Felodipin Teva. Teva Depottablett 5 mg (ljusrosa, rund, bikonvex, filmdragerad) kalciumantagonist/dihydropyridinderivat. Aktiv substans: Felodipin

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1 Felodipin Teva Teva Depottablett 5 mg (ljusrosa, rund, bikonvex, filmdragerad) kalciumantagonist/dihydropyridinderivat Aktiv substans: Felodipin ATC-kod: C08CA02 Företaget omfattas av Läkemedelsförsäkringen Miljöpåverkan Miljöinformationen för felodipin är framtagen av företaget AstraZeneca för Felodipin AstraZeneca, Logimax, Logimax forte, Plendil, Unimax, Unimax mite Miljörisk: Användning av felodipin har bedömts medföra låg risk för miljöpåverkan. Nedbrytning: Felodipin är potentiellt persistent. Bioackumulering: Felodipin har låg potential att bioackumuleras. Detaljerad miljöinformation PEC/PNEC = μg/l /0.05 μg/l = < PEC/PNEC 1 Environmental Risk Classification Predicted Environmental Concentration (PEC) PEC is based on following data: PEC (µg/l) = (A*10 *(100-R))/(365*P*V*D*100) 1

2 -6 PEC (µg/l) = 1.5*10 *A*(100-R) A (kg/year) = total sold amount API in Sweden year 2014, data from IMS Health. R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0 if no data is available. P = number of inhabitants in Sweden = *10 6 V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Note: The factor 10 converts the quantity used from kg to μg). A = 41.2 kg R = 50% (adsorption to sludge)* *The removal during sewage treatment (50%) is estimated using the EUSES model, Simple Treat, described in the ECHA Guidance Document (Ref. 1) where the following assumptions have been made: not readily biodegradable, vapour pressure -6 (VP) <1*10 Pa, water solubility 0.5 mg/l and Kd = 2800 L/kg. Felodipin is an involatile solid with sludge negliable VP at ambient conditions, a measured VP is not available, the nominal value used in this calcultion o assumes no losses to the atmosphere. Water solubility was measured at C and may therefore lead to an over esitmation of PEC, since at environmentally relevent temperatures water solubility may be lower. -6 PEC = 1.5 * 10 * 41.2* (100-50) = μg/l Metabolism Felodipine is extensively metabolised in humans. In healthy volunteers about 62% of an orally given dose of felodipine was excreted into the urine. No parent compound was found in the urine and the identified metabolites (accounting for about 23% of the dose) are known to be less pharmacologically active than the parent compound. The remaining metabolites in urine (i.e. 3% of the dose) were unidentified polar compounds which are also expected to be less active than the parent compound. Approximately 10% of the given oral dose was excreted in faeces, however the identity or pharmacological activity of these excreted products is not known (Refs 2, 3). Ecotoxicity data Endpoint Species Common E C50- Based b on Biomass E C50- Based r on Average Specific Growth Rate LC50 Name Pseudokirchne Green Alga OECD 201 riella subcapitata (f ormerly known as Selenastru m capri-cornutu m) Daphnia magna Giant Water Flea Method Time Result Ref. 2/6/EEC 72 h >0.322 mg/l 4 >0.322 mg/l US EPA h 0.62 mg/l 5 LC50 Rainbow Trout 6 h 0.05 mg/l 6 2

3 Endpoint Species Common Method Time Result Ref. Name NOEC - Based on Mortality & Symptoms of Toxicity Oncorhynchus mykiss US FDA Technical Document <0.016 mg/l LC >0.2 mg/l 7 NOEC 0.2 mg/l LC50 Pimephales Fathead US EPA h 0.3 mg/l 5 promelas Minnow LC50 Lepomis Bluegill US FDA 6 h 0.66 mg/l 8 NOEC - Based on Mortality & Symptoms of Toxicity EC50 - Based on Respiration Inhibition macrochirus Sunfish Technical 0.22 mg/l Document OECD 20 3 h >10 mg/l 5 PNEC (Predicted No Effect Concentration) Short-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. The PNEC is based on the acute toxicity to rainbow trout ( Oncorhynchus mykiss), the most sensitive species, and an assessment factor of 1000 is applied, in accordance with ECHA guidance (Ref. 1). PNEC = 0.05 mg/l/1000 = 0.05 µg/l Environmental risk classification (PEC/PNEC ratio) PEC/PNEC = µg/l /0.05 µg/l = 0.74, which justifies the phrase Use of felodipine has been considered to result in low environmental risk. In Swedish: Användning av felodipin har bedömts medföra låg risk för miljöpåverkan under the heading Miljörisk. Environmental Fate Data Endpoint Method Test Substance Percentage Biodegradation Percentage Hydrolysis Rate OECD 301B 2/6/EEC Concentration Time Result Reference mg/l 28 d < 5% ThCO 2 US FDA Technical 10 mg/l 5 d < 10 % 10 Document 3.0 US FDA Technical Document mg/l 6 h ph mg/l T1/2 = 2.2 ph 5 3

