Paliperidone

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.

EMA’s scientific discussion Invega 2007

EMA’s scientific discussion for Invega (paliperidone), Janssen‑Cilag International, 16 July 2007.

"The Applicant had initially submitted an Environmental Risk Assessment Report for paliperidone consisting of a number of aquatic ecotoxicity studies and Predicted Environmental Concentration (PEC) / PNEC calculations. From these data, it was concluded that paliperidone is not a PBT substance and that it is unlikely to represent a risk to the sewage micro-organisms. Additional PEC data were provided following the CHMP request; based on these new data no further studies were deemed necessary for the evaluation of the environmental impact of paliperidone." No data are presented.

Assessment report Invega 2010

Assessment report for Invega, new indication, 18 November 2010, Doc. Ref.: EMA/179857/2011.

"The MAH predicted that based on available epidemiological studies, the approval of the proposed indication will not significantly increase the use of paliperidone in the EU. Taking into account the updated calculation of the PEC refinement based on actual use of the product and that in the studies, both patients with schizoaffective disorder and schizophrenia were included, the ERA was considered acceptable by the CHMP." No data are presented.

Assessment report Invega 2014

Assessment report for Invega, extension of indication, Janssen-Cilag International, 25 April 2014, EMA/339041/2014.

No new ERA data were initially submitted by the MAH. As the application concerned an extension to the paediatric population, the CHMP requested updated statistical data for the estimated market penetration and a refined PEC_sw calculation (Phase II tier A). Using an estimated CON_ai of 289 kg per year, which is lower than the previously predicted 775 kg, the PEC was calculated as 0.0001 µg/L compared with 0.003 µg/L in the previous ERA. The CHMP therefore concluded that no further ERA data were required and that adding patients aged 12–17 years would not significantly affect environmental exposure, especially since schizophrenia is very rare in this age group.

Assessment report Invega 2015

Assessment report for Invega, extension of indication, Janssen-Cilag International, 23 April 2015, EMA/CHMP/213560/2015 - adopted.

No updated Environmental Risk Assessment was submitted. The applicant argued that use of Invega prolonged‑release tablets is not expected to increase significantly with the extension of the schizoaffective disorder indication to include depressive symptoms. As epidemiological data for schizoaffective disorder overlap with those for schizophrenia, previous usage estimates likely already included this population. The CHMP therefore concluded that the proposed extension would not affect overall environmental exposure to paliperidone and that no update to the Environmental Risk Assessment was required.

Assessment report Xeplion 2011

Assessment report for Xeplion (paliperidone), Janssen-Cilag International, EMA/60983/2011.

An ERA according to CHMP guidelines was performed using available studies for oral paliperidone. Based on the estimated EU sales forecast for 2016, the Predicted Environmental Concentration in surface water (PEC) was 0.0027 µg/L, below the 0.01 µg/L threshold. No further testing was required, and no additional environmental impact is expected from the use of paliperidone palmitate. No additional data are presented.

Assessment report Paliperidone Janssen 2014

Assessment report for Paliperidone Janssen, 23 October 2014, EMA/664603/2014.

As this application is an informed consent referring to the Xeplion marketing authorisation, the non‑clinical data are identical to the up‑to‑date Xeplion dossier, which has already been assessed and approved. No additional non‑clinical data were submitted. The CHMP considered that paliperidone palmitate is not expected to increase environmental risk.

Assessment report Trevicta 2016

Assessment report for Trevicta (paliperidone), Janssen-Cilag International, 1 April 2016, EMA/CHMP/323556/2016.

The MAH submitted an ERA including a Phase I assessment and several Phase II Tier A studies, using the same data previously assessed for oral paliperidone and Xeplion. In the updated ERA for Trevicta, the PEC in surface water was calculated as 0.0019 µg/L, below the 0.01 µg/L threshold. Since Trevicta is intended to replace other paliperidone products and its maximum daily dose is only slightly higher than that of Xeplion, no increase in overall use or environmental exposure is expected. The CHMP therefore concluded that no further testing was required and that the new 3‑month formulation is unlikely to pose an environmental risk when used as prescribed.

Assessment report Paliperidone Janssen-Cilag International 2020

Assessment report for Paliperidone Janssen-Cilag International, 30 April 2020, EMA/358737/2020.

