Läs upp

Cookies

Den här webbplatsen använder så kallade cookies. Cookies är små textfiler som lagras i din dator och sparar information om olika val som du gjort på en webbsida – t ex språk, version och statistik – för att du inte ska behöva göra dessa val en gång till. Tekniken är etablerad sedan många år tillbaka och används idag på väldigt många webbplatser på Internet.

Du kan när som helst ändra cookieinställningarna för denna webbplats.

FASS logotyp
Receptbelagd

Peka på symbolerna och beteckningarna till vänster för en förklaring.

Kontakt och länkar

Sök apotek med läkemedlet i lager

Sök lagerstatus

Inegy®

MiljöinformationReceptstatusFörmånsstatus
MSD

Tablett 10 mg/40 mg
(Vita till benvita, kapselformade tabletter märkta med "313" på en sida.)

Medel som påverkar serumlipidnivåerna, kombinationer

Aktiva substanser:
ATC-kod: C10BA02
Företaget omfattas av Läkemedelsförsäkringen
  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Ezetimib

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


Läs mer

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)


PEC = 0.01 μg/L


Where:

A = 92 kg (total sold amount API in Sweden year 2015, data from IMS Health).

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

Green Algae (Selenastrum capricornutum) (OECD 201) (Ref. II)

EC50 72 h (density) = >0.3 mg/L

EC50 72 h (growth rate) = >0.3 mg/L

NOEC 72 h (growth rate) = 0.3 mg/L

Non-toxic up to highest concentration tested


Crustacean, water flea (Daphnia magna):

Acute toxicity

LC50 48 h (mortality) > 4 mg/L (OECD 202) (Ref. III)

Non-toxic up to highest concentration tested


Chronic toxicity

NOEC 21 day (mortality; reproduction) = 0.3 mg/L (OECD 211) (Ref. IV)

Non-toxic up to highest concentration tested


Fish, fathead minnow (Pimephales promelas):

Acute toxicity

LC50 96 h (mortality) > 0.13 mg/L (OECD 203) (Ref.V)

Non-toxic up to highest concentration tested


Chronic toxicity

NOEC 33 days (growth, total length) = 0.05 mg/L (OECD 210) (Ref. VI)


PNEC = 0.005 mg/L = 5 µg/L (0.05 mg/L / 10) based on the most sensitive chronic NOEC for the fathead minnow and an assessment factor (AF) of 10)


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = .01/5 = 0.002, i.e. PEC/PNEC ≤ .1 which justifies the phrase “Use of ezetimibe has been considered to result in insignificant environmental risk.”


Degradation

Biotic degradation


Biodegradation Simulation Screening (OECD 301B) (Ref. VII)

Test results 7% biodegradation to CO2 by Day 28.


Biodegradation in Sludge (OECD 314) (Ref. VIII)

Test results 4% biodegradation to CO2 by Day 28

83% biodegradation to metabolites


Sediment Transformation (OECD 308) (Ref. IX)

DT50 (total system) = 11 - 23 days


Two sediments and their associated waters were utilized in the study. Test systems

were dosed with 14C-labeled Ezetimibe at a nominal concentration of 0.55 mg/L in the water layer. Test systems were incubated in the dark at approximately 20 ºC for up to 103 days, and maintained under aerobic conditions by gently bubbling air into the water layers. Effluent gasses were passed through charcoal sorbent tubes to trap organic volatiles, followed by alkali solutions to trap evolved carbon dioxide. Duplicate test chambers of each sediment-water type were sacrificed on days 0, 5, 14, 28, 56 and 103. Water layers, sediment extracts and sediment solids were analyzed separately for total radioactivity by liquid scintillation counting (LSC). In addition, water layer samples were collected on days 1 and 2.


