Canagliflozin

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.

Assessment report

Below are data from the most recent assessment report on canagliflozin, related to a Type II variation. Previous assessment reports were also submitted by Janssen-Cilag. Assessment report for Invokana (canagliflozin), Janssen-Cilag, 28 May 2020, EMA/306073/2020.

Hazard

Persistence: OECD 308:
DT_{50 water}: 2.2/6.4 d
DT_{50 whole system}: 30/39 d
DT_{50 sediment}: 25.1/38.5 d
Mineralisation: 11.4/4.0 %
Bound residues: 34.2/29.4 %
Sediment shifting: 65.2/58.1 % (14 d)
Transformation Products: 4
TP > 10%

Bioaccumulation: BCF: 11 L/kg.

Toxicity: There are data for 3 trophic levels, most sensitive crustaceans (Daphnia magna) NOEC 560 microg/L.

Risk

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

PEC = 1,5 microg/L.

PNEC = Lowest NOEC, 560 microg/L/10 (Assessment Factor (AF) for 3 chronic studies) = 56 microg/L

PEC/PNEC = 0.0268 which gives the risk insignificant.

Fass environmental information

Fass environmental information for Invokana from Janssen (retrieved on 2016-07-27).

Hazard

Persistence: Canagliflozin is not readily biodegradable according to OECD 301B. In OECD 308 simulation study using aerobic water/sediment systems (Taunton River and Weweantic River), the substance showed slow degradation:
Half-life (DT₅₀) in water phase: 2.2/6.4 days
Half-life in whole system: 30/39 days
Mineralisation (CO₂ evolution): 11.4 %/4.0 %
Sediment-bound residues: 34.2 %/29.4 %
Transformation products: Several >10%
Volatile organic compounds: Not detected
Conclusion for degradation: Canagliflozin is slowly degraded in the environment.

Bioaccumulation:
BCF_{low dose} = 7.98.
BCF_{high dose} = 5.11.

Toxicity: There are data for 3 trophic levels, most sensitive crustaceans (Daphnia magna) NOEC 560 microg/L.

Risk

PEC/PNEC is based on sales data in Sweden in year 2015.

PEC = 0.01 microg/L.

PNEC = Lowest NOEC, 560 microg/L/10 (Assessment Factor (AF) for 3 chronic studies) = microg/L.

PEC/PNEC = 0.000178 which gives the risk insignificant.