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Brilique

AstraZeneca

Filmdragerad tablett 60 mg
(Runda, bikonvexa, rosa tabletter märkta med ”60” ovanför ”T” på den ena sidan och omärkta på den andra.)

Trombocytaggregationshämmande medel, exklusive heparin

Aktiv substans:
ATC-kod: B01AC24
Utbytbarhet: Ej utbytbar
Läkemedel från AstraZeneca omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan (Läs mer om miljöpåverkan)

Ticagrelor

Miljörisk: Användning av ticagrelor har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Ticagrelor bryts ned i miljön.
Bioackumulering: Ticagrelor har låg potential att bioackumuleras.


Läs mer

Detaljerad miljöinformation

PEC/PNEC = 0.13 μg/L /53 μg/L = 0.0025→ PEC/PNEC ≤ 0.1


Environmental Risk Classification

Predicted Environmental Concentration ( PEC)


The PEC is based on the following data:


PEC (µg/L) = (A*109*(100-R))/(365*P*V*D*100)


PEC (µg/L) = 1.5*10-6*A*(100-R)


A (kg/year) = total sold amount API in Sweden year 2017, data from IQVIA (former IMS Health and Quintiles).


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


P = number of inhabitants in Sweden =9*106


V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (Ref.1)


D = factor for dilution of waste water by surface water flow = 10 (EHCA default) (Ref.1)

(Note: The factor 109 converts the quantity used from kg to μg)


A =882.3 kg


R = 0


PEC = 1.5 * 10-6 *882.3*(100-0) = 0.13 µg/L


Metabolism and excretion


The major metabolite of ticagrelor is AR-C124910XX, which is also active as assessed by in vitro binding to the platelet P2Y12 ADP-receptor. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for ticagrelor.


The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabelled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in faeces, 26.5% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the active metabolite is mostly via biliary secretion. The mean t1/2 was approximately 6.9 hours (range 4.5-12.8 hours) for ticagrelor and 8.6 hours (range 6.5-12.8 hours) for the active metabolite.


Ecotoxicity Data

Endpoint

Species

Common Name

Method

Time

Result

Reference

ErC50 – Growth Rate

Pseudokirchneriella subcapitata (formerly known as S. capricornutum)

Green Algae

OECD 201

72 h

>5.2 mg/L

Note 1, 2

4

NOEC – Based on Growth Rate

0.82 mg/L

Note 1

EbC50 – Biomass

>5.2 mg/L

Note 1, 2

NOEC - Based on Biomass

0.82 mg/L

Note 1

EC50 - Based on Immobilisation

Daphnia magna

Giant Water Flea

OECD 202

48 h

1.4 mg/L

Note 1

5

NOEC - Based on Immobilisation

0.68 mg/L

Note 1

NOEC – Based on Overall Endpoints

Daphnia magna

Giant Water Flea

OECD 211

21d

0.53 mg/L

Note 3

6

LC50 – Based on Mortality & Symptoms of Toxicity

Oncorhynchus mykiss

Rainbow Trout

OECD 203

96h

>2.7 mg/L

Note 2

7

NOEC – Based on Overall Endpoints

Note 4

Pimephales promelas

Fathead Minnow

OECD 210

32 d

1.8 mg/L

Note 5

8

EC50 – Based on Respiration Inhibition

-

-

OECD 209

3h

>100 mg/L

Note 6

9

NOEC – Based on Respiratory Inhibition

>100 mg/L

Note 6

NOEC – Based on Emergence

Chironomous riparius

Midge

OECD 218

28 d

30 mg /kg weight

10

Note 1: Results are expressed as mean measured concentrations.

Note 2: This was the limit of solubility in this study (mean measured).

Note 3: Results are expressed as time weighted mean measured concentrations. The endpoints measured were survival, number of offspring and length.

Note 4: The endpoints measured were length, dry weight, survival and hatchability.

Note 5: Concentrations were confirmed by analysis, and results expressed as nominal.

Note 6: Results expressed as nominal concentrations.


Predicted No Effect Concentration (PNEC)

Long-term tests have been undertaken for species from three trophic levels. Therefore, the PNEC is based on the chronic toxicity to the giant water flea (Daphnia magna), 0.53 mg/L, and an assessment factor of 10 is applied, in accordance with ECHA guidance.