Ezetimibe demonstrated some transformation in aerobic Brandywine Creek and Choptank River test systems. The disappearance times of 50 percent of parent (DT50) from the water layers were 4.3 and 4.1 days, respectively. The DT90 values were 19.0 and 17.6 days, respectively. The amounts of Ezetimibe in the sediment layers increased to a maximum of 43% on day 14 in Brandywine Creek samples and 20% on day 28 in Choptank River samples. The amounts of Ezetimibe in the total test systems (i.e. water layers plus sediment extracts) at the end of the test were 19% and 8%, respectively. The DT50 values for parent in the total test systems were 23.1 and 11.0 days, and the DT90 values were >103 and 47.0 days, respectively. Through all test intervals, the maximum percentages of dosed radioactivity recovered as transformation products were 58% and 73%, respectively. The fractions of radiolabeled residues that could not be extracted from the sediment layers at the end of the test were 27% and 32%. The maximum amounts of mineralization or ultimate biodegradation observed were <6% for both test systems. Total mean recoveries expressed as percentages of dosed radioactivity ranged from 91% to 103% throughout the study.


Abiotic degradation


Hydrolysis (OECD 111) (Ref. X)

Half-life of 4.5 days at pH 7


Justification of chosen degradation phrase:

Ezetimibe is inherently degradable in biological systems and via hydrolysis. The DT50 for the total system is < 32 days with > 15% parent compound remaining at the end of the study therefore the phrase, “Ezetimibe is slowly degraded in the environment” is thus chosen.


Bioaccumulation

Bioconcentration Factor (BCF) (OECD 305). (Ref.XI)

Measured BCF values were 69 (low concentration) and 137 (high concentration) in a 97 day study with bluegill sunfish


Justification of chosen bioaccumulation phrase:

Since BCF < 500, 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. Wildlife International, 2009. "Ezetimibe: A 96-hr toxicity test with the freshwater alga (Pseudokirchneriella subcapitata)", OECD 201, Project No. 105A-174, Wildlife International, 2 February 2009.


  3. Toxikon Corp., 2001. "JV-AT-A: Acute Toxicity to the water flea, Daphnia magna, under static test conditions" OECD 202 (Part 1), Project ID 01J0006c. Toxicon Corp., 17 October, 2001.


  4. Wildlife International, 2009. "Ezetimibe: A flow-through life-cycle toxicity test with the cladoceran (Daphnia magna)", OECD 211, Project No. 105A-175, Wildlife International, 26 February 2009.


  5. Toxikon Corp., 2001. "JV-AT-A: Acute Toxicity to fathead minnow, Pimephales promelas, under static test conditions" OECD 203, Project ID 01J0006e. Toxicon Corp., 17 October, 2001.


  6. Wildlife International, Ltd., Ezetimibe: an early life-stage toxicity test with the fathead minnow (pimephales promelas), WIL Project Number 105A-176, Easton MD, 17 March 2009.


  7. Toxicon, 2002. "JV-AT-A: Ready Biodegradability: CO2 Evolution (Modified Sturm Test)", Toxicon Report 01J0001, Jupiter Fl, 10 April 2002.


  8. Wildlife International, 2009. "Ezetimibe dieaway in activated sludge", WIL Project Number 105E-129, Easton MD, 2 Nov 2009.Wildlife International, 2009.


  9. Wildlife International, 2010. "EZETIMIBE: AEROBIC TRANSFORMATION IN AQUATIC SEDIMENT SYSTEMS", WIL Project Number 105E-152, Easton MD, 1 October 2010.


  10. "Ezetimibe: An evaluation of hydrolysis as a function of pH" OECD 111, Project number 105C-121. Wildlife International, 4 May 2009.


  11. Wildlife International, 2011. "Ezetimibe: A Bioconcentration Test with the Bluegill (Lepomis macrochirus)," Project No. 105A-197, WIL, Easton, MD, USA, 16 March 2011.

Simvastatin

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


Läs mer

Detaljerad miljöinformation

Simvastatin (as Simvastatin Hydroxy Acid)


Environmental risk: Use of simvastatin has been considered to result in low environmental risk.

Degradation: Simvastatin is degraded in the environment

Bioaccumulation: Simvastatin has low potential for bioaccumulation


Detailed background information


Environmental Risk Classification


Predicted Environmental Concentration (PEC)

PEC is calculated according to the following formula and includes an additional parameter for excretion to consider the conversion of simvastatin (a pro-drug) to its active metabolite simvastatin hydroxyl acid


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


PEC = 0.1 μg/L


Where:

A = 5289 kg (total sold amount API in Sweden year 2013, data from IMS Health).

