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Tablett med modifierad frisättning 850 mg/2,5 mg/5 mg
Avregistreringsdatum: 2020-08-14 (Tillhandahålls ej)

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ATC-kod: A10BD25

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Miljöinformation

Miljöpåverkan

Dapagliflozin

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

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Detaljerad miljöinformation

PEC/PNEC = 0.0032/100 = 3.2 x 10^-5

PEC/PNEC ≤ 0.1

Environmental Risk Classification

Predicted Environmental Concentration (PEC)

PEC is based on following data and calculated using the equation outlined in the fass.se guidance (Ref 1):

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

PEC (µg/L) = 1.37*10^-6*A*(100-R)

A (kg/year) = 23.54 kg, total sold amount API in Sweden year 2020, data from IQVIA Health.

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

hydrolysis or biodegradation) R = 0.

P = number of inhabitants in Sweden = 10 *10⁶

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

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

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

PEC = 1.37 * 10^-6* 23.54 * (100-0) = 0.0032 μg/L

(Note: Whilst dapagliflozin is metabolised in humans, little is known about the ecotoxicity of the metabolites. Hence, as a worst case, for the purpose of this calculation, it is assumed that 100% of excreted metabolites have the same ecotoxicity as parent dapagliflozin).

Metabolism

Dapagliflozin is rapidly adsorbed and extensively metabolised. Dapagliflozin and its related metabolites are primarily eliminated via urinary excretion with less than 2% as unchanged dapagliflozin (Ref 2). After administration of a 50 mg [¹⁴C]-dapagliflozin dose, 96% was recovered, 75% in urine and 21% in faeces. In faeces, approximately 15% of the dose was excreted as parent drug (Ref 3). Therefore, the patient use of dapagliflozin is likely to result mainly in metabolites and, to a lesser extent, the active moiety entering the environment.

Ecotoxicity data

Study Type	Method	Result	Ref
Activated sludge, respiration inhibition test	OECD209	3 h EC50 >200 mg/L 3 h NOEC = 200 mg/L	4
Toxicity to green algae, Pseudokirchinella subcapitata, growth inhibition test	OECD201	72 hour NOEC_{growth rate} = 37 mg/L 72 hour LOEC_{growth rate} = 67 mg/L 72 hour EC50_{growth rate} = 120 mg/L 72 hour NOEC_biomass = 21 mg/L 72 hour LOEC_biomass = 37 mg/L 72 hour EC50_biomass = 48 mg/L	5
Acute toxicity to the giant water flea (crustacean) Daphnia magna	OECD202	48 hour EC50 >120 mg/L 48 hour NOEC = 120 mg/L	6
Fish early-life stage toxicity with fathead minnow, Pimephales promelas	OECD210	32 day NOEC = 1.0 mg/L 32 day LOEC > 1.0 mg/L based on hatch, survival, standard length, and dry weight	7
Long-term toxicity to Daphnia magna	OECD211	21 day NOAEC = 10 mg/L based on reproduction and length	8
Long-term toxicity to the sediment dwelling midge, Chironomus riparius	OECD218	28 day NOEC = 150 mg/kg dry sediment 28 day LOEC > 150 mg/kg dry sediment, based on emergence, development rate and sex ratio	9

EC50 the concentration of the test substance that results in a 50% effect

NOEC no observed effect concentration

NOAEC no observed adverse effect concentration

LOEC lowest observed effect concentration

PNEC (Predicted No Effect Concentration)

Long-term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on the results from the chronic toxicity to fathead minnow (Pimephales promelas), the most sensitive species, and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref. 10).

PNEC = 1000/10 µg/L = 100 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC = 0.0032 µg/L

PNEC = 100 µg/L

PEC/PNEC = 3.2 x 10^-5

The PEC/PNEC ratio is < 0.1 which justifies the phrase: ‘Use of dapagliflozin has been considered to result in insignificant environmental risk’.

