Leflunomide

Detailed information

Fass environmental information

Fass environmental information for Arava (leflunomide) from Sanofi AB (retrieved on 2025-10-01).

Hazard

Persistence: Biotic degradation: Leflunomide is potentially persistent with < 20% degradation in 28 days (OECD 301B). The metabolite A771726 is not readily biodegradable (~1%, OECD 301E). Abiotic degradation: Hydrolysis is not expected to be a relevant degradation pathway as the compound lacks hydrolysable functional groups.

Bioaccumulation: Log P_ow for leflunomide has been experimentally determined as 3.49 (method unknown). For the active metabolite A771726 (teriflunomide), Log P_ow is 0.925 at pH 7 (OECD 107). Bioaccumulation in organisms is considered unlikely (Log K_ow < 4).

Toxicity: There are data for 3 trophic levels, most sensitive fish LC₅₀ 2640 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2023.

PEC = 0.001241233 microg/L

PNEC = Lowest LC₅₀, 2640 microg/L/1000 (Assessment Factor (AF) for 3 acute studies) = 2.64 microg/L.

PEC/PNEC = 0.000470164 which gives the risk insignificant.

General information about assessment reports

Since 2006, an Environmental Risk Assessment (ERA) for the active pharmaceutical substance shall accompany an application for a marketing authorisation in EU for a medicinal product for human use. Parts of environmental data are available in the public assessment report (PAR/EPAR for centrally approved medicines). Environmental considerations are not included in the benefit-risk assessment for human medicines. If new data emerge after approval that necessitate an update of the environmental risk assessment, a variation application (“type IB C.I.z variation”) must be submitted to the regulatory authority.

The PEC (predicted environmental concentration) values used to calculate risk in the manufacturers' assessment reports are based on the estimated use of the medicinal product to which the assessment report relates, as well as possibly other products from the same company, not all medicinal products containing the same active substance.

EMA’s scientific discussion

EMA’s scientific discussion on Arava, 23 November 2005.

Ecotoxicity/Environmental Risk Assessment: A comprehensive environmental risk assessment indicates that the use of leflunomide is likely to pose a low environmental risk. No data have been presented.

Assessment reports on generics

There are assessment reports for generics. Two are presented here.

Assessment report for Leflunomide Medac, 30 May 2013, EMA/CHMP/478482/2013.

"No Environmental Risk Assessment was submitted. This was justified by the applicant as the introduction of Leflunomide Medac 15 mg film-coated tablets is considered unlikely to result in any significant increase in the combined sales volumes for all leflunomide-containing products and the exposure of the environment to the active substance. Thus, the environmental risk is expected to be similar and not increased. The CHMP agrees with the above."

Assessment report for Leflunomide ratiopharm, London, 23 September 2010, EMA/789404/2010.

"The applicant did not present an environmental risk assessment (ERA) in the application by justifying that an increase in the environmental exposure is not expected and an environmental risk assessment was deemed not necessary. This was agreed by the CHMP."

Comments 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.