Seroquel Depot - FASS Vårdpersonal

Vad är en miljöinformationstext?

Svensk miljöklassificering av läkemedel

Nedspolade rester av läkemedel och substanser som passerar kroppen kan via avloppen hamna i vattendrag om substanserna inte kan renas av reningsverken.

På initiativ av LIF – de forskande läkemedelsföretagen, har Sverige som första land i världen därför infört ett system för miljöklassificering av läkemedel, vilken publiceras här på Fass.se. Modellen har utarbetats av LIF i samarbete med Läkemedelsverket, Sveriges kommuner och Landsting, Apoteket AB (numera genom Sveriges Apoteksförening) samt Stockholms Läns Landsting.

Miljörisk

Miljörisken baserar sig på förhållandet mellan den förväntade koncentrationen av läkemedelssubstansen i svenska vattendrag (PEC, Predicted Environmental Concentration) och den maximala koncentration som förväntas vara säker för de vattenlevande djur och växter som lever där (PNEC, Predicted No Effect Concentration). Testerna har normalt gjorts på alger, vattenloppor och fisk i laboratoriemiljö.

Om den beräknade koncentrationen i miljön är lägre än den koncentration som, baserat på tester, förväntas vara säker för organismer (dvs. PEC/PNEC är lägre än 1), så bedöms risken för miljöpåverkan vara låg eller till och med försumbar. Om däremot kvoten PEC/PNEC är större än 1, så är det en medelhög till hög risk för miljöpåverkan.

En substans kan få klassificeringen ”försumbar”,” låg”, ”medelhög” eller ”hög miljörisk”.

Nedbrytning

En substans som är svårnedbrytbar kan föra med sig att exponeringen ökar på sikt eftersom koncentrationen i miljön ökar, vilket kan öka risken för miljöpåverkan med tiden. Hur snabbt och fullständigt ett organiskt ämne bryts ned i reningsverk eller i naturen, av mikroorganismer, bestäms i strängt standardiserade metoder t.ex. OECDs tester. Ämnen som i naturen bryts ned mycket långsamt eller inte alls benämns persistenta.

En substans kan få klassificering ”bryts ner i miljön”, ”bryts ner långsamt” eller ”potentiellt persistent”.

Bioackumulering

Bioackumulerande substanser har en tendens att lagras i vävnader t.ex. hos vattenlevande organismer såsom fisk. En indikation på ett ämnes bioackumulerbarhet kan bland annat fås genom att studera ämnets fördelning i en blandning av oktanol (som simulerar fettvävnad) och vatten.

En substans kan få klassificeringen ”har inte potential…” respektive ”har potential att bioackumuleras”.

Bakgrundsdata

All bakomliggande data till de bedömningar som redovisas om miljörisk, nedbrytbarhet och bioackumulation redovisas under” Läs mer>>” och visar även hur beräkningar gjorts. Denna nivå vänder sig främst till experter och miljöspecialister.

Läs gärna mer på www.fass.se/miljö

Publiceringsdatum: 2016-06-14

Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Kvetiapin

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

Läs mer

Detaljerad miljöinformation

PEC/PNEC = 5.64 x 10^-³ μg/L /10.0 μg/L = 5.64 x 10^-4

PEC/PNEC ≤ 0.1

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 2016, 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)

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

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

A = 37.6 kg

R = 0

PEC = 1.5 * 10^-6 * 37.6 * (100-0) = 5.64 x 10^-³ μg/L

Metabolism

After oral administration, quetiapine is eliminated almost completely by metabolism, as < 5% of the excreted dose can be recovered in urine and faeces as the parent compound (quetiapine). Approximately 73% of the dose is excreted as metabolites in urine and 21% is excreted in faeces. (Ref. 1)