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

Environmental Fate Data

Study Type	Method	Result	Ref
Aerobic biodegradation	OECD301F	11% after 28 days. Not readily biodegradable	11
Adsorption/desorption to sludge	OPPTS guideline 835.1110	K_d(ads) = 51 L/Kg K_oc = 138 L/Kg	12
Aerobic transformation in aquatic sediment systems	OECD308	Mass balance 83-120% of applied radioactivity The half-lives (DT50) in the water 6.0 – 8.7 days The half-lives (DT50) in the sediment ranged 95 - 128 days Extensive mineralisation (¹⁴CO₂ formation) observed in both high and low organic matter vessels with 35 and 68% of the applied radioactivity after 99 days Kd_sediment = 12 kg/L, based on measured partitioning at 8 days	13

Kd Distribution coefficient for adsorption

Koc Organic carbon normalized adsorption coefficient

Biotic degradation

Dapagliflozin is not readily biodegraded as measured in an OECD 301F study (Ref 11), but based on the Aerobic Transformation in Aquatic Sediment System OECD 308 (Ref 12), dapagliflozin slowly degrades in the environment.

The degradation of dapagliflozin in aquatic sediment systems was assessed according to the OECD 308 Test Guideline. In this test two different sediments were used, one with high organic matter (HOM) and one with low organic matter content (LOM). 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 99 day test period. Since mineralisation was very strong the test vessels were kept to monitor CO2 production over 148 days.

The partitioning of dapagliflozin in aquatic sediment systems appears to stop at Day 8 and no further significant amounts of radioactivity moved into the sediment. Afterwards degradation and mineralisation took place, apparently in the water phase.

Transformation of dapagliflozin into a possible seven transformation products was rapid as was partitioning to the sediment. Extensive mineralisation was seen in both the high and low organic matter sediment vessels with 35 and 68%, respectively of the applied radioactivity produced as CO² after 99 days.

Following extensive sediment extration, using a variety of organic solvents of varying polarity, a significant proportion of the applied radioactivity, 44% in the high organic matter system and 24% in the low organic matter system, on Day 99, remained as non-extractable residue (NER). At Day 99 the amount of applied radioactivity removed from the total system as¹⁴CO₂ and NER, accounted for 79 and 92% in the high and low organic matter sediment vessels, respectively. Accordingly the half life of dapagliflozin in both aquatic sediment systems is <120 days.

Based on the data above dapagliflozin has been assigned the risk phrase: ‘Dapagliflozin is slowly degraded in the environment.’

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

Bioaccumulation

Dapagliflozin is not ionisable within the environmentally relevant pH range (estimated pKa = 12.6). The octanol-water partition coefficient was 2.34, measured at pH 7.4. Since Log P_OW < 4, dapagliflozin has low potential to bioaccumulate and the phrase “Dapagliflozin has low potential for bioaccumulation” is assigned.

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

Physical Chemistry Data

Study Type	Method	Result	Ref
Octanol-water distribution coefficient	OECD107, Shake flask	log P_ow = 2.34 at pH 7	14
Water solubility	OECD105, Shake flask	pH 5 = 720 mg/L pH 7 = 538 mg/L pH 9 = 946 mg/L	15
Hydrolysis	OECD111	<10% after 5 days at 50°C (pH 5 & 7) 11.5 % after 5 days at 50°C (pH 9) t½ at 25°C ≥ 1 year	16

References

Environmental Classification of Pharmaceuticals in www.fass.se – Guidance for Pharmaceutical Companies. (2012 v 2.0).
Kasichayanula, S., Liu, X., LaCreta, F. et al. 2014. Clinical Pharmacokinetics and Pharmacodynamics of Dapagliflozin, a Selective Inhibitor of Sodium-Glucose Co-transporter Type 2. Clin Pharmacokinet 53: 17-27
Mass balance and metabolism of [¹⁴C]BMS-512148 in healthy male subjects. Bristol-Myers Squibb, Princeton, New Jersey 08543, USA. Protocol Number MB102006. November 2006
Dapagliflozin: Effect on the respiration rate of activated sludge. BLS8577/B. Brixham Environmental Laboratory, Brixham, UK. October 2008.
Dapagliflozin: Toxicity to the green alga Pseudokirchneriella subcapitata. BL8587/B. Brixham Environmental Laboratory, Brixham, UK. December 2008.
Dapagliflozin: Acute toxicity to Daphnia magna. BL8590/B. Brixham Environmental Laboratory, Brixham, UK. September 2008.
Dapagliflozin: Determination of effects on the Early-Life Stage of the fathead minnow (Pimephales promelas). BL8638/B. Brixham Environmental Laboratory, Brixham, UK. December 2008.
Dapagliflozin: Chronic toxicity to Daphnia magna. BL8622/B. Brixham Environmental Laboratory, Brixham, UK. May 2009.
[14C]Dapagliflozin: Effects in sediment on emergence of the midge, Chironomus riparius. BL8661/B. Brixham Environmental Laboratory, Brixham, UK. March 2009.
ECHA (European Chemicals Agency) 2008. Guidance on information requirements and chemical safety assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm
Dapagliflozin: Determination of 28 day ready biodegradability. Report No. BL8586/B. Brixham Environmental Laboratory, Brixham, UK. July 2008.
Dapagliflozin: Activated sludge sorption isotherm. Report No. BL8614/B. Brixham Environmental Laboratory, Brixham, UK. August 2008.
Dapagliflozin: Aerobic transformation in aquatic sediment systems. BL8594/B. Brixham Environmental Laboratory, Brixham, UK. February 2009.
Dapagliflozin: Determination of 1-octanol/water partition coefficient. Report No. BL8585/B. Brixham Environmental Laboratory, Brixham, UK. June 2008.
Dapagliflozin: Determination of Water Solubility Shake Flask Method. Report No. BLS3433/B. Brixham Environmental Laboratory, Brixham, UK. June 2008.
Dapagliflozin: Hydrolysis as a function of pH - preliminary study results summary. BLS3434/B. Brixham Environmental Laboratory, Brixham, UK. July 2008.