Environmental Risk Classification (PEC/PNEC ratio)


PNEC = 530/10 µg/L = 53 µg/L.

PEC/PNEC = 0.13 μg/L /53 μg/L = 0.0025

PEC/PNEC = ≤ 0.1


The PEC/PNEC ratio decides the wording of the aquatic environmental risk phrase, and the risk phrase for PEC/PNEC = ≤ 0.1 reads as follows; “Use of ticagrelor has been considered to result in insignificant environmental risk” has been assigned.


In Swedish: “Användning av Tikagrelor har bedömts medföra försumbar risk för miljöpåverkan” under the heading Miljörisk.


Environmental Fate Data

Endpoint

Method

Test Substance Concentration

Time

Result

Reference

Dissipation Half Life in High Organic Matter (HOM) Sediment

OECD 308

-

-

Total system DT50 = 11.3 days Overall (2.2 days in the overlying water, 30.9 days in the sediment)

11

Dissipation Half Life in Low Organic Matter (LOM) Sediment

Total sytem DT50 = 19.6 days Overall (2.87 days in the overlying water, 22.8 days in the sediment)

Percentage Aerobic Mineralisation (HOM, total system)

0.1 mg/L

99 d

14%

Percentage Aerobic Mineralisation (LOM, total system)

29%

Hydrolysis Half-Life

OECD 111

-

-

T1/2 at pH 7 and pH 9 ≥ 1 yr at 25oC

12

Percentage Biodegradation

OECD 301F

100 mg/L

28 d

<5%

13


Ticagrelor was found to be hydrolytically stable (estimated half-life ≥ 1 yr at 25oC) at pH 7 and 9. Under environmental conditions, the hydrolysis of ticagrelor is not expected to be a significant environmental fate process.


In OECD301F, ticagrelor was not readily biodegradable with observed <5% degradation after 28 days.


Overall, evidence from the OECD 308 study suggests that ticagrelor will not be persistent in the aquatic environment. Aerobic transformation in aquatic sediment systems showed that in both the high organic matter (HOM) and low organic matter (LOM) test vessels rapid dissipation of [14C]ticagrelor from the overlying water to the sediment was observed. By Day 14, 61% and 62% of the applied radioactivity were associated with the sediment phase, dissipation half lives of ticagrelor from the water phase were 2.2 and 2.9 days in the HOM and LOM sediments, respectively.


A maximum concentration of [14C]ticagrelor was observed in the high and low sediment extracts on Day 14 (33 and 48% of the applied radioactivity, respectively), which died away to <10% of the applied radioactivity by Day 99. Despite the investigation of a number of different extraction solvents (methanol, acetone, tetrahydrofuran (THF), dimethylsulfoxide (DMSO) and SolueneTM), at the end of the study >50% of the applied radioactivity in the HOM and >30% in LOM vessels was irreversibly bound to the sediment. The total system half life of ticagrelor, calculated using the percentage of applied radioactivity measured as [14C]ticagrelor by radio-TLC, was 11.3 days in the HOM and 19.6 days in LOM sediments.


Increasing mineralisation was observed throughout the study, with 14CO2 accounting for 14% and 29% of the applied radioactivity in the HOM and LOM test systems, respectively. In addition, volatile organic compounds accounted for up to 13% of the applied radioactivity in the low organic matter vessels.


Therefore, the phrase “Ticagrelor is degraded in the environment” has been assigned.


In Swedish: “Tikagrelor bryts ned i miljön” under the heading ‘Nedbrytning’.


Bioaccumulation Data

Endpoint

Species

Common Name

Method

Concentration

Time

Result

Reference

BCF – Based on Whole Body

Oncorhynchus mykiss

Rainbow Trout

OECD 305

0.001 mg/L

28 d

BCF = 6.36

14

Bioconcentration of ticagrelor in Oncorhynchus mykiss was assessed, and the whole body BCF at 1.0 µg/L of ticagrelor was 6.36 after 28 days uptake. Since the BCF is < 500, ticagrelor has a low potential for bioaccumulation, no further PBT evaluation of ticagrelor is required. Therefore, the phrase ‘Ticagrelor has low potential for bioaccumulation’ has been assigned.


