Under eftermiddag, kväll och natt 24 februari till 25 februari kan tillfälliga driftstörningar förekomma på Fass. För akuta behov finns Fass för vårdpersonal som app.

FASS logotyp
Receptbelagd

Peka på symbolerna och beteckningarna till vänster för en förklaring.

Kontakt

Sök apotek med läkemedlet i lager

Sök lagerstatus

Komboglyze

AstraZeneca

Filmdragerad tablett 2,5 mg/850 mg
(Filmdragerad tablett. Ljusbruna till bruna, bikonvexa, runda, filmdragerade tabletter med ”2,5/850” tryckt på ena sidan och ”4246” tryckt på den andra sidan med blått bläck.)

Diabetesmedel, perorala diabetesmedel, kombinationer

Aktiva substanser (i bokstavsordning):
ATC-kod: A10BD10
Utbytbarhet: Ej utbytbar
Läkemedel från AstraZeneca omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Metformin

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


Läs mer

Detaljerad miljöinformation

PEC/PNEC = 23.4 µg/L / 100 µg/L = 0.23

PEC/PNEC ≤ 1


Environmental Risk Classification


Predicted Environmental Concentration (PEC)

The 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 2017, data from IQVIA (former IMS Health and Quintiles).

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. 1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref. 1)

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


A = 155977.33 kg

R = 0 

PEC = 1.5 x 10-6 x 155977.33 x (100-0) = 23.4 µg/L


Metabolism

Metformin hydrochloride is excreted unchanged in the urine. No metabolites have been identified in humans (Ref. 2).

Ecotoxicity data


Endpoint

Species

Common Name

Method

Time

Result

Ref

ErC50 – Based on Growth Rate

Pseudokirchneriella subcapitata

Green Alga

OECD 201

72 h

>100 mg/L

3

NOEC – Based on

Growth Rate

100 mg/L

NOEC – Based on

Growth Rate

Note 1

Unknown

Green Alga

99.5 mg/L

4

EC50 – Based on Immobilisation

Daphnia magna

Giant Water Flea

FDA 4.08

48 h

130 mg/L

5

NOEC - Based on Immobilisation

78 mg/L

NOEC – Based on Survival, Reproduction and Growth Rate

OECD 211

21 d

67 mg/L

6

NOEC – Based on Survival, Reproduction and Growth Rate

Note 2

54.1 mg/L

4

NOEC – Based on Reproduction

Ceriodaphnia dubia

Water Flea

ISO 20665

7 d

1 mg/L

LC50

Lepomis macrochirus

Bluegill sunfish

US FDA Technical Assistance Document 4.11

96 h

>982 mg/L

7

NOEC – Based on lack of mortality and abnormal effects

982 mg/L

NOEC – Based on hatch, survival, standard length and dry weight

Pimephales promelas

Fathead Minnow 

OECD 210

32 d

10 mg/L

8

NOEC – Based on hatch, survival, standard length and dry weight

Note 3

2.2 mg/L

6

NOEC – based on hatch, survival, standard length and dry weight

Note 1

Danio rerio

Zebra fish

11.1 mg/L

NOEC - Based on emergence and development rate

Chironomus riparius

Midge

OECD 218

28 d

100 mg/kg (dry weight)

9

NOEC - Based on emergence and development rate

>100 mg/kg

(dry weight)

Microbial Inhibitory Concentartion (MIC)

Anabaena flos-aquae

Nitrogen fixing bluegreen algae

FDA 4.02

-

100 mg/L

10

NOEC – Based on growth inhibition

80 mg/L

Microbial Inhibitory Concentartion (MIC)

Azobacter chroococcum

Nitrogen fixing Bacterium

800 mg/L

NOEC – Based on growth inhibition

400 mg/L

NOEC – Based on growth inhibition

Aspergillus clavatus

Fungi

1000 mg/L

Penicillium canescens

Chaetomium globosum

Pseudomonas fluorescens

Bacterium

Bacillus megaterium

Note 1 - Geometric average (GA) of 2 data points

Note 2 - Geometric average (GA) of 4 data points

Note 3 - Geometric average (GA) of 3 data points


PNEC (Predicted No Effect Concentration)

Long-term tests have been undertaken for species from three tropic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on results from the assessment of water flea (Ceriodaphnia dubia) study, NOEC = 1 mg/L, and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref. 11).


