines Agency (EMA) announces that it has 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.
Patient 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 stopping flucytosine 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 has a deficiency of DPD, 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.
Information for patients:
Fluorouracil, capecitabine or tegafur
- Before starting cancer treatment with fluorouracil given by injection or infusion (drip), capecitabine or tegafur, their doctor should do a test to check whether they have a working DPD enzyme.
- If they have a known complete lack of DPD, they will not be given these treatments as they will increase the risk of severe and life-threatening side effects.
- If they have a partial DPD deficiency, their doctor may start treatment at low doses, which can be increased if there are no serious side effects.
- If they know that they have a partial DPD deficiency or if they have a family member who has partial or complete DPD deficiency, talk to their doctor or pharmacist before taking these medicines.
- If they are using fluorouracil applied to the skin for conditions such as actinic keratosis and warts they do not need a DPD test, as the level of fluorouracil absorbed through the skin into the body is very low.
- If they have any questions about their treatment or about DPD testing, talk to their doctor or pharmacist.
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 they have a known complete DPD deficiency they must not be given flucytosine, due to the risk of life-threatening side effects.
- In case of side effects, their doctor may consider stopping treatment with flucytosine. Their doctor may also consider testing DPD activity, since the risk of severe side effects is higher in patients with a low DPD activity.
- If they have any questions about their treatment or about DPD testing, speak to their doctor.
Information for healthcare professionals:
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.
Please refer to the following website in EMA for details:
http://www.ema.europa.eu/en/news/ema-recommendations-dpd-testing-prior-treatment-fluorouracil-capecitabine-tegafur-flucytosine
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 91 cases of adverse drug reaction related to fluorouracil, 53 cases related to capecitabine (of which one case is related to dihydropyrimidine dehydrogenase deficiency) 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 EMA, and was posted on Drug Office website on 18 Mar 2019 and 14 Mar 2020. Letters to inform local healthcare professionals were issued by the DH on 18 Mar 2019. As previously reported, the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Saturday, May 2, 2020
Issued at HKT 12:00
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