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Kisqali

Novartis

Filmdragerad tablett 200 mg
(Ljust grålila, utan skåra, rund, med avfasade kanter (ungefärlig diameter: 11,1 mm), präglad med ”RIC” på den ena sidan och ”NVR” på den andra.)

Antineoplastiska medel, proteinkinashämmare

Aktiv substans:
ATC-kod: L01XE42
Läkemedel från Novartis omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Ribociklib

Miljörisk: Användning av ribociklib har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Ribociklib bryts ned i miljön.
Bioackumulering: Ribociklib 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) = 0.000737 μg/L

Where:

A = 4.915 kg ribociclib succinate (total sold amount API in Sweden year 2018, data from IQVIA).

R = 0 % removal rate.

P = number of inhabitants in Sweden = 9 *106 

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata):

EC10 72 h (growth rate) = 0.71 mg/L (OECD201) (Will Research Project 504754)


Crustacean (Daphnia magna, waterflea):

Acute toxicity

EC50 48 h (immobilisation) > 33.0 mg/L; highest concentration tested due to substance’s water solubility limit (OECD202) (Wil Research Project 504755)

Chronic toxicity

NOEC 21 days (growth of parental daphnids) = 1.4 mg/L; (OECD 211) (Wil Research Project 508584)


Fish:

Acute toxicity (Cyprinus carpio, carp)

LC50 96 h (mortality) = 38.0 mg/L (OECD203) (Wil Research Project 504756)

Chronic toxicity (Pimephales promelas, fathead minnow)

NOEC 33 days (fish larvae length) = 1.0 mg/L (OECD 210) (Wil Research Project 508583)


Other ecotoxicity data:

Bacterial respiration inhibition

EC50 3 h > 1000 mg/L (activated sludge respiration inhibition) (OECD209) (Wil Research Project 504753)


Sediment-dwelling organisms (Chironomus riparius, non-biting midge)

NOEC 28 days (emergence rate and development rate) = 1000.0 mg/kg dry weight (OECD 218) (Charles River Laboratories Den Bosch Project 509180)


PNEC derivation:

PNEC = 71.0 μg/L

PNEC (μg/L) = lowest NOEC or EC10 / 10, where 10 is the assessment factor used if three chronic toxicity studies from three trophic levels are available. The EC10 for algae growth inhibition has been used for this calculation.


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.000737 μg/L / 71.0 μg/L = 0.00001, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of ribociclib has been considered to result in insignificant environmental risk."


Degradation 

Biotic degradation

Ready degradability:

5-14 % degradation in 28 days, not readily biodegradable (OECD301B). (Wil Research Project 504757)

Simulation studies:

DT50 (total system) = 0.31 – 0.35 days (OECD 308). (Wil Research Project 508585)

Extraction of sediment with acetonitrile/water or methanol/water did not release more than 5% of the applied activity. Therefore harsh conditions were required to be able to extract LEE011-BBA from the sediment. The sediment phase was extracted four times with 100 mL 80/20 methanol/1M NaOH. Approximately half of the combined extracts (200 mL) were centrifuged and a subsample of approximately 6 mL was ultra-centrifuged. Prior to HPLC analysis the subsamples were acidified. In the sediment extracts 85% (SW) and 88% (SL) of applied radioactivity was recovered and in the final concentrated samples 83% (SW) and 85% (SL) of applied radioactivity was recovered.

In both test systems negligible organic volatiles were detected (≤ 0.1%). Up to 11% of applied activity was recovered as CO2 in the SL system and maximum 2% of applied activity in the SW system. Non-extractable residues accounted for 34% of applied activity in the SL system and 44% of applied activity in the SW system at the end of the incubation period (100 days).


Justification of chosen degradation phrase:

According to the pass criteria for OECD308 studies, ribociclib can be classified as ‘Ribociclib is degraded in the environment' (DT50 for total system ≤ 32 days)


Bioaccumulation

Partitioning coefficient:

log D at pH 4 < -0.8

log D at pH 7 = 0.6

log D at pH 9 = 2.2 (OECD107) (Wil Research Project 504758)

Justification of chosen bioaccumulation phrase:

Since log Dow < 4 at pH 7, ribociclib has low potential for bioaccumulation.


Excretion (metabolism)

Following oral administration of a single 600 mg dose of [14C] ribociclib to humans, ribociclib was extensively metabolized, with the unchanged drug accounting for 17.3% and 12.1% of the dose in feces and urine, respectively. Metabolite LEQ803 was a significant metabolite in excreta and represented approximately 13.9% and 3.74% of the administered dose in feces and urine, respectively. Numerous other metabolites were detected in both feces and urine in minor amounts (≤2.78% of the administered dose).

Ribociclib is eliminated mainly via the feces, with a small contribution from the renal route. In 6 healthy male subjects, following a single oral dose of [14C] ribociclib, 91.7% of the total administered radioactive dose was recovered within 21 days; feces were the major route of excretion (69.1%), with 22.6% of the dose recovered in the urine. (KISQALI®/™, KRYXANA®/™ (ribociclib) Core Data Sheet)


PBT/vPvB assessment

Ribociclib has low potential for bioaccumulation based on the screening criteria for B and is degraded in the environment based on total system DT50s obtained in a simulation study following OECD308. Ribociclib can therefore not be considered a potential PBT substance.


References

  • ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm

  • Wil Research Project 504754. Fresh water algal growth inhibition test with LEE011-A4 (=LEE011-NXA). Final report: 29. August 2014.

  • Wil Research Project 504755. Acute toxicity study in Daphnia magna with LEE011-A4 (=LEE011-NXA) (static). Final report: 29. August 2014.

  • Wil Research Project 508584. Daphnia magna, reproduction test with LEE011-BBA (semi-static). Final report: 01. September 2015.

  • Wil Research Project 504756. 96-hour acute toxicity study in carp with LEE011-A4 (=LEE011-NXA) (static). Final report: 29. August 2014.

  • Wil Research Project 508583 Fish early-life stage toxicity test with LEE011-BBA (flow-through). Final report: 28. October 2015.

  • Wil Research Project 504753 Activated sludge respiration inhibition test (carbon and ammonium oxidation) with LEE011-A3. Final report: 22. May 2014.

  • Charles River Laboratories Den Bosch Project 509180 Sediment-water Chironomid toxicity test using sediment spiked with LEE011-BBA. Final report: 26. July 2016.

  • Wil Research Project 504757 Determination of ‘ready’ biodegradability: carbon dioxide (CO2) evolution test (modified Sturm test) of LEE011-A4. Final report: 17. April 2014.

  • Wil Research Project 508585 Aerobic degradation of LEE011-BBA in two water/sediment systems. Final report: 29. July 2016.

  • Wil Research Project 504758 Determination of physico-chemical properties of LEE011-BBA. Final report: 05. January 2015.

  • KISQALI®/™, KRYXANA®/™ (ribociclib) Core Data Sheet Version 2.0 & 2.1. 04 July 2019.