PNEC = 1000 µg/L/10 = 100 µg/L


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 23.4 / 100 µg/L = 0.23 µg/L, i.e. PEC/PNEC ≤ 1 which justifies the phrase “Use of metformin hydrochloride has been considered to result in low environmental risk.”.


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


Environmental Fate Data

Endpoint

Method

Test Substance Concentration

Time

Result

Ref

Percentage Aerobic Biodegradation

FDA 3.11

10 mg/L

28 d

0.6%

Not readily biodegradeable

12

Dissipation Half-life

OECD 308

1.0 mg/L (High Organic Matter Sediment)

102 d

DT50 = 6.59 days

(Total System)

13

1.0 mg/L (Low Organic Matter Sediment)

DT50 = 55.0 days

(Total System)

Hydrolysis Half-life

FDA 3.09

-

5 d

pH 5 = 0%

pH 7 & pH 9 = 1%

T1/2 = 25°C ≥ 1 year

14

Photolysis % deagradation and half -life

FDA 3.10

-

5 d

84.9 % (parent)

T1/2 28.3 days (Estimated)

15

Biodegradation


Results from the aerobic biodegradation test (Ref. 12), showed that metformin hydrochloride is not readily biodegradable.


Evidence from the OECD 308 study (Ref. 13) is that metfromin hydrochloride is likley to dissipate from the aqueous phase and partition into the sediment phase.


High organic matter (HOM) sediment system:


The average mass balance ranged from 93.3 – to 100.2% of applied radioactivity (AR) throughout the 102-day study. The AR declined rapidly in the water phase, by Day 14 26.3% and by Day 27 only 4.5% remained, with < 1% of the initial concentration remaining in the water phase by Day 102. At the end of the test, Day 102, 13.1% of the AR was associated with the sediment. Despite the investigation of a number of different extraction solvents (acetoniltrile: purified reagent water: concentrated hydrochloric acid), 12.8% remained non-extractable.


Metformin hydrochloride was extensively biodegraded, the cumulative amount of 14CO2 evolved was 64% of AR by Day 27. The total system half-life was 6.59 days.


In the water and the sediment combined, two degradation products were present at >10% AR at Day 14. However, these were transient degradation products and neither was detected from Day 56 onwards. These were not considered further.


Low organic matter (LOM) sediment system:


The average mass balance ranged from 93.3 – to 103.9% of AR. Dissipation of the radioactivity from the water to the sediment was slower than that observed in the HOM test vessels, with 28.8% remaining in the water phase at Day 14, and 11.2% remaining at Day 102. Very little mineralisation was observed (3.2% at Day 102). The radioactivity in the test vessel remained associated with the sediment. At Day 14, 73.6% remained associated with the sediment, of which 30.7% of the AR was extractable. At Day 102, 81.5% of the AR was associated with the sediment in the low organic matter (LOM) vessels, however the extractable fraction had decreased to 14.0% of the AR.


Extractability of metformin hydrochloride was good. The proporotion of radioactivity associated with the non-extractable residues (NER) increased throughout the study, 68% AR at Day 102. The NER are considered non-bioavailable and therefore removed in the calculation of the LOM DT50 value. The total system half-life was 55 days.


Differences in the two systems can be explained by the fact that the degradation of metformin hydrochloride is believed to depend on the specific microorganisms in the HOM matrix at the time of dosing the can use metformin hydrochloride as a carbon source and subsequently biodegrade metformin hydrochloride, whereas the microorganisms in the LOM matrix do so to a lower extent. Additionally, the HOM sediment system had a higher microbial biomass which may also contribute to a higher amount of biodegradation in the HOM systems versus the LOM system.


Based on the data above, metformin hydrochloride is not predicted to be readily biodegraded during wastewater treatment. However, there is evidence that metformin hydrochloride will degrade within the aquatic environment, both in biotic and abiotic transformation (FDA 3.10 and OECD 308).


Based on the above, the phrase “Metformin hydrochloride is slowly degraded in the environment.” has been assigned.


In Swedish: “Metforminhydroklorid bryts ner långsamt i miljön.” under the heading “Nedbrytning”.


Bioaccumulation

Metformin hydrochloride has has no significant bioaccumulation potential, as indicated by the low Log Kow (Log Kow = -1.43). Therefore the statement “Metformin hydrochloride has low potential for bioaccumulation” has been assigned.
 

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



Physical Chemistry Data

Endpoint

Method

Test Substance Conditions

Result

Ref.

