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NovoNorm®

MiljöinformationReceptstatusFörmånsstatus
Novo Nordisk

Tablett 0,5 mg
(vit, rund, märkt med apistjur, 6,0 x 6,0 mm)

Peroralt antidiabetikum

Aktiv substans:
ATC-kod: A10BX02
Läkemedel från Novo Nordisk omfattas av Läkemedelsförsäkringen.
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Miljöpåverkan (Läs mer om miljöpåverkan)

Repaglinid

Miljörisk: Risk för miljöpåverkan av repaglinid kan inte uteslutas då det inte finns tillräckliga ekotoxikologiska data.
Nedbrytning: Repaglinid är potentiellt persistent.
Bioackumulering: Repaglinid har låg potential att bioackumuleras.


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Detaljerad miljöinformation

Environmental risk assessment of Repaglinide in pharmaceutical products marketed in Sweden in 2016.


This document includes environmental risk assessment of Repaglinide in pharmaceutical products marketed in Sweden in 2016. The risk assessment is performed in accordance with the FASS.se guidelines on environmental classification of pharmaceuticals (ref. 1).


1. Available data on Repaglinide


1.1 The pharmaceutical product


Repaglinide is used by Novo Nordisk as the active pharmaceutical ingredient (API) in NovoNorm.

NovoNorm is applied for glycaemic control of type II diabetes and is administered orally via tablets. The API content per tablet is 0.5, 1 or 2 mg and the total maximum daily dose is 16 mg.


Metabolism and excretion:

Repaglinide is completely metabolised in the body and excreted primarily via the bile. Ca. 8% is excreted via urine, primarily as metabolites, and less than 2% of the parent drug is recovered in faeces.


Reference: 2.


1.2 Repaglinide


  • Chemical name: Benzoic acid, 2-ethoxy-4-[2-[[(1S)-3-methyl-1-[2-(1-piperidinyl)phenyl]butyl]amino]-2-oxoethyl]-

  • CAS Number: 135062-02-1

  • Molecular formula: C27H36N2O4

  • Molecular weight: 452.6 g/mol

Reference: 3.


1.3 Physical/Chemical properties of Repaglinide


Dissociation (Ref. 4):


pH

Ionic form

< 3.9

Cationic

3.9 ≤ pH ≤ 6.1

Zwitter ionic

> 6.1

Anionic


Octanol/Water partition coefficient (Ref. 4):


pH

Log Dow

3.0

2.4

7.4

2.5

9.0

1.7


Water solubility (Ref. 4):


pH

mg/L

2.0

583

5.0

8.6

7.0

55.7

8.3

915


Hydrolysis (Ref. 4):

Repaglinide is only hydrolysed in strong acid media (pH 1).


1.4 Eco-toxicological studies on Repaglinide


Biodegradability (Ref. 5):

A biodegradation test on Repaglinide showed that only 16% of the substance was biodegraded within 28 days. Repaglinide is thus not readily biodegradable. Method: US-FDA, Tech. Assist. Doc. 3.11.


Eco-toxicity (Ref. 6):

Acute toxicity to daphnids, 48h, static: EC50 = 66 mg/L and NOEC = 34 mg/L.

Method: US-FDA, Tech. Assist. Doc. 4.08.


2. Environmental risk assessment (ERA)


2.1 Sold amount in Sweden


The total amount of Repaglinide sold in Sweden in 2016 was 13.31 kg API based on Quintiles IMS Health sales data.


2.2 Calculation of PEC in surface water


According to ref. 1, PEC (Predicted Environmental Concentration) in surface water is calculated according to the following formula:

PEC = 1.5*10-6*A*(100-R) µg/L, where

• A = Total amount of API (kg) sold in Sweden in a given year. Reduction of A may be justified based on metabolism data.

• R = Removal rate (%) due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation. R = 0 if no data is available.


Due to insufficient or lack of data, the calculation of PEC of Repaglinide in surface water is based on the following assumptions:

• no metabolism in the human body

• no removal in the waste water treatment plants.


Without taking removal effects of metabolism and waste water treatment into consideration the following PEC can be calculated according to ref. 1:

PECSurface water = 1.5 * 10-6 * 13.31 * 100 = 0.002 µg/L.


Since PECSurface water is below the action limit 0.01 µg/L stated in ref. 1 it is unlikely that Repaglinide constitutes a risk for the environment.


2.3 Calculation of PNEC and PEC/PNEC


Since eco-toxicological data is only available for one trophic level (daphnia) a valid PNEC and the risk quotient (PEC/PNEC) cannot be calculated according to ref. 1.


3. PBT and vPvB assessment


Persistence:


Since only 16% was degraded in the biodegradation test stated in section 1.4, it cannot be excluded that Repaglinide is potentially persistent in the aquatic environment according to ref. 1.


Bioaccumulation:

The highest estimated Log Dow for Repaglinide is 2.5; see section 1.3.

Since Log Dow < 4, it indicates that Repaglinide has low potential for bioaccumulation according to ref. 1.


Eco-toxicity:

Acute toxicity test on daphnids resulted in EC50 = 66 mg/L and NOEC = 34 mg/L; see section 1.4.


Since 1 mg/L < EC50 ≤ 100 mg/L, Repaglinide is considered to be moderate acute toxic to crustaceans.


Conclusion on PBT/vPvB:

Considering all three PBT aspects, Repaglinide does not meet the criteria as a PBT or vPvB substance.


4. Environmental risk classification of Repaglinide


In conclusion:

- A valid risk quotient (PEC/PNEC) for Repaglinide cannot be calculated due to lack of eco-toxicity data

- Repaglinide:

  • is potentially persistent in the environment

  • has low potential for bioaccumulation

  • is moderate toxic to crustaceans (daphnids)

  • does not meet the criteria for classification as a PBT or vPvB substance

Since the PEC/PNEC cannot be calculated due to lack of eco-toxicity data the following environmental risk phrase should be applied to pharmaceutical products containing Repaglinide according to the criteria in ref. 1:


”Risk of environmental impact of Repaglinide cannot be excluded due to lack of eco-toxicity data”.


5. References


1) Environmental classification of pharmaceuticals in www.fass.se – guidance for pharmaceutical companies 2012.

2) Company Core Data Sheet on Repaglinide by Novo Nordisk, 2005.

3) ERA Data sheet on Repaglinide from Boehringer-Ingelheim, 02/2007.

4) Report no. U96-2543, Boehringer-Ingelheim

5) Report no. U98-3272, Boehringer-Ingelheim

6) Report no. U98-3271, Boehringer-Ingelheim