E = 0.125 (fraction of active metabolites excreted based on pharmacokinetic data)

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)


Excretion

Simvastatin is an inactive prodrug with several of its metabolites, most notably simvastatin hydroxy acid, being active and capable of competitively inhibiting HMG-CoA reductase, the enzyme responsible for cholesterol synthesis [II]. The absorption, distribution, metabolism, and excretion (ADME) of simvastatin has been studied in humans using radiolabelled material and with concomitant metabolite identification [II, III]. The following figure presents the structures of the metabolites of simvastatin identified in the studies:


The figure presents the structures of the metabolites of simvastatin identified in the studies


Of the metabolites identified, simvastatin hydroxy acid is the most active in inhibiting HMG-CoA reductase based on enzyme assays. Therefore, simvastatin hydroxy acid is considered the active moiety in this assessment. Other metabolites vary in activity, with metabolite V considered 90 % as active of simvastatin hydroxy acid and metabolite II having no activity at all.


Based on total radioactivity eliminated, 13 % of the radioactivity was collected in the urine and 58 % in the feces [II]. All of the metabolites underwent extensive biodegradation in the body such that only a small percentage of these known metabolites is excreted. Renal excretion of simvastatin or any enzymatically active metabolites were below the detection limits in urine [IV]. Additionally, neither simvastatin nor simvastatin hydroxy acid was detected in the bile, indicating that none is excreted in the feces [III]. Other metabolites of significantly less activity were found in the bile with the maximum being metabolite VI with an activity of 40 % of simvastatin hydroxy acid and percent radioactivity of 20 % total metabolites. Five percent (5 %) of Metabolite V was found in the bile (of which a portion would be eliminated in the feces).


Because no simvastatin hydroxy acid is excreted but some less active metabolites are, estimates of excretion were determined by multiplying the percent simvastatin hydroxy acid activity by the percent in bile or urine and summing the total metabolites excreted. This summed value, 12.5 %, was conservatively assumed to have the same environmental profile as simvastatin hydroxy acid (SVA).


Metabolite

Activity (% of SVA activity)

% in Urine

% in Bile (assumed to be % in Feces)

% Excreted as SVA activity

I

50 %

Not detected

Not detected; I rearranges to II

0 %

II

0 % (non-active)

Not detected

10 %

0 %

III

20 %

Not detected

Not detected

0 %

IV

Further degraded to V and VI

Not detected

Not detected

0 %

V

90 %

Not detected

5 %

4.5 %

VI

40 %

Not detected

20 %

8 %

SVA

100 %

Not detected

Not detected

0 %


This assessment is based on the active metabolite of simvastatin, simvastatin hydroxy acid.


Predicted No Effect Concentration (PNEC)


Ecotoxicological studies for Simvastatin Hydroxy Acid

Green algae (Pseudokirchneriella subcapitata) (OECD 201) (Ref. V):

EC50 72 h (growth rate) = 120 mg/L

EC50 72 h (yield) = 27.4 mg/L

NOEC 72 h (yield) = 2.4 mg/L


Crustacean, water flea (Daphnia magna) (OECD 202) (Ref. VI):

Acute toxicity

EC50 48 h (immobility) = 88 mg/L


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

Chronic toxicity

NOEC 21-day (reproduction) = 0.002 mg/L


Fish, rainbow trout (Salmo gairdneri) (OECD 203) (Ref. VIII):

Acute toxicity

LC50 96 h (mortality) = 220 mg/L


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

Chronic toxicity

NOEC 31-day (survival) = 0.008 mg/L


PNEC = 0.2 μg/L (2 µg/L / 10 based on the most sensitive chronic NOEC for the Daphnid and an assessment factor (AF) of 10).


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.1/0.2 = 0.5, i.e. 0.1 < PEC/PNEC ≤ 1 which justifies the phrase "Use of simvastatin has been considered to result in low environmental risk."


Degradation of Simvastatin Hydroxy Acid

Ready degradability

27 % degradation (measured as oxygen depletion) in 28 days (OECD 301D) (X).


Inherent degradability

58 % degradation (measured as DOC) in 28 days (OECD 302B). (XI)


100 % degradation (loss of parent in activated sludge) in 28 days (OECD 314D). (XII)

Very little (4 %) conversion to CO2. The amount of simvastatin ammonium salt declined, in the biotic sludge, from 84.5 % AR at 30 minutes to 0.4 % AR at 21 days and was not detected at 28 days. An unidentified component D increased to 17.0% AR after 28 days. The remaining unknown components were each <8.7 %.