4 Rate Rate Partition Coefficient Octanol Water Experimental method unknown 10 mg/l ph 7 10 mg/l T1/2 = 2.1 ph7 10 mg/l ph 10 mg/l T1/2 = 2.6 ph - - Log P = Biotic degradation Felodipine is not readily biodegradable. There are no further studies available regarding degradation of felodipine. Therefore, the substance has been assigned the risk phrase: Felodipine is potentially persistent. In Swedish: Felodipin är potentiellt persistent under the heading Nedbrytning. Abiotic degradation Felodipine is photodegradable (T½ = 2.1 h at ph 7). Bioaccumulation Since Log P < 4 the phrase Felodipine has low potential for bioaccumulation is assigned. In Swedish: Felodipin har låg potential att bioackumuleras under the heading Bioackumulering. Physical Chemistry Data Endpoint Method Test Conditions Result Reference Solubility Water Activated Sludge Adsorption Coefficient o C 0.5 mg/l 13 OPPTS mg/l Kd = References ECHA, European Chemicals Agency. October 2012 Version: 2.1 Guidance on information requirements and chemical safety assessment. Edgar B, Regårdh C G, Johnsson G, Johansson L, Lundborg P, Löfberg I and Rönn, O. Felodipine kinetics in healthy men. Clinical Pharmacology and Therapeutics 38: Hoffman, K-J and Andersson L. Metabolism of [ C] felodipine, a new vasodilating drug, in healthy volunteers. Drugs 34: H154/82: Inhibition of growth to the alga Selenastrum capricornutum. 4

5 Covance, USA. Report No. 265/55-D2145. June 1 (Brixham Environmental Laboratory Report BD377). 5. Ecotoxicological characterisation of felodipine, MK0218. Environmental Engineering Laboratory (EEL), UK. (Brixham Environmental Laboratory Report BD4166). March Felodipine: Acute toxicity to Rainbow trout, Oncorhynchus mykiss, under static test conditions. Toxikon Environmental Sciences, USA. May 14. (Brixham Environmental Laboratory Report BD4165). 7. Photodegradates of felodipine: Acute toxicity to rainbow trout, conditions. Toxikon Environmental Sciences, USA. Report No J410003b, USA, April 15. Oncorhynchus mykiss, under static 8. Felodipine: Acute Toxicity to Bluegill, Lepomis macrochirus, under Static Test Conditions. Toxicon Environmental Sciences, USA. Report No: J312003a. May 14. (Brixham Environmental Laboratory, Report BD410).. H154/82: Assessment of ready biodegradability by measurement of carbon dioxide evolution. Covance, USA. Report No: / Sept 17. (Brixham Environmental Laboratory Report BD371). 10. Felodipine (MK-218): Determination of the Rate of Hydrolysis as a Function of ph at 50C. Toxicon Environmental Sciences, USA. Report No: J307008b.December 13. (Brixham Environmental Laboratory, Report BD4188). 11. Felodipine (MK-218): Determination of Aqueous. Toxicon Environmental Sciences, USA. Report No: J307008a July 14. (Brixham Environmental Laboratory Report BD418) 12. Sangster, J., Log KOW Databank, Montreal, Quebec, Canada, Sangster Research Laboratories, General Properties for Felodipine. AstraZeneca, June (Brixham Environmental Laboratory, Report BD4182). 14. Felodipine: Adsorption and desorption to activated sludge. Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7813 October