Solubility Water 

Unknown

25oC

300.5 mg/L

16

Partition Coefficient

Octanol-Water 

Unknown

-

Log Kow = -1.43

Sorption/Desorption

FDA 3.08

Wareham activated sludge

Kd = 10.3

Koc = 32.1

17


References

  1. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (Version 3.0). February 2016.


  2. Summary of Product Characteristics for Komboglyze Film-Coated Tablets. Accessed 21st April 2016, and available at Link to document EMA


  3. Hoberg, J., Metformin Hydrochloride - Acute Toxicity to the Freshwater Green Alga,Pseudokirchneriella subcapitata OECD 201, Springborn Smithers Laboratories, Inc.:Report No. 12534.6219, 2007.


  4. Environmental Risk Assessment for metformin and its transformation product guanylurea in surface water. Caldwell.D, et al. SETAC Europe 24th Annual Meeting, Basle, Switzerland, May 11th–15th, 2014.


  5. Hicks, S. L.; Acute Toxicity of Metformin HCl to Daphnia magna ABC Laboratories, Inc. Report No. 41778, Jul 14, 1994.


  6. Putt, A., Metformin Hydrochloride - Full Life-Cycle Toxicity Test with Water Fleas Daphnia magna, Under Static-Renewal Conditions OECD 211, Springborn Smithers Laboratories, Inc.: Report No. 12534.6220, 2007.


  7. Sword M. Static Acute Toxicity of Metformin HCl to Bluegill (Lepomis macrochirus) ABC Laboratories, Inc. Report number 41779, July 1994.


  8. York, D., Metformin (BMS 207150) – Early Life-Stage Toxicity Test with Fathead Minnow, (Pimephales promelas), Following OECD Guideline 210. Smithers Viscient: Report No. 12534.6394, 2012.


  9. Bradley, M., Metformin Hydrochloride – Toxicity Test with Sediment-Dwelling Midges (Chironomous riparius) Under Static Conditions, Following OECD Guideline 218. Smithers Viscient: Report No. 12534.6396, 2011.


  10. Wood, J.; Microbial Growth Inhibition with Metformin HCl, ABC Laboratories, Inc. Report No. 41776, Jul 13, 1994.


  11. [ECHA] European Chemicals Agency. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment. May 2008.


  12. Bielefeld, T.A.; Aerobic Biodegradation of 14C-Metformin HCl in Water, ABC Laboratories, Inc. Report No. 41775, Aug 10, 1994.


  13. McKnight, C. [14C]Metformin Hydrochloride [14C](BMS 201750) – Aerobic

    Transformation in Aquatic Sediments Following OECD Guideline 308. Smithers

    Viscient: Report No. 12534.6398, 2011.


  14. Hallberg, C.; Hydrolysis of Metformin HCl as a function of pH, ABC Laboratories, Inc. Report No. 41774, Aug 10, 1994.


  15. Putman, K.; Determination of the Aqueous Photodegradation of 14C-Metformin HCl, ABC Laboratories, Inc. Report No. 41950, Aug 11, 1994.


  16. AstraZeneca Environmental Risk Assessment of Saxagliptin/Metformin Fixed Dose Combination [CV.000-594-251], June 2010.


  17. Sorption / Desorption Springborn Smithers Laboratories FDA-3.08 12534.6221. July 2007.


Saxagliptin

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


Läs mer

Detaljerad miljöinformation


PEC/PNEC = 0.00034 µg/L / 950 µg/L

PEC/PNEC = 3.5 x10-7


Environmental Risk Classification


Predicted Environmental Concentration (PEC)

The PEC is based on the following data:


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

A (kg/year) = 2.2355 kg = total sold amount API (both saxagliptin and saxagliptin hydrochloride) in Sweden year 2018, data from IQVIA.

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

P = number of inhabitants in Sweden =9*106

V (L/day) = volume of wastewater per capita and day = 200 L/day (Ref 1)

D = factor for dilution of waste water by surface water flow = 10 (Ref 1) (Note: The factor 109 converts the quantity used from kg to μg)


PEC = 1.5 * 10-6 *2.2355*(100-0) = 0.00034 µg/L


Metabolism and excretion

Saxagliptin is extensively metabolised in humans to numerous metabolites (Ref 2). Saxagliptin is excreted in urine and faeces together with the primary metabolite BMS-510849. This metabolite has approximately half of the pharmacological activity of saxagliptin in in vitro studies and is believed to contribute to the effects of saxagliptin in vivo (Ref 3). Overall, following oral administration (Ref 1) saxagliptin accounted for 34.1% of the excreted dose (urine + faeces) and BMS-510849 accounted for 36.6% of excreted dose (urine + faeces).