In Swedish: ”Tikagrelor har låg potential att bioackumuleras,” under the heading ”Bioackumulering”.


Physical Chemistry Data

Endpoint

Method

Test Conditions

Result

Reference

Partition Coefficient

Octanol/Water

OECD 107

100 mg/L

Log Dow >4.02

@ pH 5,7,9 & 11

15

Solubility Water

OECD 105

30°C for 24 h, then 20°C for

24 h

5.3 mg/L @ pH 5,

3.5 mg/L @ pH 7,

11 mg/L @ pH 9

16

Adsorption Coefficient

OPPTS 835.1110

0.1 mg/L in Activated Sludge

Kd = 1571

17

Adsorption Coefficient

Koc = 4246

Desorption Coefficient

Kd = 2196

Adsorption Coefficient

OECD 308

Aerobic, High Organic Matter

Kd = 40.6

18

Adsorption Coefficient

Aerobic, Low Organic Matter

Kd = 4.78

References

  1. [ECHA] European Chemicals Agency. 2008. Guidance on Information Requirements and Chemical Safety Assessment.

    http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

  2. An Absorption-Distribution-Metabolism-Excretion (ADME) Study of Oral [14C] AZD6140 in Healthy Male Subjects. Report no. D5130C00013. AstraZeneca. May 2005.

  3. AZD6140: Investigation into the Identity of Radiolabelled Metabolite Present in Urine, Plasma and Faeces Collected from Human Volunteers Following a Single Oral Administration of [14C]-AZD6140. Sponsor Document No. 41312-0452. Study No. 208066. AstraZeneca. December 2006.

  4. AZD6140: Toxicity to the green alga Selenastrum capricornutum. Brixham Environmental Laboratory, UK. Report No BL8237. December 2006.

  5. AZD1640: Acute Toxicity to Daphnia Magna. Brixham Environmental Laboratory, UK. Report No BLS3310. October 2005.

  6. AZD1640: Chronic Toxicity to Daphnia Magna. Brixham Environmental Laboratory, UK. Report No BL8604. September 2008.

  7. AZD1640: Acute Toxicity to rainbow trout (Oncorhynchus mykiss).
    Brixham Environmental Laboratory, UK. Report No BLS3359. October 2005.

  8. AZD1640: Determination of effects on the early-life stage of the fathead minnow (Pimephales promelas). Brixham Environmental Laboratory, UK. Report No BL8362. July 2007

  9. AZD1640: Effect on the respiration rate of activated sludge.
    Brixham Environmental Laboratory, UK. Report No BL8213. December 2005.

  10. [14C]AZD1640: Effects in sediment on emergence of the midge, Chironomus riparius. Brixham Environmental Laboratory, UK. Report No BL8659. February 2009.

  11. AZD1640: Aerobic transformation in aquatic sediment. Brixham Environmental Laboratory, UK. Report No BL8610. December 2008.

  12. AZD1640: Hydrolysis as a function of pH – preliminary study results summary. Brixham Environmental Laboratory, UK. Report No BLS3343. July 2006.

  13. AZD1640: Determination of 28 day ready biodegradability.
    Brixham Environmental Laboratory, UK. Report No BL8262. March 2006.

  14. [14C]AZD1640: Determination of the accumulation of [14C]AZD1640 in rainbow trout (Oncorhynchus mykiss). Brixham Environmental Laboratory, UK. Report No BL8680. September 2008.

  15. ADZ1640: Determintation of n-octanol-water partition coefficient.
    Brixham Environmental Laboratory, UK. Report No BL8280. January 2007.

  16. AZD1640: Water solubility. Brixham Environmental Laboratory, UK. Report No BL8220. December 2005.

  17. AZD1640: Adsorption and desorption of sewage sludge. Brixham Environmental Laboratory, UK. Report No BL8344. December 2006.

  18. AZD1640: Aerobic transformation in aquatic sediment.
    Brixham Environmental Laboratory, UK. Report No BL8610. December 2008.