Fingolimod

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 Gilenya 2011

Assessment report for Gilenya (fingolimod), London, 17 February 2011, Doc.Ref.: EMA/108602/2011.

An environmental risk assessment (ERA) for fingolimod was submitted in accordance with CHMP guidelines. The substance shows high water solubility and moderate lipophilicity (Log K_ow (pH 6): 3.6 and Log D pH 7: 2.6), with a predicted environmental concentration in surface water of < 0.01 μg/L. Although the Log D value was initially questioned, the CHMP concluded—after clarifications—that fingolimod is not expected to pose an environmental risk at the intended clinical use.

Assessment report Gilenya 2014

Assessment report for Gilenya, type II variation, 25 April 2014, EMA/195551/2014.

An updated environmental risk assessment (ERA) was submitted at CHMP’s request. As the target population remains unchanged, no significant increase in fingolimod exposure is expected. Based on a daily dose of 0.5 mg and a market penetration of 1%, the predicted environmental concentration (PEC) is 0.0025 μg/L—well below the Phase II trigger. No environmental risk is anticipated.

Assessment report Gilenya 2015

Assessment report for Gilenya, type II variation, 24 September 2015, EMA/CHMP/549382/2015.

Hazard

Persistence: OECD 308: DT₅₀ (total system) = 0.35–0.39 days.

Bioaccumulation: Although fingolimod shows a log D of 4.5—exceeding the trigger value for bioaccumulation screening—it does not meet the criteria for a bioaccumulative substance due to its rapid degradation in the environment, low persistence, and extensive metabolism in patients. Therefore, fingolimod is not considered to pose a significant bioaccumulation risk.

Toxicity: There are data for 3 trophic levels, most sensitive algae NOEC 20.3 microg/L.

Risk

The risk, PEC/PNEC, calculated from data in the assessment report from a European perspective:

PEC = 0.0025 microg/L.

PNEC = Lowest NOEC, 20.3 microg/L/10 (Assessment Factor (AF) for 3 chronic studies) = 2.03 microg/L

PEC/PNEC = 0.00123 which gives the risk insignificant.

Conslusion

Due to its high lipophilicity, fingolimod was screened for PBT properties. Although it is not readily biodegradable, it shows rapid degradation in water-sediment systems and does not meet persistence criteria. Extensive metabolism in patients leads to minimal environmental exposure. Despite some aquatic toxicity, chronic data do not meet the threshold for concern. Fingolimod is therefore not considered a PBT or vPvB substance, and no environmental risk is anticipated.

Assessment report Gilenya 2018

Assessment report for Gilenya, a new strength of hard capsule, 20 September 2018, EMA/779102/2018.

"Fingolimod is not expected to pose a risk to the environment."

Assessment report Fingolimod Mylan

Assessment report for Fingolimod Mylan, 24 June 2021, EMA/CHMP/386085/2021.

"No Environmental Risk Assessment studies were submitted. This was justified by the applicant as the introduction of Fingolimod Mylan manufactured by Mylan Ireland Limited is considered unlikely to result in any significant increase in the combined sales volumes for all fingolimod containing products and the exposure of the environment to the active substance. Thus, the ERA is expected to remain unchanged."

Assessment report Fingolimod Accord

Assessment report for Fingolimod Accord, 30 April 2020, EMA/CHMP/267804/2020.

No new Environmental Risk Assessment (ERA) studies were submitted, as the introduction of Fingolimod Accord is not expected to significantly affect overall sales or environmental exposure. The ERA is therefore considered similar, and the justification is deemed acceptable under the applicable guideline (EMEA/CHMP/SWP/4447/00).

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 Gilenya from Novartis (retrieved on 2025-07-01).

Hazard

Persistence: OECD 308: DT₅₀ (total system) = 0.35–0.39 days.

Bioaccumulation: Log D = 3.4 (pH 7.4; dual-phase potentiometric titration)

Toxicity: There are data for 3 trophic levels, most sensitive algae NOEC 20.3 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2021. PEC/PNEC = 0.0000092 which gives the risk insignificant.