Ecotoxicity Data

Study

Result

Reference

Activated sludge, respiration inhibition test, OECD 209

3 hour NOEC (EC10) = 821 mg/L

3 hour EC50 > 1000 mg/L

4

Acute Toxicity to Zebra Fish, Danio rerio, OECD 203

96 hour NOEC (mortality) = 45 mg/L

96 hour LC50 (mortality) > 91 mg/L

5

Toxicity to green algae, Pseudokirchneriella subcapitata, OECD 201

72 hour NOEC (growth rate) = 21 mg/L

72 hour EC50 (growth rate) > 140 mg/L

72 hour NOEC (biomass) = 8.5 mg/L

72 hour EC50 (biomass) = 91 mg/L

6

Chronic toxicity to Daphnia magna, OECD 211

21 day LOEC (survival, reproduction and length) = 94 mg/L

21 day NOEC (survival, reproduction and length) = 35 mg/L

7

Fish Early-Life Stage Toxicity with Pimephales promelas, OECD 210

32 day LOEC (hatch, survival, weight and length) > 9.5 mg/L

32 day NOEC (hatch, survival, weight and length) = 9.5 mg/L

8

EC50 50% Effect Concentration

LOEC Lowest Observed Effect Concentration

NOEC No Observed Effect Concentration


Predicted No Effect Concentration (PNEC)

Long-term tests have been undertaken for species from three trophic levels. Therefore, the PNEC is based on the lowest No Observed Effect Concentration (NOEC), 9.5 mg/L (Fish Early-Life Stage Toxicity with Pimephales promelas), and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref 9)


PNEC = 9.5 mg/L/10

= 950 µg/L


Environmental Risk Classification (PEC/PNEC ratio)


PEC/PNEC = 0.00034 µg/L /950 µg/L

PEC/PNEC = 3.5 x10-7


The PEC/PNEC ratio decides the wording of the aquatic environmental risk phrase. As the PEC:PNEC ≤0.1 the phrase ’Use of saxagliptin has been considered to result in insignificant environmental risk’ has been assigned.


In Swedish:Användning av saxagliptinhydroklorid har bedömts medföra försumbar risk för miljöpåverkan


Environmental Fate Data

Study

Result

Reference

Aerobic biodegradation, OECD 310

The mean ultimate biodegradation value based on CO2 evolution peaked at 5.90% of theoretical at Day 28.

Not readily biodegradable.

10

Adsorption/desorption to sediments, soils and sludge, OECD 106

5 Soils

Mean % Adsorption = 70.5% ± 9.51%

Mean Kd (ads) = 13.7 ± 6.63

Mean Koc = 700 ± 327

Activated sewage sludge

Mean % Adsorption = 8.8%

Mean Kd = 19.6

Mean Koc = 71.6 

11

Aerobic transformation in aquatic sediment systems, OECD308

  • Mass balance 92-103.7% of applied radioactivity

  • The half-lives (DT50) in the water 18.0 - 23.2 days

  • The half-lives (DT50) in the total system ranged 20-31.5 days

  • Four major metabolites, each accounting of >10% of the applied radioactivity

12

Biodegradation


Saxagliptin cannot be classified as readily biodegradable (Ref 10) and, in domestic sewage, is unlikely to partition to the sludge solids during wastewater treatment (Ref 11).


The rate of aerobic and anaerobic transformation of [14C]Saxagliptin (Red 12) was studied in four sediments varying in pH, textural characteristics, organic matter content and microbial content (Goose River aerobic, Golden Lake aerobic, Goose River anaerobic and Golden Lake anaerobic sediments) with associated overlying waters for 102 Days.


The half-life (DT50) of saxagliptin in the water fraction ranged from 18.0 to 23.2 days in the aerobic and anaerobic test systems.


By Day 102 approximately 40-70% of the applied radioactivity was associated with the sediment, with 20-30% of the applied radioactivity extractable. Sediment samples were extracted twice using acetonitrile:water (80:20) and once with acetonitrile:water:concentrated hydrochloric acid (80:20:0.1). The half-life of saxagliptin in the total water/sediment test systems ranged from 20.0 to 31.5 days for the aerobic and anaerobic test systems.


