Darunavir

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.

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exposure has not increased (via total sales volumes) belong to the previous ERA guideline system (2006–2024) and are no longer applicable.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.

Assessment reports

There are several assessment reports containing environmental information on darunavir, including those for generics. Here, the latest report with more comprehensive environmental information is presented. For generics, the following statement may apply: "No Environmental Risk Assessment was submitted. This was justified by the applicant as the introduction of Darunavir KrKa manufactured by KRKA, d.d., Novo mesto is considered unlikely to result in any significant increase in the combined sales volumes for all darunavir containing products and the exposure of the environment to the active substance. Thus, the ERA is expected to be similar and not increased."

Assessment report for Symtuza (darunavir, cobicistat, emtricitabine and tenofovir alafenamide) about darunavir, Janssen-Cilag, 20 July 2017, EMA/496527/2017.

Hazard

Persistence: DT_{50, water} = 15/51 d (r/r)
DT_{50, sediment} = 141/267 d (r/r)
DT_{50, system} = 50/86 d (r/r)
Konklusion: "r=river; DT₅₀ values corrected to 12°C. Conclusion: vP.

OECD 308: DT_{50, water} = 8.1/27 d (r/r)
DT_{50, sediment} = 75/142 d (r/r)
DT_{50, system} = 26/46 d (r/r)
% shifting to sediment = 30.9 and 22.9. Values determined at 20°C; Significant shifting to sediment.

Bioaccumulation: log K_ow 2.41.

Toxicity: There are data for 3 trophic levels, most sensitive fish (P. promelas) NOEC ≥ 9400 microg/L. Comment: Values reported as greater than are not according to the guidelines. The actual value may be lower.

Risk

"Considering the above data, darunavir is not expected to pose a risk to the environment."

Fass environmental information

Fass environmental information for Presista (darunavir) from Janssen-Cilat (accessed on 2025-05-13).

Hazard

Persistence: "Darunavir was investigated for its ready biodegradation in a 28-day manometric respirometry test according to OECD 301B [Reference VII]: Result: Not readily biodegradable. [...] Conclusion for degradation: Darunavir is slowly degraded in the environment."Refer to the Fass text for further data.

Bioaccumulation: log D_ow = 2.4 (pH = 4, 7 and 9).

Toxicity: There are data for 3 trophic levels, most sensitive most sensitive fish (P. promelas) NOEC 9400 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2022. PEC/PNEC = 0.0000331892 which gives the risk insignificant.