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 = 0.0001488 µg/L / 950 µg/L = 1.83 x10-7

PEC/PNEC ≤ 0.1

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) = 1.37*10^-6*A*(100-R)

PEC = 1.37 * 10^-6 *1.2722*(100-0)

= 0.00017429 µg/L

A (kg/year) = total sold amount API sold in Sweden year 2021, data from IQVIA/Lif.

= 1.2722kg

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

= 0 (default).

P = number of inhabitants in Sweden =10*10⁶

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

= 200 L/day (ECHA default) (Ref 1)

D = factor for dilution of wastewater by surface water flow

= 10 (ECHA default) (Ref 1)

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

Metabolism and excretion

Saxagliptin is extensively metabolised in humans to numerous metabolites. It is excreted in urine and faeces together with the primary metabolite, BMS-510849. This metabolite was indicated to be approximately half as potent as Saxagliptin in in vitro studies (Ref 15). Overall, following oral administration Saxagliptin accounted for 34.1% of the excreted dose (urine + faeces) and BMS-510849 accounted for 36.6% of excreted dose (urine + faeces) (Ref 2).

Ecotoxicity Data

Study	Method	Result	Ref
Activated sludge respiration inhibition test	OECD 209	3 hour NOEC (EC10) = 821 mg/L 3 hour EC50 >1000 mg/L	3
Acute Toxicity to Zebra Fish, Danio rerio	OECD 203	96 hour NOEC_(mortality) = 45 mg/L 96 hour LC50_(mortality) >91 mg/L	4
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	5
Chronic toxicity to Daphnia magna,	OECD 211	21 day NOEC_{(survival, reproduction and length)} = 35 mg/L 21 day LOEC_{(survival, reproduction and length) =} 94 mg/L	6
Fish Early-Life Stage Toxicity with Pimephales promelas	OECD 210	32 day NOEC_{(hatch, survival, weight and length)} = 9.5 mg/L 32 day LOEC_{(hatch, survival, weight and length)} > 9.5 mg/L	7
Toxicity to Chironomus riparius under Static Conditions	OECD 218	28 day NOEC = 6.4mg/kg dry weight 28 day LOEC = 16mg/kg dry weight 28 day EC50 > 100mg/kg dry weight	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 = 0.00017429 µg/L / 950 µg/L

PEC/PNEC = 1.83 x10^-7

As the PEC/PNEC ratio ≤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	Method	Result	Ref
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 soils and sludge	OECD 106	5 Soils Mean Kd (ads) = 13.7 ± 6.63 Mean Koc = 700 ± 327 Activated sewage sludge Mean Kd = 19.6 Mean Koc = 71.6	11
Aerobic transformation in aquatic sediment systems	OECD 308	The half-lives (DT50) in the water were 20 days [LOC] and 23.2 days [HOC] The half-lives (DT50) in the total system were 20 days [LOC] and 30 days [HOC] <15% of applied radioactivity remaining as parent compound at the end of the study	12

Study

Method

Result

Ref

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.