Ecotoxicity data

Aquatic Toxicity Data

Endpoint	Species	Common Name	Method	Time	Result	Reference
NOEC - Based on Largest Specific Growth Rates	Microcystis aeruginosa	Cyanobacterium (Blue-Green Alga)	US FDA Technical Assistance Document 4.01	21 d	32 mg/L ^{Note 1}	2
LOEC - Based on Largest Specific Growth Rates	Microcystis aeruginosa	Cyanobacterium (Blue-Green Alga)	US FDA Technical Assistance Document 4.01	21 d	64 mg/L ^{Note 1}
NOEC - Based on Maximum Standing Crops	Microcystis aeruginosa	Cyanobacterium (Blue-Green Alga)	US FDA Technical Assistance Document 4.01	21 d	4.0 mg/L ^{Note 1}
LOEC - Based on Maximum Standing Crops	Microcystis aeruginosa	Cyanobacterium (Blue-Green Alga)	US FDA Technical Assistance Document 4.01	21 d	8.0 mg/L ^{Note 1}
EC50 - Based on Largest Specific Growth Rates	Pseudokirchneriella subcapitata (formerly known as Selenastrumcapricornutum)	Green Alga	US FDA Technical Assistance Document 4.01	96 h	8.03 mg/L ^{Note 1}	3
EC50 - Based on Maximum Standing Crop	Pseudokirchneriella subcapitata (formerly known as Selenastrumcapricornutum)	Green Alga	US FDA Technical Assistance Document 4.01	96 h	3.59 mg/L ^{Note 1}
NOEC - Based on Largest Specific Growth Rates	Pseudokirchneriella subcapitata (formerly known as Selenastrum capricornutum)	Green Alga	US FDA Technical Assistance Document 4.01	14 d	2.5 mg/L ^{Note 1}
LOEC - Based on Largest Specific Growth Rates	Pseudokirchneriella subcapitata (formerly known as Selenastrum capricornutum)	Green Alga	US FDA Technical Assistance Document 4.01	14 d	5.0 mg/L ^{Note 1}
NOEC - Based on Maximum Standing Crops	Pseudokirchneriella subcapitata (formerly known as Selenastrum capricornutum)	Green Alga	US FDA Technical Assistance Document 4.01	14 d	2.5 mg/L ^{Note 1}
LOEC - Based on Maximum Standing Crops	Pseudokirchneriella subcapitata (formerly known as Selenastrum capricornutum)	Green Alga	US FDA Technical Assistance Document 4.01	14 d	5.0 mg/L ^{Note 1}
LC50	Daphnia magna	Giant Water Flea	US FDA Technical Assistance Document 4.09	21 d	> 32 mg/L ^{Note 1}	4
NOEC - Based on Reproduction & Length	Daphnia magna	Giant Water Flea	US FDA Technical Assistance Document 4.09	21 d	18 mg/L ^{Note 1}
LOEC - Based on Reproduction & Length	Daphnia magna	Giant Water Flea	US FDA Technical Assistance Document 4.09	21 d	32 mg/L ^{Note 1}
EC50 - Based on Emergence	Chironomus riparius	Midge	OECD 218	28 d	465 mg/kg dry sediment	5
NOEC - Based on Emergence	Chironomus riparius	Midge	OECD 218	28 d	125 mg/kg dry sediment
LOEC - Based on Emergence	Chironomus riparius	Midge	OECD 218	28 d	250 mg/kg dry sediment
LC50	Lepomis macrochirus	Bluegill Sunfish	US FDA Technical Assistance Document 4.11	96 h	19.3 mg/L ^{Note 1}	6
NOEC - Based on Symptoms of Toxicity	Lepomis macrochirus	Bluegill Sunfish	US FDA Technical Assistance Document 4.11	96 h	1.8 mg/L ^{Note 1}	6
LC50	Oncorhynchus mykiss	Rainbow Trout	US FDA Technical Assistance Document 4.11	96 h	22.0 mg/L ^{Note 1}	7
NOEC - Based on Symptoms of Toxicity	Oncorhynchus mykiss	Rainbow Trout	US FDA Technical Assistance Document 4.11	96 h	1.0 mg/L ^{Note 1}	7
NOEC - Based on Overall Endpoints ^{Note 2}	Pimephales promelas	Fathead Minnow	OECD 210	32 d	0.1 mg/L ^Note 1	8
LOEC - Based on Overall Endpoints ^{Note 2}	Pimephales promelas	Fathead Minnow	OECD 210	32 d	0.32 mg/L ^Note 1	8
EC50 - Based on Respiration Inhibition	-	-	OECD 209	3 h	>100 mg/L ^{Note 3}	9

Note 1: Concentrations were confirmed by analysis, and results expressed as nominal.

Note 2: The relevant endpoints measured were hatch, survival, length, wet and dry weight.

Note 3: Results are expressed as nominal concentrations.

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. 8).

PNEC = 100 µg /L/10 = 10 µg/L

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 5.64 x 10^-³ μg/L /10.0 μg/L = 5.64 x 10^-4

PEC/PNEC ≤ 0.1 which justifies the phrase

“Use of Quetiapin has been considered to result in insignificant environmental risk.”

In Swedish: “ Användning av Quetiapin har bedömts medföra försumbar risk för miljöpåverkan.”.

