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Nexium® HP

MiljöinformationReceptstatusFörmånsstatus
AstraZeneca

Tablett
(Nexium: ljust rosa, avlånga, bikonvexa, märkta med 20 mg på ena sidan och A/EH på den andra), (Amimox: vita, ovala med brytskåra, märka A/CM), (Klacid: ljust gula, ovala).

Kombinationer för eradikering av Helicobacter pylori

ATC-kod: A02BD06
Utbytbarhet: Ej utbytbar
Företaget omfattas av Läkemedelsförsäkringen
  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Esomeprazol

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


Läs mer

Detaljerad miljöinformation

PEC/PNEC = 0.852 µg/L/100 µg/L = 0.0085

PEC/PNEC ≤ 0.1


Environmental Risk Classification

Total sales of esomeprazole and omeprazole are included in the calculation of the Predicted Environmental Concentration (PEC), as a worst case, as esomeprazole is the S-enantiomer of the racemate omeprazole. Only short-term (acute) toxicity data are availble for omeprazole (these data are available at www.astrazeneca.com). Therefore, in the absence of comprehensive environmental data for omeprazole, the more scientifically robust long-term data set for esomeprazole has been used to generate the Predicted No Effect Concentration (PNEC). These data are in accordance with the EU European Medicines Agency (EMA) guideline (ref. 1).


Predicted Environmental Concentration (PEC)

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 2014, data from IMS Health.

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilization,

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. 2)

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

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


A = 5682.709 kg. This figure is based on sales figures (801.29 kg esomeprazole + 4881.42 kg omeprazole) from IMS Health for 2014.


R = 0


PEC = 1.5 x 10-6 x 5682.709548.68 x (100-0) = 0.852µg/L

(Note: Whilst esomeprazole and omeprazole are extensively metabolised, little is known about the ecotoxicity of the excreted metabolites. Hence, for the purpose of this calculation , it is assumed that 100% of excreted metabolites have the same ecotoxicity as the parent compounds.)


Metabolism

After administration, esomeprazole and omeprazole are almost completely metabolised, with <1% found in urine as the parent compound. Approximately 80% of the metabolites are excreted by urine and approximately 20% via faeces. The two main excreted human metabolites are both excreted via urine, and are considerably less pharmacologically active than the parent compounds (ref 3).


Ecotoxicity data - Esomeprazole

Endpoint

Species

Common Name

Method

Time

Result

Ref.

NOEC - Based on Biomass

Pseudokirchneriella subcapitata (formerly known as Selenastrum capri-cornutum)

Green Alga

OECD 201

72 h

3.9 mg/L

Note 1

4

LOEC - Based on Biomass

8.4 mg/L

Note 1

NOEC - Based on Logarithmic Growth Rate

8.4 mg/L

Note 1

LOEC - Based on Logarithmic Growth Rate

19 mg/L

Note 1

ErC50 - Based on Logarithmic Growth Rate

85 mg/L

Note 1

EbC50 - Based on Biomass

19 mg/L

Note 1

NOEC - Overall

Note 2

Daphnia magna

Giant Water Flea

OECD 211

21 d

10 mg/L

Note 3

5

LOEC - Overall

Note 5

Pimephales promelas

Fathead Minnow

OECD 210

32 d

3.2 mg/L

Note 3

6

NOEC - Overall

Note 5

1.0 mg/L

Note 3

EC50 - Based on Activated Sludge Respiration Inhibition

-

-

OECD 209

3 h

>100 mg/L

Note 6

7

NOEC - Based on Activated Sludge Respiration Inhibition

100 mg/L

Note 6

NOEC – Based on overall endpoints

Note 4

Chironomus riparius

Midge

OECD 218

28 d

400 mg/kg

Note 3

8

LOEC – Based on overall endpoints

1000 mg/kg


PNEC (Predicted No Effect Concentration)

Long-term tests of esomeprazole have been undertaken for species from three trophic levels, based on internationally accepted guidelines. The most sensitive species of these is the fathead minnow. Therefore, the PNEC is based on the results from the fathead minnow early life stage test, and an assessment factor of 10 is applied, in accordance with ECHA guidance (ref. 2).


PNEC = 1000/10 µg/L = 100 µg/L


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.852 µg/L/100 µg/L = 0.0085, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase ‘Use of esomeprazole has been considered to result in insignificant environmental risk’


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


Environmental Fate Data - Esomeprazole


Endpoint

Method

Test Substance Concentration

Time

Result

Ref.