Adsorption/ desorption to soils and sludge

OECD 106

5 Soils

Mean Kd (ads) = 13.7 ± 6.63

Mean Koc = 700 ± 327

Activated sewage sludge

Mean Kd = 19.6

Mean Koc = 71.6

Aerobic transformation in aquatic sediment systems

OECD 308

The half-lives (DT50) in the water were 20 days [LOC] and 23.2 days [HOC]
The half-lives (DT50) in the total system were 20 days [LOC] and 30 days [HOC]
<15% of applied radioactivity remaining as parent compound at the end of the study

Biodegradation

Saxagliptin cannot be classified as readily biodegradable (Ref 10) and is unlikely to partition to the sludge solids during wastewater treatment based on finding from an OECD106 study (Ref 11).

The rate of aerobic and anaerobic transformation of [¹⁴C]Saxagliptin (Ref 12) was studied in two sediments (Goose River with a high organic carbon content of ~2.8% and Golden Lake with a low organic carbon content of ~1%) with associated overlying waters for 102 Days. Only the observations in under aerobic conditions are reported here.

The half-life (DT50) of Saxagliptin in the water fraction was 20 days and 23.2 days in the LOC and HOC systems, respectively.

Sediment samples were extracted twice using acetonitrile:water (80:20) and once with acetonitrile:water:concentrated hydrochloric acid (80:20:0.1). By Day 102 an average of 42.2% and 67.6% of the applied radioactivity was associated with the sediment in the LOC and HOC systems, respectively. Of this, an average of 21.9% and 26.4% were extractable in the LOC and HOC systems, respectively. The half-life of saxagliptin in the total systems was 20 days [LOC] and 30 days [HOC] in the LOC and HOC systems, respectively.

Two major degradation products (>10% of the applied radioactivity) were observed in each of the aerobic test systems. These metabolites were detected at HPLC retention times of approximately 13 and 18 minutes in the HOM system, and 18 and 20 minutes in LOM system. 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 0.1% of the applied radioactivity was detected as volatile organics.

At the end of the study, 3% and 7.3% of the applied radioactivity were identified as parent in the LOC and HOC systems, respectively.

As the total system half-life was ≤32 days, and less than 15% parent compound was remaining at the end of the study, the phrase ‘Saxagliptin is degraded in the environment’ has been assigned.

In Swedish: Saxagliptinhydroklorid bryts ned i miljön.

Bioaccumulation Data

Saxagliptin is ionisable, therefore the Log D_ow was determined across the environmentally relevant pH-range. The Log D_ow 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	Method	Result	Ref
Octanol/water partition coefficient, OECD 107	OECD 107	Log D_ow at pH 4 = -1.74 Log D_ow at pH 8.2 = 0.114 Log D_ow at pH 9 = 0.169	13
Hydrolysis, OECD 111	OECD 111	DT50 at pH 7, 20^oC = 34.5 days DT50 at pH 9, 20^oC = 41.0 days	14
Dissociation Constant	-	pKa = 7.3	15

References

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

Doc ID-002352373
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
12534.6297. Saxagliptin (BMS 477118-11) – Toxicity to the Freshwater Green Alga Pseudokirchneriella subcapitata. Report No. 12534.6297, 2007.

Doc ID-002352369
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
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
Saxagliptin (BMS-477118) - Full Life-Cycle Toxicity Test with Sediment-Dwelling Midges (Chironomus riparius) Under Static Conditions, Following OECD Guideline 218. Report 12534.6346, 2008. Doc ID-002352378
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
12534.6295. Determining 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
12534.6320. [¹⁴C]Saxagliptin (BMS 477118-15) – Determining the Adsorption Coefficient (Koc) Following OECD Guideline 106. Report No. 12534.6320, 2008. Doc ID-002352347
12534.6321. [¹⁴C]Saxagliptin (BMS 477118-14) – Aerobic and Anaerobic Transformation in Aquatic Sediments Systems Following OECD Guideline 308. Report No. 12534.6321, 2008.

Doc ID-002352352
12534.6318. Saxagliptin – Determination of the n-Octanol/Water Partition Coefficient. Report No. 12534.6318, 2008.

Doc ID-002352381
12534.6319. [¹⁴C]Saxagliptin (BMS 477118) – 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
Investigator Brochure BMS-477118 Saxagliptin. Version 7, 22-Jul-2009. Doc ID-002352235

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