Palonosetron

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 reports on Aloxi and Akynzeo

There are assessment reports for Aloxi (palonosetron) and Akynzeo (netupitant, palonosetron) that include environmental information for palonosetron provided by Helsinn Birex Pharmaceuticals Ltd. Below is the assessment report for Akynzeo, dated 26 March 2015, EMA/236963/2015.

Hazard

Persistence: No data.

Bioaccumulation: log K_ow = 4.3 at pH 7.4. Conclusion not B.

Toxicity: No data.

Risk

PEC in the assessment report from a European perspective:

PEC_{surface water} = 0.0025 microg/L.

"Palonosetron PEC_{surface water} is below the action limit of 0.01 µg/L and is not a PBT substance as log K_ow does not exceed 4.5. Therefore, palonosetron is not expected to pose a risk to the environment.

Palonosetron has only undergone a phase I study in accordance with regulatory requirements for environmental risk assessments (Guideline on the environmental risk assessment of medicinal products for human use, EMEA/CHMP/SWP/4447/00 Rev. 1- Corr.) A phase I study includes data on bioaccumulation and an estimation of the environmental concentration of palonosetron (PEC_{surface water}). If the specified threshold values are not exceeded, the company is not required to conduct a Phase II study, which includes data on toxicity, persistence, and risk assessment based on PEC/PNEC.

Assessment report on Palonosetron Accord

Assessment report on Palonosetron Accord, 1 April 2015, EMA/287566/2016.

"No Environmental Risk Assessment was submitted. This was justified by the applicant as the introduction of Palonosetron Accord manufactured by Accord Healthcare Limited is considered unlikely to result in any significant increase in the combined sales volumes for all palonosetron containing products and the exposure of the environment to the active substance. Thus, the environmental risk 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.