Partition Coefficient Octanol Water

OECD 117

10 and 20 mg/L

-

Log Dow = 1.65 @ pH 5

9

Log Dow = 1.58 @ pH 7

Log Dow = 1.53 @ pH 9

Percentage Anaerobic Mineralisation

OECD 308

0.42 mg/L in high organic matter

95 d

<2 % Mineralisation

10

Percentage Aerobic Mineralisation

<2 % Mineralisation

Degradation Half-life




T1/2 =20 h @ 25oC, pH 7

11

DT50 

OECD 308

0.1 mg/L in sediment with high organic matter content

-

3.1 d in total system

12

0.1 mg/L in sediment with low organic matter content

6.3 d in total system

0.1 mg/L in sediment with high organic matter content

2.2 d in water compartment

0.1 mg/L in sediment with low organic matter content

3.0 d in water compartment


Biotic degradation

Omeprazole is not readily biodegradable during wastewater treatment.

However, esomperazole is rapidly degraded in aquatic sediment systems. The biological degradation of esomeprazol in aquatic sediments was assessed according to the OECD 308 Test Guideline (ref 12). In this test two different sediments were used, one with high and one with low organic matter content. Radiolabelled test substance was dosed into the overlying water and the subsequent dissipation from the water phase and partitioning and/or degradation in the sediment was observed over a 100 day test period, leaving less than 7 % of the parent substance in the sediment-water system.  In both the high organic matter (HOM) and low organic matter (LOM) test vessels, esomeprazol was observed to be rapidly dissipated from the water phase and total system, with a half-life <14 days, respectively). Greater than 90 % of the partitioned radioactivity was extractable from the sediment using 3 solvent extractions of acetonitrile plus 0.5% ammonium hydroxide. HPLC analysis of the extracts showed that >95% of the 14C was associated with the parent test substance peak.


Adsorption to sludge

The adsorption and desorption of esomeprazole to sludge was assessed according to the OPPTS guideline 835.1110 (ref 13). The Kd(ads) was 48, indicating that esomeprazole is likely to partition into the aqueous phase during wastewater treatment.


Therefore, the substance has been assigned the phrase:“Esomeprazole is slowly degraded in the environment”.


In Swedish: ”Esomeprazol bryts ned långsamt i miljön.” under the heading ”Nedbrytning”


Bioaccumulation

Since Log Dow < 4, esomeprazol has low potential to bioaccumulate and the phrase “Esomeprazole has low potential for bioaccumulation” is assigned.


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


Physical Chemistry Data - Esomeprazole

Endpoint

Method

Test Substance Concentration

Result

Ref.

Adsorption Coefficient 

Note 1

OPPTS 835.1110

40 mg/L

Note 5

Kd (Adsorption) = 48

13

Solubility Water 

Note 7

-

340 mg/L

14

Dissociation Constant

Note 7

-

pKa(1) = 4 (Pyridinium ion)

14

Dissociation Constant

pKa(2) = 8.8 (Benzimidazole)


Note 1: Results are expressed as mean measured concentrations.

Note 2: The population relevant endpoints measured were survival, fecundity and adult length.

Note 3: Concentrations were confirmed by analysis, and results expressed as nominal.

Note 4: The population relevant endpoints measured were total number of emerged adult insects, sex ratio and replicate mean plus individual emergence times (development rates).

Note 5: The population relevant endpoints measured were hatch, survival, length and dry weight.

Note 6: Results are expressed as nominal concentrations.

Note 7: This study predates current ERA regulatory requirements and may not have been undertaken to standardised test guidelines.


References

1. Committee for Medicinal Products for Human Use (CHMP); Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. 1 June 2006, Ref EMEA/CPMP/SWP/4447/00.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/10/WC500003978.pdf

ABC Laboratories (Europe) Ltd.

August-1996


2. 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


3. www.fass.se (Nexium, AstraZeneca Oct 2013)


4. Esomeprazole Na: Toxicity to the green alga Selenastrum capricornutum.

Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8021

March 2005


5. Esomeprazole sodium: Chronic toxicity to Daphnia magna.

Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8555

February 2008


6. Esomeprazole Sodium: Determination of Effects on the Early-Life Stage of Fathead Minnow (Pimephales promelas).

Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8452

July 2007


7. Esomeprazole sodium: Effect on the Respiration Rate of Activated Sludge.

Brixham Environmental Laboratory, AstraZeneca, UK, Report BR0162

March 2010


8. [14C]Esomeprazole sodium: Effects in sediment on emergence of the midge, Chironomus riparius

Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8557

March 2008


9. Esomeprazole sodium: Partition Coefficient (n-octanol-water), HPLC correlation.

Brixham Environmental Laboratory, AstraZeneca, UK, Report BR0547

October 2011


10. Esomeprazole sodium: OECD 308 Screening Test.

Brixham Environmental Laboratory, AstraZeneca, UK, Report BLS3431

June 2008


11. AstraZeneca Exisitng Product Review: Omeprazole and Esomeprazole Brixham Environmental Laboratory, AstraZeneca, UK, Report BL7930

September 2007


12. Esomeprazole sodium: Aerobic Transformation in Aquatic Sediment Systems.

Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8602

May 2008


13. Esomeprazole Sodium: Adsorption and desorption to sewage sludge.

Brixham Environmental Laboratory, AstraZeneca, UK, Report BL8468

February 2008


14. Marketing. S1-03 General Properties: Esomeprazole Sodium.

Brixham Environmental Laboratory, AstraZeneca, UK, Report BD4174. Doc ID-002134457, document status date: January 2015.

