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Bayer

Filmdragerad tablett 40 mg
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Regorafenib

Miljörisk: Särskilt miljöfarliga egenskaper
PBT/vPvB-klass: I enlighet med EU:s fastställda kriterier ska substansen betraktas som en PBT/vPvB-substans


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Detaljerad miljöinformation

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)

Where:

A = 0.3864 kg (total sold amount API in Sweden year 2015, data from IMS).
R = 0 % removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 9 *106 

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

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

PEC = 0.000058 μg/L


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus):

NOEC/72 h (growth inhibition, growth rate) 0.13 µg/L (guideline OECD 201) (1)

Crustacean (waterflea Daphnia magna):

Chronic toxicity

NOEC /21d (mortality) = 10.5 µg/L (guideline OECD 211) (2)

Fish:

Chronic toxicity (fathead minnow Pimephales promelas)

NOEC 28d (post hatch) (larval survival) 0.007 µg/L (guideline OECD 210) (3)

Microorganisms (activated sludge respiration inhibition)

40000 µg/L (guideline OECD 209) (4)

PNEC = 0.0007 μg/L (Lowest NOEC fish 0,007 µg/L; AF 10)



Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC ratio: 0.000058 : 0.0007 = 0.08, i.e. PEC/PNEC ≤ 0,1


Degradation

Biotic degradation

Ready degradability: Not readily biodegradable

The aerobic biodegradability of regorafenib in water was investigated in accordance with the guideline OECD 301F (5) . No biodegradation could be observed according to the CO2 production in three replicates.


A study on transformation in aquatic/sediment systems was performed to investigate distribution and degradation behavior in a water-sediment system (6).


The study was conducted using two sediments with differed in grain size (silt/clay and sandy sediment) and organic carbon content. Regorafenib was incubated in glass vessels containing sediment and overlaying water over 100 days. Samples of water and sediments were taken on a regular basis. The mass balance showed a concentration of regorafenib in sediments, only marginal amounts remained in the water phase, and insignificant degradation was observed. The extraction of the sediments showed no relevant non-extractable residues and no transformation products >10% of the originally applied compound (as total radioactivity). The dissipation half-life of regorafenib in the water phase was less than 1 day.


The results of the degradation studies justify the phrase: Regorafenib is potentially persistent in the environment.


Abiotic degradation

Hydrolysis:

The hydrolytical stability could not be tested due to the low water solubility (<0.056 mg/L) of regorafenib.


Bioaccumulation

In a bioaccumulation study, juvenile fish (Lepomis macrochirus) were exposed to two concentrations of (C-14 labelled) regorafenib over a period of 28 days for uptake and a depuration phase of 14 days. The concentrations were 0.16 µg/L and 1.6 µg/L (nominal). The bioconcentration factor at steady state (BCFss) was determined with 2900 and 4400 for the low and high concentration, respectively (7).


Justification of chosen bioaccumulation phrase:

The BCF of 2900/4400 justifies the phrase:
Regorafenib has high potential for bioaccumulation


Excretion (metabolism)

Regorafenib is introduced unmetabolized as parent compound at about 50% of the applied dose, while the rest is excreted as different metabolites, which have no higher pharmacological activity than the parent compound.


PBT/vPvB assessment

The calculated PEC/PNEC value is <0.1. Hence, risk assessment procedures would indicate that regorafenib has insignificant long-term risk to the environment. However, the half-life in freshwater sediment is >120d, the BCF is >2000, and the chronic toxicity is <0.01 mg/L (NOEC). Regorafenib should therefore be regarded as PBT substance, according to the ECHA guidance criteria, and as such the current PEC/PNEC ratio may underestimate the potential for long-term risks to aquatic organisms. 


References


  1. Growth inhibition test with regorafenib (BAY73-4506) on green algae Desmodesmus subspicatus. Report no. PH-39194, study no. T102316-3, Bayer Pharma AG, Berlin.

  2. Reproduction study of regorafenib (BAY73-4506) in Daphnia magna. Report no. PH-37250, study no. T100349-7, Bayer Pharma AG, Berlin.

  3. Early life-stage test fish with regorafenib (BAY73-4506). Report no. PH-38249, study no.T100932-5. Bayer Pharma AG, Berlin

  4. Respiration inhibition test with regorafenib (BAY73-4506) on activated sludge microorganisms. Report no. A51602, study no. TOXT8081559, Bayer Schering Pharma AG, Berlin.

  5. Study on the biodegradability of regorafenib (BAY73-4506) in the manometric respiration test. Report no. A51400, study no.TOXT3082139. Bayer Schering Pharma AG, Berlin

  6. Aquatic–sediment study (aerobic) with regorafenib (BAY73-4506 (C-14)). Report no. A53445, study no. TOXT1082461, Bayer Healthcare AG. Berlin.

  7. Bioconcentration flow-through test with regorafenib (BAY73-4506 (C-14)). Report no. A57715, study no. TOXT9082937. Bayer Healthcare AG, Berlin



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