Teriflunomide

Detailed information

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.

Assessment report Aubagio 2013

Assessment report for Aubagio (teriflunomide), Sanofi-Aventis, 27 June 2013, EMA/529295/2013.

Phase I and parts of the Phase II assessment were included in the environmental risk assessment (ERA).

Hazard

Persistence: In an OECD 301 ready biodegradability test, the substance showed only about 1% degradation within 28 days.

Bioaccumulation: The bioaccumulation potential is considered low based on log K_ow values determined according to OECD 107 and U.S. FDA protocol 3.02. The log K_ow was measured as 0.925 at pH 7 and 2.66 at pH 3.

Toxicity: No data.

Risk

PEC in the assessment report from a European perspective:

PEC_surfacewater = 0.0058 microg/L.

Assessment report Aubagio 2021

Assessment report for Aubagio, extension of the marketing authorisation, Sanofi-Aventis, 22 April 2021, EMA/CHMP/289596/2021.

Hazard

Persistence: In an OECD 301 ready biodegradability test, the substance showed only about 1% degradation within 28 days.

Bioaccumulation: OECD 107 Log K_ow = 2.66 at pH 3.

Toxicity: No data.

Risk

PEC in the assessment report from a European perspective:

PEC_surfacewater = 0.0068 microg/L.

The PEC_surfacewater value for teriflunomide is below the action limit of 0.01 µg/L, and the substance is not considered PBT since its log K_ow does not exceed 4.5. The environmental risk assessment therefore stops at Phase I, and teriflunomide is considered unlikely to pose an environmental risk when used as prescribed.

Assessment report Teriflunomide Mylan

Assessment report for Teriflunomide Mylan, Mylan Pharmaceuticals, 15 September 2022, EMA/CHMP/792181/2022.

The applicant has provided PEC_surfacewater estimates based on annual consumption (0.002145 microg/L) and European disease prevalence (0.00798 microg/L assuming full theoretical treatment). As only about 9% of eligible European patients are currently treated with teriflunomide, PEC values above 0.003 microg/L are considered unlikely, even with increased use of generics. The action limit of 0.01 microg/L would not be exceeded, and a Phase II assessment is therefore not required. The data support that no increase in environmental exposure is expected, and the environmental risk assessment is considered acceptable. No data have been reported.

Assessment report Teriflunomide Accord 2022

Assessment report for Teriflunomide Accord, Accord Healthcare, 15 September 2022, EMA/CHMP/805980/2022.

As this was a generic application, no standalone ERA studies were submitted. API consumption data from 2018–2021 showed an increase in overall teriflunomide use and were therefore used to calculate refined Fpen and PEC_surfacewater values, both below the trigger for a Phase II assessment. According to the reference product Aubagio, teriflunomide is not persistent, bioaccumulative, or toxic, and its log K_ow does not exceed the trigger value. Teriflunomide Accord is therefore considered unlikely to pose any significant environmental risk. The CHMP concluded that environmental exposure is not expected to increase and that the absence of a full ERA is justified for this application.

Assessment report Teriflunomide Accord 2024

Assessment report for Teriflunomide Accord, extension of the marketing authorisation, Accord Healthcare, 22 February 2024, EMA/CHMP/108990/2024.

Hazard

Persistence: No data.

Bioaccumulation: OECD 107 Log K_ow = 2.66 at pH 3.

Toxicity: No data.

Risk

The proposed product will be marketed as a generic medicine, and its authorization is not expected to increase environmental risk. Therapeutic indications and target patient groups are the same as for the reference product Aubagio, and use is not expected to rise but rather replace existing products. An environmental risk assessment was provided, and the calculated PEC (using a refined Fpen value) was below 0.01 µg/L. Teriflunomide is not persistent, bioaccumulative, or toxic, and its log K_ow does not exceed the trigger value. A Phase II assessment is therefore not required. Overall, the proposed teriflunomide product is considered unlikely to pose an environmental risk when used as prescribed.

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.

Fass environmental information

Fass environmental information for Aubagio from Sanofi (retrieved on 2026-01-27).

Excretion (metabolism)

"Teriflunomide was found to be moderately metabolized. Metabolites identified are nine in the urine, counting the 4‑trifluoro‑methylaniline (TFMA) oxanilic acid, and three in the feces (Ref VII). The pharmacological activity of the metabolites is not known."

Hazard

Persistence: In an OECD 301 ready biodegradability test, the substance showed only about 1% degradation within 28 days.

Bioaccumulation: Log P_ow = 0.925 at pH 7(OECD 107).

Acute toxicity: There are data for 3 trophic levels, most sensitive algae EC₅₀ 30000 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2022.

PEC = 0.0002 microgg/L.

PNEC = Lowest EC₅₀, 30000 microg/L/1000 (Assessment Factor (AF) for 3 acute studies) = 30 microg/L.

PEC/PNEC = 8,19*10^-6 which gives the risk insignificant.