Klaritromycin

Miljörisk: Användning av klaritromycin har bedömts medföra låg risk för miljöpåverkan.
Nedbrytning: Klaritromycin är potentiellt persistent.
Bioackumulering: Klaritromycin har låg potential att bioackumuleras.


Läs mer

Detaljerad miljöinformation

PEC/PNEC = 0.031 µg/L/ 0.26 µg/L = 0.12


0.1 < PEC/PNEC ≤ 1


Environmental Risk Classification


Predicted Environmental Concentration (PEC)


PEC is based on 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 2011, = 205.39 kg (data from Quintiles IMS)


R (%) = removal rate (due to loss by adsorption to sludge particles, volatilization, hydrolysis or biodegradation) = 0 (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)


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

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


PEC = 1.5 * 10-6 * 205.39 * (100-0) = 0.031 µg/L


Metabolism

Reported observations suggest that the metabolism of clarithromycin is saturable and that elimination may be dose-dependent (Ref 2). Following administration of a single 250 mg dose approximately 18 and 4% of clarithromycin were recovered in the urine and faeces, respectively. Following administration of a single 1200 mg dose the recovery of unchanged clarithromycin increased by 75%.


Ecotoxicity data

Study Type

Method

Result

Ref

Toxicity to green alga, Pseudokirchneriella subcapitata, growth inhibition test

OECD 201 Note 1

72 hour NOEC(growth rate) = 0.0031 mg/L

72 hour EC50(growth rate) = 0.011 mg/L

3

ISO 8692 (1989) Note 1

72 hour EC50(growth rate) = 0.002 mg/L

4

Toxicity to green alga, Desmodesmus subspicatus, growth inhibition test

ISO 8692 (1989)

72 hour NOEC(growth rate) = 0.025 mg/L

72 hour EC50(growth rate) = 0.037 mg/L

5

Toxicity to cyanobacteria, Anabaena flos-aquae, growth inhibition test

OECD201

72 hour NOEC(growth rate) = 0.0026 mg/L

72 hour EC50(growth rate) = 0.012 mg/L

Acute toxicity to the Giant Water Flea, Daphnia magna

ISO 6341 (1996) Note 1

48 hour EC50(Immobilisation) >2.1 mg/L

24 hour EC50(Immobilisation) =25.7 mg/L

6

Acute toxicity to the Water Flea, Ceriodaphnia dubia 

EPA 600-4-90-027F 

24 hour EC50(Immobilisation) =18.7 mg/L

Acute toxicity to the freshwater Rotifer, Brachionus calyciflorus

ASTM E1440-91 Note 1

24 hour LC50(mortality) = 35.46 mg/L

Acute toxicity to the Beavertail Fairy Shrimp, Thamnocephalus platyurus 

MicroBio-Test Procedure

24 hour LC50(mortality) = 33.64 mg/L

Acute toxicity to Japanese Ricefish, Oryzias latipes

Not standard method

96 hour LC50(mortality) >100 mg/L

7

Acute toxicity to Zebra fish, Danio rerio

ISO 7346 (1996)

96 hour NOEC(mortality) =1000 mg/L

96 hour LC50(mortality) >1000 mg/L

6

Toxicity testing to the aquatic macrophyte, Lemna minor

OECD 221

7 day NOEC(frond, area) >1.9 mg/L

7 day NOEC(dry weight) = 0.80 mg/L

5

Reproductive toxicity to the Giant Water Flea, Daphnia magna

OECD 211 Note 1

21 day EC50(Reproduction) = 0.040 mg/L

21 day NOEC(Reproduction) =0.0031 mg/L

3

21 day NOEC(Reproduction) >2.1 mg/L

5

Reproductive toxicity to the Water Flea, Ceriodaphnia dubia 

ISO/CD 20665 Note 1

7 day EC50(Reproduction) = 8.16 mg/L

6

Reproductive toxicity to the freshwater Rotifer, Brachionus calyciflorus

ISO/CD 20666 (2001)Note 1

48 hour EC50(Population Growth Inhibition) = 12.21 mg/L

Note 1: Results are expressed as nominal concentrations


PNEC (Predicted No Effect Concentration)


Long-term tests have been undertaken for species from two trophic levels, algae and invertebrates, based on internationally accepted guidelines. In accordance with the Fass guideline an assessment factor of 10 is applied to the NOECgrowth rate for the cyanobacteria (Anabaena flos-aquae), since cyanobacteria are considered a particularly sensitive species to antibiotics, to derive the PNEC.