An environmental risk assessment for paliperidone palmitate from 2009 was submitted. It concluded that no environmental risk is expected under the approved conditions of use, but several deficiencies were identified. The CHMP requested an experimental log K_ow, a correct PEC calculation, a terrestrial assessment due to high Koc values, and an OECD 308 study since paliperidone is not readily biodegradable. These studies may be provided as post‑marketing measures, and the company has agreed to this and submitted a timeline.

Assessment report Byannli 2021

Assessment report for Byannli (paliperidone), Janssen-Cilag International, EMA/502561/2021.

Hazard

Persistence: Paliperidone is not readily biodegradable according to OECD 301F, and is therefore classified as persistent. The OECD 308 study is ongoing. If more than 10 percent of the parent compound including NER shifts to the sediment, effects on sediment‑dwelling organisms should be further investigated in Phase II B.

Bioaccumulation: Log D_ow at pH 7: 0.9.

Toxicity: There are data for 3 trophic levels, most sensitive crustaceans (Daphnia magna) NOEC 2500 microg/L.

Risk

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

PEC_surfacewater = 0.022 microg/L.

PNEC = Lowest NOEC, 2500 microg/L/10 (Assessment Factor (AF) for 3 chronic studies) = 250 microg/L

PEC/PNEC = 0.000088 which gives the risk insignificant.

As no complete ERA has been submitted, it is not possible to fully conclude on the environmental risk of paliperidone. The remaining studies (OECD 232, 307 and 308), together with an updated ERA, should be submitted as a Type II variation. If OECD 308 shows more than 10 percent of the substance in sediment after or at 14 days, a study in sediment‑dwelling organisms must be added. The applicant committed to completing the studies and finalising the ERA within the agreed timeline, which was accepted. Although a Type IB variation was proposed, submission of the remaining ERA data as a Type II variation remains preferred.

Assessment report Niapelf 2024

Assessment report for Niapelf (paliperidone), Neuraxpharm Pharmaceuticals, 25 January 2024, EMA/100717/2024.

Hazard

Persistence: No data.

Bioaccumulation: The predicted log K_ow is 1.95 according to PubChem (2023), while an experimental log K_ow of 1.8 is reported in DrugBank (2023), with the method not specified.

Toxicity: No data.

Risk

The predicted PEC in surface water is below 0,01 µg/L in all assessed countries, remaining under the EMA threshold and therefore not requiring a Phase II evaluation. However, for related substances such as clozapine, chlorpromazine and risperidone, environmental risk quotients above 600 have been reported, indicating a very high risk.

Summarised ecotoxicological data for paliperidone were included in the ERA. Related substances such as clozapine, chlorpromazine and risperidone show very high environmental risk quotients, indicating a need for improved control of antipsychotic emissions and enhanced wastewater treatment. Debaveye (2019) reported that the environmental burden of paliperidone is outweighed by its human health benefits. Measures to reduce emissions are described in the Niapelf product information. Under the current guideline, generic products are not required to submit an ERA, but the draft revised guideline recommends submitting an ERA regardless of legal basis, with the option to cross‑refer to the originator’s ERA with consent.

The applicant submitted an adequate ERA, and since the log K_ow is < 4.5 and PEC values are below the EMA threshold, a Phase II assessment is not required.

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 Invega from Janssen-Cilag AB (retrieved on 2026-02-24).

Hazard

Persistence: Paliperidone showed no degradation in the OECD 301F test over 28 days and is therefore not considered readily biodegradable. No abiotic degradation occurred, and no inhibition of microbial activity was observed. The reference substance sodium benzoate degraded as expected, confirming test validity. Overall, paliperidone is considered potentially persistent.

Bioaccumulation: The octanol/water partition coefficient determined by the shaking‑flask method yielded a log K_ow of 2.39 at pH 11.9. Open literature reports lower values, including an ACD/LogP of 1.52, an ACD/LogD (pH 7.4) of 0.88, and estimated log K_ow values around 1.95. Overall, paliperidone is considered to have a low potential for bioaccumulation.

Toxicity: There are data for 3 trophic levels, most sensitive crustaceans (Daphnia magna) NOEC 2500 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2024.

PEC = 0.000743461 microg/L.

PNEC = Lowest NOEC, 2500 microg/L/10 (Assessment Factor (AF) for 3 chronic studies) = 250 microg/L.

PEC/PNEC = 0.0000029738 which gives the risk insignificant.