Simulation Studies (OECD 308) (XIII)

DT50 in water: 5-5.8 days;

DT50 in sediment: 19.2-25 days;

DT50 in total system: 5.6–7.8 days


Material balances at Day 100 indicate very little parent molecule present (0% in aqueous phase, max of 1.2% in sediment phase). Sixteen degradates were identified quantitatively, none > 10%. Sediments were extracted with ethanol and soxhlet extractions.

Day 100 Results

System 1 (%)

System 2 (%)

Water Phase

33.6-35.8

31.0-30.4

Sediment Phase:

Ethanol Extract

18.1-20

13.3-16.1

Soxhlet Extract

1.2-1.6

2.5-3.1

Total Extractable

19.4-21.5

15.8-19.2

Non-Extractable

21.1-22

31.9-35.1

Total in Sediment

40.5-43.5

50.8-51.1

Volatile Organics

0.1-0.3

0.2-0.2

CO2

14.1-16.2

13.6-14.9

Total Recovery

91.4-92.8

95.9-96.3


Abiotic Degradation:

Hydrolysis half-life > 1 year (EEC Test C10) (XIV)


Justification of chosen degradation phrase:

Because the OECD 308 study demonstrated a DT50 ≤ 32d for the total system, the summary phrase “Simvastatin is degraded in the environment” was selected.


Bioaccumulation of Simvastatin Hydroxy Acid

Partitioning coefficient (Ref. XV):

Log Kow = 2 (OECD 107)


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://echa.europa.eu/guidance-documents/guidance-on-information-requirements-and-chemical-safety-assessment

  2. Mauro VF. Clinical pharmacokinetics and practical applications of simvastatin. Clin Pharmacokinet 1993;24(3):195-202.

  3. Vickers S, Duncan CA, Vyas KP, Kari PH, Arison B, Prakash SR, et al. In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase. Drug Metab Dispos 1990;18(4):476-83.

  4. Duggan D. and S. Vickers. Physiological disposition of HMG-CoA-Reductase Inhibitors. Drug Metabolism Reviews 1990; 22(4): 333-362.

  5. Huntingdon Life Sciences, Simvastatin ammonium salt: algal growth inhibition assay (HLS Study Number: PPM0005), 2011.

  6. Huntingdon Research Centre, Ltd., The acute toxicity of L654,969 to Daphnia Magna (MSD 169 (b) /89545), 1990.

  7. Huntingdon Life Sciences, Simvastatin ammonium salt: Daphnia Magna reproduction toxicity test (HLS Study Number: PPM0006), 2011.

  8. Huntingdon Research Centre Ltd, The acute toxicity of L654,969 to rainbow trout (Salmo gairdneri) (MSD 169 (c) / 89546), 1990.

  9. Huntingdon Life Sciences, Simvastatin ammonium salt: fish early life stage toxicity test for fathead minnow (HLS Study Number: PPM0007), 2011.

  10. Huntingdon Research Centre, 1990. "Assessment of ready biodegradability of L654,969", Huntingdon Research Centre report MSD169(a)/89585, Huntingdon, Cambridgeshire, England. 21 February 1990.

  11. Huntingdon Research Centre, 1997. "Simvastatin Ammonium Salt Inherent Biodegradability (modified Zahn-Wellens/EMPA Test", Huntingdon Research Centre report MSD 350(b)/970992, Huntingdon, Cambridgeshire, England. 12 May 1997.

  12. Huntingdon Life Sciences, Simvastatin ammonium salt: determination of the biodegradability of a test substance in activated sludge based on OECD Method 314B (HLS Study Number: PPM0003), 2011.

  13. Huntingdon Life Sciences, 2011. "Simvastatin Ammonium Salt: Aerobic Transformation in Aquatic Sediment Systems," Study No. PPM0008, HLS, UK, 19 Dec 2011

  14. Huntingdon Research Centre Ltd., The determination of the hydrolysis of simvastatin ammonium salt (MSD 179/891430), 1990.

  15. Huntingdon Life Sciences, Simvastatin ammonium salt: physicochemical properties (HLS Study Number: PPM0002), 2010.

Välj läkemedelstext
Hitta direkt i texten
Av