Environmental Fate Data


Endpoint	Method	Test Substance Concentration	Time	Result	Reference
Percentage Aerobic Biodegradation	OECD 301F	100 mg/L	28 d	0 % ThOD	10
Percentage Carbon Removal	OECD 301F	100 mg/L	28 d	10 %
Percentage Compound Removal	OECD 301F	100 mg/L	28 d	24 %
Percentage Anaerobic Biodegradation	DoE Modified According to ISO/CD 11734	50 & 100 mg Carbon/L	57 d	0 %	11
Percentage Compound Removal	DoE Modified According to ISO/CD 11734	50 & 100 mg Carbon/L	57 d	52 %	11
Dissipation Half-life	OECD 308	-	-	T_1/2= 5.2 d (in aqueous phase over high organic matter sediment)	12
Dissipation Half-life	OECD 308	-	-	T_1/2 = 18 d (in aqueous phase over low organic matter sediment)	12
Percentage Hydrolysis	US FDA Technical Assistance Document 3.09	-	5 d	< 10 % @ pH 5,7, & 9, 50C	13
Hydrolysis Half-life	US FDA Technical Assistance Document 3.09	-	-	≥ 1 yr @ 25C	13
Partition Coefficient Octanol Water	FDA Technical Assistance Handbook 3.02	-	-	LogP = 0.5	14
Partition Coefficient Octanol Water (Buffer)	FDA Technical Assistance Handbook 3.02	-	-	LogDow = 1.4 @ pH 5
Partition Coefficient Octanol Water (Buffer)	FDA Technical Assistance Handbook 3.02	-	-	LogDow = 2.7 @ pH 7
Partition Coefficient Octanol Water (Buffer)	FDA Technical Assistance Handbook 3.02	-	-	LogDow = 2.6 @ pH 9

Biodegradation

Aerobic biodegradation (OECD 301F) (ref. 10)

A ready biodegradation test of quetiapine fumarate was undertaken by using aerobic microorganisms from a sewage treatment works to investigate their potential to readily degrade the substance. The test ended after 28 days. The results showed that quetiapine fumarate is not readily biodegradable (BOD28/ThOD <0.6).

Anaerobic degradation (UK Department of the Environment ISO/CD 11734) (Ref. 11)

Primary anaerobic digested sludge was obtained from a sewage treatment works, to determine the anaerobic biodegradability of quetiapine fumarate. The day 57 results show that quetiapine, in the presence of anaerobic slugde remains only to 48 %, and to 81 % in absence of anaerobic sludge. Some degree of elimination was observed, probably attributable to the adsorption processes. The conclusion is that quetiapine fumarate is not anaerobically biodegradable under the conditions of the test.

Aerobic transformation in aquatic sediment systems

The degradation of quetiapine fumarate in aquatic sediment systems was assessed according to the OECD 308 Test Guideline (Ref. 12). Two different sediments were used, one with high and one with low organic matter content over the 100 d test period.

Dissipation half-life = 5.2 days in water (sediment with high organic matter)

Dissipation half-life = 18 days in water (sediment with low organic matter)

In conclusion, in both the high and low organic matter test vessels, quetiapine fumarate was rapidly dissipated from the water phase. In the sediment there was evidence to show that quetiapine fumarate was degraded, but there was insufficient analytical data to quantify the rate. Overall, the evidence from this study suggests that quetiapine fumarate will not be persistent in the environment.

Based on the information from all three studies above, the statement ‘The medicine is slowly degraded in the environment’ is justified under the heading ‘Degradation’.

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

Bioaccumulation

Since Log P < 4 at pH 7, the substance has been assigned the phrase: ‘Quetiapin has low potential for bioaccumulation’.

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

Physical Chemistry Data


Endpoint	Method	Test Conditions	Result	Reference
Solubility Water	US FDA Technical Assistance Handbook 3.01	16 d @ pH 5	10800 mg/L	15
Solubility Water	US FDA Technical Assistance Handbook 3.01	20 d @ pH 7	1600 mg/L
Solubility Water	US FDA Technical Assistance Handbook 3.01	6 d @ pH 9	360 mg/L
Dissociation Constant	Not-specified	-	pKa = 6.83	16
Dissociation Constant	Not-specified	-	pKa = 3.32	16
Sewage Adsorption Coefficient	OPPTS 835.1110	0.2 mg/L	Kd = 335 Koc = 905 L/Kg*	17
Soil Adsorption Coefficient	US FDA Technical Assistance Document 3.08	25 mg/L	Koc = 220000 in Nebo Soil	18
Soil Adsorption Coefficient	US FDA Technical Assistance Document 3.08	25 mg/L	Koc = 1400 in Kenny Hill Soil
Soil Adsorption Coefficient	US FDA Technical Assistance Document 3.08	25 mg/L	Koc = 8000 in East Jubilee Soil
Soil Adsorption Coefficient	US FDA Technical Assistance Document 3.08	25 mg/L	Kd = 3633 in Nebo Soil
Soil Adsorption Coefficient	US FDA Technical Assistance Document 3.08	25 mg/L	Kd = 45 in Kenny Hill Soil
Soil Adsorption Coefficient	US FDA Technical Assistance Document 3.08	25 mg/L	Kd = 177 in East Jubilee Soil

