Capecitabine

Detailed information

Fass environmental information

Fass environmental information for Xeloda (kapecitabin) from Roche (retrieved on 2013-07-08). Capecitabine is an orally administered precursor to the cytotoxic compound 5-fluorouracil (5-FU).

Hazard

Persistence: Capecitabine is not readily biodegradable, with inherent biodegradability ranging from 29–58 % over 28 days in three tests. Its degradation likely begins with an abiotic primary step that limits the overall rate, but long-term biodegradability is observed. The excreted active metabolite, 5-fluorouracil (5FU), is rapidly degradable, while no data are available for further inactive metabolites. Hydrolysis of capecitabine shows a half-life of approximately 21 days at pH 7 and 20 °C; photodegradation data are not available.

Bioaccumulation: "Capecitabine itself theoretically has a significant bioaccumulation potential with a log K_ow over 4; however, it is not excreted as such but rapidly metabolised to the active substance, 5FU, which has a negative log K_ow of –0.89 and no bioaccumulation potential; further metabolites are inactive and also have a low log K_ow."

Toxicity: There are data for 3 trophic levels, most sensitive bacteria NOEC 2 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2010.

PEC = 0.00828 microg/L.

PNEC = Lowest NOEC, 2 microg/L/10 (Assessment Factor (AF) for 3 chronic studies) = 0.2 microg/L.

PEC/PNEC = 0.0414 for 5FU which gives the risk insignificant.

EMA’s scientific discussion

EMA’s scientific discussion on Xeloda 2005-12-07.

"Data on the environmental effects and exposure of capecitabine have been presented. Exposure to the environment is considered very limited and therefore no risk of concern would be expected."

Assessment reports on generics

There are several assessment reports on capecitabine as generic medicinal products containing similar information. The following summarizes the content of the report for Capecitabine Medac, 20 September 2012, EMA/711212/2012.

"No Environmental Risk Assessment (ERA) was submitted. This was justified by the applicant as the introduction of Capecitabine Medac is considered unlikely to result in any significant increase in the combined sales volumes for all capecitabine containing products and the exposure of the environment to the active substance. Thus, the ERA is expected to be similar and not increased."

Comment on generics

After the implementation of the latest European Medicines Agency (EMA) ERA guideline (1 September 2024), a generic company has the following options for Article 10 procedures under Directive 2001/83/EC:

i) to argue that a full ERA is not required because the pharmaceutical substance belongs to certain substance groups (e.g., so-called natural substances);

ii) to identify an official ERA from a previously accepted product and use it; or

iii) to develop its own ERA according to the latest EMA ERA guideline.

Arguments for not submitting an Environmental Risk Assessment (ERA) based on the claim that total environmental exposure has not increased (via total sales volumes) belong to the previous ERA guideline system (2006–2024) and are no longer applicable. Regarding option ii), it should be noted that if a reference ERA exists, the generic company must demonstrate that its conclusions remain technically relevant (since the latest ERA guideline introduced several new technical requirements absent in the previous ERA guideline) and in terms of exposure (showing that the estimated exposure used in the reference ERA remains reasonable). Regulatory authorities (national and EMA) recommend that generic companies attempt to obtain reference ERA documentation from other companies via a so-called Letter of Access (LoA). However, if this is not possible, it remains feasible to argue that the conclusions of an existing reference ERA are still relevant based on information gathered from public assessment reports (summarized descriptions of environmental risk assessments) and product information (to confirm that dosages, indications, etc., have not changed). It should be noted that in some cases, reference ERAs approved between 2006 and 2024 may need to be modified (e.g., with additional experimental studies). If no previous reference ERA can be identified or used, the generic company must commit to developing its own ERA.