Entecavir

Detailed information

EMA’s scientific discussion on Baraclude

EMA’s scientific discussion on Baraclude (entecavir) 21/05/2007. Ecotoxicity/environmental risk assessment. "An assessment of the risk was performed and no significant risk to the environment related to the use of entecavir is anticipated." No data are presented.

Assessment report on Baraclude 2014

Assessment report on Baraclude, type II variation, 24 July 2014, EMA/563133/2014.

Hazard

Persistence: No data.

Bioaccumulation: "An experimentally determined (Shake Flask method) log K_ow of -0.82 at pH 7.1 was included in previous submissions of entecavir. Additionally, log K_ow values of -1.3 and -1.1 have been reported at pH 2.1 and pH 9.4, respectively."

Toxicity: No data.

Risk

"As the calculated PEC_surfacewater value is <0.01 μg/L, no Phase II assessment is necessary in accordance with the “Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use” EMEA/CHMP/SWP/4447/00."

Comment

Entecavir 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 entecavir (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 reports on generic entacavir

There are assessment reports on Entecavir Mylan, 20 July 2017, EMA/555410/2017 and Entecavir Accord, 20 July 2017, EMA/520001/2017, containing similar statements. From the latter: "No Environmental Risk Assessment was submitted. This was justified by the applicant as the introduction of Entecavir Accord manufactured by Accord Healthcare Ltd is considered unlikely to result in any significant increase in the combined sales volumes for all entecavir containing products and the exposure of the environment to the active substance. Thus, the ERA is expected to be similar and not increased."

Statement regarding generic medicines

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.