Four major degradation products (>10% of the applied radioactivity) were observed at HPLC retention times of approximately 13, 18, 20 and 22 minutes for the aerobic and anaerobic test systems. Characterisation of these metabolites was performed by HPLC/MS/MS. The cumulative amount of evolved 14CO2 was 2% of the applied radioactivity in each of the test systems. Less than 0.5% of the applied radioactivity was detected as volatile organics in the aerobic and anaerobic test systems and as 14CH4 in the anaerobic test systems.


The total system half-life was ≤32 days; therefore the phrase ‘saxagliptin is degraded in the environment’ has been assigned.


In Swedish:saxagliptinhydroklorid bryts ned i miljön.


Bioaccumulation Data


Saxagliptin is ionisable (pKa 7.2), therefore the Log Dow was determined across the environmentally relevant pH-range. The Log Dow values are low; as such saxagliptin has no significant bioaccumulation potential and the phrase ‘Saxagliptin has low potential for bioaccumulation’ has been assigned.


In Swedish: saxagliptinhydroklorid har låg potential att bioackumuleras


Physical Chemistry Data

Study

Result

Reference

Octanol/water partition coefficient, OECD 107

Log Dow at pH 4 = -1.74

Log Dow at pH 8.2 = 0.114

Log Dow at pH 9 = 0.169

13

Hydrolysis, OECD 111

DT50 at pH 7, 20oC = 34.5 days

DT50 at pH 9, 20oC = 41.0 days 

14


References

  1. ECHA [European Chemicals Agency] 2016. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0). February 2016.

    http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

  2. 930016961. Comparative Biotransformation of [14C]Saxagliptin after Oral Administration to Bile-Duct Cannulated Rats, Intact Rats, Dogs, Monkeys, and Humans. Bristol-Myers Squibb Company Internal Report 930016961, 2007.

    Doc ID-002356123

  3. 930008287. In Vitro Potency and Specificity of BMS-477118 and Its Metabolite BMS-510849. Bristol-Myers Squibb Company Internal Report 930008287, 2004.

    Doc ID-002355026

  4. 12534.6296. McLaughlin, S., Saxagliptin (BMS 477118-11) – Determination of Activated Sludge Respiration Inhibition. Report No. 12534.6296, 2007.

    Doc ID-002352373

  5. 12534.6322. Saxagliptin (BMS 477118-11) – Acute Toxicity to Zebra Fish (Brachydanio rerio), Under Static Conditions Following OECD Guideline Number 203. Report No. 12534.6322, 2008.

    Doc ID-002352357

  6. 12534.6297. Saxagliptin (BMS 477118-11) – Toxicity to the Freshwater Green Alga Pseudokirchneriella subcapitata. Report No. 12534.6297, 2007.

    Doc ID-002352369

  7. 12534.6323. Saxagliptin (BMS 477118-11) – Full Life-Cycle Toxicity Test with Water Fleas, (Daphnia magna), Under Static Renewal Conditions, Following OECD Guideline #211. Report No. 12534.6323, 2008.

    Doc ID-002352365

  8. 12534.6325. Saxagliptin (BMS 477118-11) – Early Life-Stage Toxicity Test with Fathead Minnow, (Pimephales promelas), Following OECD Guideline #210. Report No. 12534.6325, 2008.

    Doc ID-002352361

  9. ECHA [European Chemicals Agency] 2008. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment. May 2008

    http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf

  10. 12534.6295. Determination of the Biodegradability of Saxagliptin (BMS 477118-11) Based on the Draft OECD 310 Sealed Vessel CO2 Evolution Biodegradation Test. Report No. 12534.6295, 2007.

    Doc ID-002352343

  11. 12534.6320. [14C]Saxagliptin (BMS 477118-15) – Determining the Adsorption Coefficient (Koc) Following OECD Guideline 106. Report No. 12534.6320, 2007.

    Doc ID-002352347

  12. 12534.6321. [14C]Saxagliptin (BMS 477118-14) – Aerobic and Anaerobic Transformation in Aquatic Sediments Following OECD Guideline 308. Report No. 12534.6321, 2008.

    Doc ID-002352352

  13. 12534.6318. Saxagliptin – Determination of the n-Octanol/Water Partition Coefficient. Report No. 12534.6318, 2008.

    Doc ID-002352381

  14. 12534.6319. [14C]Saxagliptin – Determination of the Abiotic Degradation of the Test Substance by Hydrolysis at Two Different pH Values Following OECD Guideline 111. Report No. 12534.6319, 2008.

    Doc ID-002352339