^* Calculated K_oc = K_d(ads) / 0.37

From the results on the three soils tested, it is evident that the Kd may vary in different soils. However, the data suggests that quetiapine fumarate will be essentially immobile.

The Kd values are not proportional to the carbon content, so the Koc is not likely to be a reliable predictor of adsorption to soil. It is more likely that the adsorption is dependent on pH, with higher adsorption in more acidic soils. There is also evidence to suggest that the adsorption of quetiapine fumarate is irreversible, especially in more acidic soils.

References

Investigator’s Brochure Seroquel (Quetiapine fumarate; ICI 204,636 fumarate). AstraZeneca. 10th edition, September 2005.
Seroquel: Toxicity to the blue-green alga Microcystis aeruginosa. BL5018/B. Brixham Environmental Laboratory, Brixham, UK. February 1994.
Seroquel: Toxicity to the green alga Selenastrum capricornutum. BL5017/B. Brixham Environmental Laboratory, Brixham, UK. February 1994.
Seroquel: Chronic toxicity to Daphnia magna. BL5232/B. Brixham Environmental Laboratory, Brixham, UK. September 1994.
Quetiapine fumarate Toxicity to the sediment-dwelling phase of the midge

Chironomus riparius. Report No. VKS0391/073509. Sponsors reference number: 06-0052/A. Huntingdon Life Sciences Ltd. UK. December 2007.
Seroquel: Acute toxicity to bluegill sunfish Lepomis macrochirus. BL5085/B. Brixham Environmental Laboratory, Brixham, UK. February 1994.
Seroquel: Acute toxicity to rainbow trout Oncorhynchus mykiss. BL5084/B. Brixham Environmental Laboratory, Brixham, UK. February 1994.
Quetiapine fumarate: Determination of effects on the early-life stage of the fathead minnow (Pimephales promelas). BL8351/B. Brixham Environmental Laboratory, Brixham, UK. August 2006.
Quetiapine fumarate: Effect on the respiration rate of activated sludge. Report No. BL8333/B. Brixham Environmental Laboratory, Brixham, UK. June 2006.
Seroquel: Determination of 28 day ready biodegradability. Report No. BL5078/B. Brixham Environmental Laboratory, Brixham, UK. February 1994.
Seroquel: Determination of anaerobic biodegradability. Report No. BL5077/B. Brixham Environmental Laboratory, Brixham, UK. February 1994.
Quetiapine fumarate: Aerobic transformation in aquatic sediment systems. BL8364/B. Brixham Environmental Laboratory, Brixham, UK. August 2007.
Data generated in the US to support the environmental assessment report for ICI 204,636. Pharmaceutical research & development Report no. SP2900/B. BD4185 Zeneca Pharmaceuticals Group, Wilmington, USA. 29 March 1995.
ICI 204,636 log partition coefficient measurements in partial fulfillment of FDA

environmental assessment requirements. Pharmaceutical research & development Report No. SP3011/B. BD4119. Zeneca Pharmaceuticals, Wilmington, USA. 3 October 1995.
ICI 204,636 solubility measurements in partial fulfillment of FDA environmental assessment requirements. Pharmaceutical research & development report no. SP3010/B. BD4118. Zeneca Pharmaceuticals, Wilmington, USA. 22 September 1995.
Clinical, S1-03, General Properties, Quetiapine, ZD5077. Report no. BD4184
Quetiapine fumarate: Adsorption and desorption to sludge. Report No. BL8343/B. Brixham Environmental Laboratory, Brixham, UK. August 2006.
Seroquel: Soil sorption and adsorption. Report no. BL5062/B. Brixham Environmental Laboratory, Brixham, UK. February 1994.

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Miljöpåverkan (Läs mer om miljöpåverkan)

Kvetiapin

Detaljerad miljöinformation