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Lixiana

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ATC-kod: B01AF03
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Vad är viktig säkerhetsinformation?
2019-05-20: Viktig säkerhetsinformation
Apixaban (Eliquis), dabigatranetexilat (Pradaxa), edoxaban (Lixiana/Roteas) och rivaroxaban (Xarelto) rekommenderas inte till patienter med antifosfolipidsyndrom på grund av en möjlig förhöjd risk för återkommande trombotiska händelser.
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Miljöpåverkan (Läs mer om miljöpåverkan)

edoxaban

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


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Detaljerad miljöinformation

Detailed background information


Environmental Risk Classification


Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula:


PEC (μg/L) = (A*109 *(100-R))/(365*P*V*D*100) = 1.5*10-6 *A(100-R)


PEC = 0.1 μg/L


Where:

A = <1000 kg (maximum estimated 5 year sales in Sweden, data blinded for confidentiality

R = 0 % removal rate (worst case assumption)

P = number of inhabitants in Sweden = 9 *106 

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

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


Predicted No Effect Concentration (PNEC)


Ecotoxicological studies

Algae (Pseudokirchneriella subcapitatum) (OECD 201) (Reference II): 

EC50 (72 hours) (growth rate) > 4.9 mg/L

NOEC (72 hours) (growth rate) = 4.9 mg/L


Crustacean, water flea (Daphnia magna) (OECD 211) (Ref. III): 

Chronic toxicity

NOEC (21 day) (Endpoint not reported) = 5570 ug/L 


Fish, fathead minnow (Pimephales promelas) (OECD 210) (Ref. III): 

Chronic toxicity

NOEC (28 day) (Endpoint not reported) = 2320 ug/L


PNEC = 232 μg/L (2320 ug/L/ 10 based on the most sensitive NOEC for the fathead minnow and an assessment factor (AF) of 10)


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.1/232 = 0.00043, i.e. PEC/PNEC ≤ .1 which justifies the phrase "Use of edoxaban has been considered to result in insignificant environmental risk.


Biotic degradation

Sediment Transformation (OECD 308) (Ref. IV)


The degradation of [14C]edoxaban (DU-176b) in two natural water-sediment systems under aerobic conditions was studied at 20 ± 2°C in the dark. [14C]edoxaban, in water, was applied at a rate of 0.6 mg/L (equivalent to 1000 x the Predicted Environmental Concentration in the surface water). This study was conducted in accordance with OECD guideline 308.


The test system consisted of individual glass vessels (diameter 4.5 cm) containing sediment to a depth of 3 cm and associated water to a depth of 9 cm above the sediment. Samples were removed for analysis immediately after application of [14C]edoxaban and at 4, 7, 14, 45 and 101 DAT (days after treatment).


The surface water was separated from the sediment and analysed by high performance liquid chromatography (HPLC). Sediment samples were extracted with acetonitrile : water (1:1, v/v) followed by acetonitrile : water (1:1, v/v) with 1 % ammonia solution. The combined extracts were concentrated prior to analysis by HPLC. Confirmation of the presence of [14C]edoxaban was by thin layer chromatography (TLC).


Findings

The recovery of AR (applied radioactivity) ranged from 97% to 101%. The percent of the applied radioactivity present in the surface water, decreased from 97% and 96% at 0 DAT, to 5 and 15% at 101 DAT for Calwich Abbey and Swiss Lake water-sediment systems, respectively. Levels of radioactivity extracted from the sediment increased from < 1% at 0 DAT, to reach maximum values of 61% AR at 45 DAT and 49% AR at 14 DAT for Calwich Abbey and Swiss Lake water-sediment systems, respectively. Levels of radioactivity extracted for both water-sediment system decreased slightly after reaching the maximum to 57% and 43% AR at 101 DAT for Calwich Abbey and Swiss Lake water-sediment systems, respectively. Non-extracted radioactivity in the sediment increased from < 1% at 0 DAT to 37% and 40% at 101 DAT for Calwich Abbey and Swiss Lake water-sediment systems, respectively. < 1% AR at 101 DAT was recovered in the sodium hydroxide traps for both water-sediment systems.


The percent of applied radioactivity present as [14C]edoxaban in the surface water decreased from 95% and 94% at 0 DAT to < 1% at 101 DAT for the Calwich Abbey and Swiss Lake water-sediment systems, respectively. One degradate, which was identified as D21-3231-0101 by HPLC co-chromatography with the reference standard was detected up to 33% (7 DAT) and 23% (4 DAT) AR, for Calwich Abbey and Swiss Lake water-sediment systems, respectively. Thereafter, D21-3231-0101 declined to ≤ 10% AR by the end of the incubation period.

The percent of applied radioactivity in the sediment, present as [14C]edoxaban, increased to maximum values of 35% (14 DAT) and 33% (14 DAT) for Calwich Abbey and Swiss Lake water-sediment systems, respectively. Levels of radioactivity present as [14C]edoxaban for both water-sediment systems decreased after reaching the maximum to 14% and 12% AR at 101 DAT. The same degradate, D21-3231-0101, was also observed in the sediment at up to 34% and 21% AR at 101 DAT for Calwich Abbey and Swiss Lake water-sediment systems, respectively.

[14C]edoxaban decreased in the total water-sediment system from 95 and 94% at 0 DAT to 14% and 12% at 101 DAT for the Calwich Abbey and Swiss Lake water-sediment systems, respectively. One degradate, D21-3231-0101 was detected up to 46% (7 DAT) and 37% (45 DAT) AR, for Calwich Abbey and Swiss Lake water-sediment systems, respectively. Thereafter, D21-3232-01010 declined to 38% and 31% AR by the end of the incubation period for Calwich Abbey and Swiss Lake water-sediment systems, respectively.


Edoxaban dissipated quickly from the surface water into the sediment with DT50 values of 2 to 3 days (Single First Order kinetics, SFO). Edoxaban degraded quickly in the total water-sediment system to other degradates and a formation of bound residue.

The DT50 of edoxaban in natural water sediment systems, under aerobic conditions, in the dark at 20 ± 2°C was in the range 10 to 15 days (SFO Kinetics).

The proposed degradation pathway for [14C] edoxaban  in water-sediment is presented below:

The proposed degradation pathway for edoxaban in water-sediment

Justification of chosen biotic degradation phrase:

Since half-life < 32 days for total system and >15% remaining as parent compound, the substance is slowly degraded in the environment.


Bioaccumulation

Partitioning coefficient (OECD 107) (Ref. II):

Log Kow = 1.7 at pH 8


Justification of chosen bioaccumulation phrase:

Since log Kow < 4 the substance has low potential for bioaccumulation


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. Personal communication Daiichi Sankyo, 2016.

  3. European Medicines Agency Assessment Report for Lixiana, 23 April 2015.

  4. Covance Laboratories, 2010. “Environmental Risk Assessment Program for DU-176b: Degradation in Water Sediment Systems under Aerobic Conditions,” Study Number 8215952, Covance, North Yorkshire, United Kingdom, August 2010.