Valsartan

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 Entresto

Assessment report for valsartan from Entresto (sacubitril, valsartan) 24 September 2015, EMA/671279/2015.

"The ERA (Environmental Risk Assessment, red. anm.) for valsartan was based on the earlier assessment of the compound in procedures EMEA/H/C/1068, EMEA/H/C/1159, EMEA/H/C/1160, EMEA/H/C/1161 and post-authorisation measures to these procedures. Valsartan is not a PBT, nor vPvB substance. A risk of valsartan for the STP, surface water, sediment, soil and groundwater compartments from the prescribed use of the product was not anticipated."

Assessment report for Dafiro HCT

Assessment report for valsartan from Dafiro HCT (amlodipine, valsartan, hydrochlorothiazide) EMEA/CHMP/471165/2009.

Hazard

Persistence: "... is not readily biodegradable." No data is reported.

Bioaccumulation: "The substance is not expected to bio-accumulate." No data is reported.

Toxicity: "VAL (valsartan, ed. note) shows moderate chronic toxicity to aquatic species; the reproduction rate in Daphnia magna being specially affected. [...] In addition, the Algae Growth Inhibition Test (OECD 201) for VAL was not valid as both, the water and the solvent control exceeded the coefficient of variation of average specific growth rates."

Comments

"Due to the fact that full results of the evaluation were not presented as study reports, the CHMP requested the detailed information on all performed test with all three substances in order to fully evaluate the ERA for AML/VAL/HCT. [...] For VAL following studies will be conducted and results to be provided together with updated: - Algae growth inhibition (OECD201). - Activated sludge respiration inhibition (OECD209). - An additional study to confirm the octanol/water partition coefficient as a study protocol for the log Kow value is not available. - Toxicity to sediment-dwelling organisms." No such information has been found on EMA's website. Upon request to EMA, documentation has been received (2021-01-12). Algae growth inhibition test (OECD201) sets the 72-hour NOEC value at 100 mg/L. For activated sludge respiration inhibition (OECD209), set the 3 hour value for NOEC to 200–750 mg/L.

Fass environmental information

Fass environmental information for Diovan (valsartan) from Novartis (downloaded 2021-01-21).

Hazard

Persistence: DT_{50 (total system)} = 12.0–16.1 days. "According to the pass criteria for OECD308 studies, valsartan can be classified as ‘Valsartan is degraded in the environment' (DT₅₀ for total system < 32 days)."

Bioaccumulation: Log D_ow = 1.2 at pH 7 (OECD117). "Since log D_ow < 4 at pH 7, valsartan has low potential for bioaccumulation."

Toxicity: There are data for 3 trophic levels, most sensitive crustacean (Daphnia magna) NOEC 5 600 microg/L.

Risk

PEC/PNEC utis based on sales data in Sweden in year 2018. PEC/PNEC = 0.00037 which gives the risk insignificant.

Report Goodpoint 2019

Comparative assessment of environmental risk when using angiotensin II antagonists candesartan, losartan, valsartan, irbesartan, eprosartan and telmisartan from a Swedish perspective (Report Goodpoint 2019).

Angiotensin receptor blockers are relatively stable and can reach the aquatic environment at concentrations higher than that of many other pharmaceuticals. They are all fat-soluble, suggesting high potential for bioconcentration in biota, which has been documented for irbesartan, since telmisartan does not bioconcentrate in proportion to its very high fat solubility. Bioconcentration data for the other substances are missing. The target is preserved in fish but not invertebrates and algae. However, growth studies (28–32 days) of fish for four of the substances (candesartan, losartan, valsartan, irbesartan) show low toxicity, but mechanism-based efficacy data are completely lacking for all.

Based on the information, none of the angiotensin receptor blockers can be attributed to "high" environmental risk, at the same time irbesartan stands out as a substance with higher risk than the others, based on available data. Sales of irbesartan are low in relation to candesartan and losartan. In 2018, over 18 times more losartan than irbesartan was prescribed and just over 18 times more candesartan than irbesartan in Sweden (in DDD count, excluding combination preparation). Therefore, if irbesartan was substituted for losartan or candesartan, the levels of losartan or candesartan in the environment would probably only increase by about 6% on average and therefore increase the environmental risk for these marginally, but it would eliminate the environmental risk with irbesartan. However, it should be mentioned that the environmental risk is unclear for all substances studied.

Based on concentrations of irbesartan over CEC (critical environmental concentration) in Swedish surface water, as well as bioconcentration in wild fish and a relatively high persistence in wastewater treatment plants and the environment, there is a risk picture that should be further investigated. The reasons for the replacement of irbesartan are moderate at present, and the situation is difficult to assess. An exchange of irbesartan with either losartan or candesartan may be justified, primarily based on the fact that the environmental exposure to losartan or candesartan would increase only marginally.