PNEC = 2.6 µg /L / 50 = 0.26 µg/L


Environmental risk classification (PEC/PNEC ratio)


The PEC/PNEC ratio is calculated as= 0.031 /0.26 = 0.12


Since the PEC to PNEC ratio is 1 ≤ 0.1 the phrase ‘Use of Clarithromycin has been considered to result in low environmental risk’ has been assigned.


In Swedish: “ Användning av Klaritromycin har bedömts medföra låg risk för miljöpåverkan”.


Environmental Fate Data

Endpoint

Method

Test Substance Concentration

Time

Result

Ref

Percentage Biodegradation


OECD 301D

0.003 mg/L

28 d

0 % ThOD

8

2.43 mg/L

0 % ThOD

ThOD – Theoretical Oxygen Demand


Biotic degradation

Based on the data above (considering that no other data is available), the phrase ‘Clarithromycin is potentially persistent ’ is chosen.


In Swedish:

Klaritromycin är potentiellt persistent.


Physical Chemistry Data

Endpoint

Method

Test Conditions

Result

Ref

Water solubility

Predicted - ALOGPS

-

0.217 mg/mL

9

Solubility in test media, verified by chemical analysis

pH 7.8, room temperature

~2 mg/L

5

Octanol-water Partition Coefficient

Potentiometric Method

25oC

Log P = 3.16

10

Predictied

Log D = 1.57

Dissociation Constant

Potentiometric Method

25oC

pKa = 8.99

11


Bioaccumulation


Since Log P < 4, the substance has been assigned the phrase: ‘Clarithromycin has low potential for bioaccumulation’.


In Swedish: “Klaritromycin har låg potential att bioackumuleras” under the heading “Bioackumulering”.


References

  1. ECHA, European Chemicals Agency. May 2008 Guidance on information requirements and chemical safety assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment. https://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf/bb902be7-a503-4ab7-9036-d866b8ddce69 

  2. Clinical Pharmacokinetics of Clarithromycin. Rodvold, KA. Clin Pharmacokinet 1999 Nov; 37 (5): 385-398

  3. Effects of Anti-bacterial Agents, Levofloxacin and Clarithromycin, on Aquatic Organisms. Yamashita N.; Yasojima N.; Nakada N.; Miyajima K.; Komori K.; Suzuki Y.; Tanaka H. Water Sci. Technol. 2006 v53 n11 p65-72

  4. Growth-Inhibiting Effects of 12 Antibacterial Agents and Their Mixtures on the Freshwater Microalga Pseudokirchneriella subcapitata. Yang L.H.; Ying G.G.; Su H.C.; Stauber J.L.; Adams M.S.; Binet M.T. Environ. Toxicol. Chem. 2008 v27 n5 p1201-1208

  5. Aquatic toxicity of the macrolide antibiotic clarithromycin and its metabolites. Baumann M., Weiss K., Maletzkib D., Schüssler W., Schudoma D., Kopf W. and Kühnen U. Chemosphere 120 (2015) 192–198

  6. Toxic and Genotoxic Evaluation of Six Antibiotics on Non-target Organisms. Isidori M.; Lavorgna M.; Nardelli A.; Pascarella L.; Parnella A. Sci. Total Environ. 2005 v346 n1 p87-98

  7. Acute Toxicity of Pharmaceutical and Personal Care Products on Freshwater Crustacean (Thamnocepalus platyurus) and Fish (Oryzias latipes). Kim Joon-Woo ; Ishibashi H.; Yamauchi R.; Ichikawa N.; Takao Y.; Hirano M.; Koga M.; Arizono K. J. Toxicol. Sci. 2009 v34 n2 p227-232

  8. Assessment of Degration of 18 Antiobiotics in the Closed Bottle Test. Alexy R.; Kumpel T.; Kummerer K. Chemosphere 2004 v57 p505-512

  9. Drug bank. Clarithromycin, available at http://www.drugbank.ca/drugs/DB01211 accessed on 5 May 2017 

  10. PhysProp Database. Syracuse Research Corporation

  11. Quantitative Structure-Activity Relationships Among Macrolide Antibacterial Agents: In Vitro & In Vivo Potency Against Pasteurella multocida. McFarland J.W.; Berger C.M.; Froshauer S.A.; Hayashi S.F.; Hecker S.J.; Jaynes B.H.; Jefson M.R.; Kamicker B.J.; Lipinski C.A.; Lundy K.M.; Reese C.P.; Vu C.B. J. Med. Chem. 1997 v40 n9 p1340-1346

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