Rivastigmine

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 can be found in the public investigation report (PAR/EPAR for medicinal product through a centralized procedure). Since the benefit/risk assessment for human medicinal products at present does not include environmental effects, an update of the environmental risk assessment is not required for renewals of marketing authorizations. There is thus no requirement for companies to stay informed about the development of their substances from an environmental point of view and consequently to update the environmental risk assessment as new data are published.

Assessment report for Exelon (rivastigmine), Novartis, 17 September 2007, EMEA/H/C/169/X/38

"Rivastigmine was found not to be readily biodegraded and not bioaccumulative. Acute toxicity was studied in the base-set of aquatic organisms. Potential environmental risks were identified for surface water and groundwater using literature ecotoxicity data of low relevance for the aquatic environmental risk assessment for rivastigmine. The risk for microorganism was evaluated, and concluded by the MAH to be unlikely, using MICresults for soil micro-organisms. The CHMP concluded that the adequacy of the obtained risk quotients and identified possible environmental risk potential cannot be assessed at this stage due to limited data. Therefore, the MAH was asked to complete the ERA with several tests, including chronic ecotoxicity, toxicity to a sludge microbial community, and sludge and sediment partitioning tests. [...] The CHMP concluded that the adequacy of the obtained risk quotients and identified possible environmental risk potential cannot be assessed at this stage due to limited data. Therefore, the MAH was asked to complete the ERA with several tests, including chronic ecotoxicity, toxicity to a sludge microbial community, and sludge and sediment partitioning tests." No such data has been found on the EMA website (2021-04-12).

Assessment report for Exelon, Novartis, 15 November 2012, EMA/54888/2013

"No new environmental risk assessment was provided for this application. The MAH considers that an environmental risk assessment is not necessary for the current line extension, based on the fact that the introduction of the 15 cm² patch on the European market will not lead to a significantly increased use of rivastigmine. The MAH submitted the justification of use of the STP modelling with the SimpleTreat model and includes a refinement of the PEC_{surface water} and PEC_sediment in the Phase II Tier B assessment. Rivastigmine is not expected to bio-accumulate in aquatic species according to the screening criteria for bioaccumulation. Adsorption of rivastigmine to sewage sludge is low and therefore partitioning into the soil compartment via spreading of sludge on agricultural soils is not expected. The highest respective risk ratio has been found for the sediment compartment (PEC/PNEC_sediment) with 0.0026. Based on these informations available, rivastigmine does not present environmental risk and the CHMP considered the justification for the absence to be acceptable."

Utredningsrapport för Rivastigmine Actavis 21 February 2013, EMA/CHMP/739928/2012

"No Environmental Risk Assessment was submitted. This was justified by the applicant as the introduction of Rivastigmine Actavis transdermal patch is considered unlikely to result in any significant increase in the combined sales volumes for all rivastigmine containing products and the exposure of the environment to the active substance. Thus, the ERA is expected to be similar and not increased."

Fass environmental information

Fass environmental information for Exelon from Novartis (downloaded 2021-04-12).

Hazard

Persistence: "DT₅₀ (total system) = 119–266 days. [...] Based on the fact that rivastigmine is not readily biodegradable and according to the pass criteria for OECD308 studies, rivastigmine can be classified as ‘Rivastigmine is potentially persistent.’ (DT₅₀ for total system > 120 days)." The database, Pharmaceuticals and Environment, reference group believes that based on these results, a drug substance is persistent and not potentially persistent, hence the information that rivastigmine is persistent in the initial summary information.

Bioaccumulation: "Log K_ow < 1 at pH 7 (FDA TAD 3.02 'shake-flask method, value of the tartrate salt)."

Toxicity: There are data for 3 trophic levels, most sensitive crustacean (Daphnia magna) NOEC 500 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2018. PEC/PNEC = 0.000095 which gives the risk insignificant.

Report from Goodpoint 2020

Comparative assessment of environmental risk when using medicinal products in the treatment of Alzheimer's disease/dementia (memantine, donepezil, rivastigmine, galantamine) from a Swedish perspective.

All investigated substances are likely to occur in concentrations close to or below 20 ng/L in Swedish aquatic environments exposed to treated wastewater. The environmental risk is very low for galantamine and rivastigmine, based on expected water exposure in relation to both potential for bioconcentration and potency in humans (fish plasma model) as well as available ecotoxicological data. The environmental risk is also low for memantine, although the ecotoxicity information is more scarce. However, the use of donepezil is associated with a certain environmental risk. [...] The use of galantamine, rivastigmine and memantine is not considered to pose an environmental risk. There is an increased risk of donepezil, but due to the lack of ecotoxicity studies, the scientific support is not currently considered strong enough to recommend an exchange. Continued measurements of donepezil in treated wastewater are recommended together with measurements in exposed aquatic biota.