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GlaxoSmithKline

Filmdragerad tablett 50 mg/25 mg
(Rosa, ovala, bikonvexa tabletter, cirka 14 x 7 mm, präglade med ”SV J3T” på ena sidan.)

Virushämmande medel för systemiskt bruk, virushämmande medel mot hiv-infektioner, kombinationer.

Aktiva substanser:
ATC-kod: J05AR21
Utbytbarhet: Ej utbytbar
Läkemedel från GlaxoSmithKline omfattas av Läkemedelsförsäkringen.
Vad är viktig säkerhetsinformation?
2018-06-01: Viktig säkerhetsinformation
Neuralrörsdefekter rapporterade hos spädbarn vars mödrar exponerats för dolutegravir vid tidpunkten för befruktningen
  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Dolutegravir

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


Läs mer

Detaljerad miljöinformation

Detailed background information

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 = 3.63 x 10- 3 μg/L

Where:

A = 24.19 kg (total sold amount API in Sweden year 2015, data from IMS Health). Total volume of Dolutegravir sodium 25.4673 = 24.19 sodium free base. Total Dolutegravir = 24.19.

R = 0% removal rate (conservatively, it has been assumed there is no loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation)

P = number of inhabitants in Sweden = 9 *106

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

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


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies


Green Algae (Pseudokirchneriella subcapitata):

IC50 96h (biomass) = 233 μg/L (OECD 201) (Reference 5)

NOEC = 95 μg/L


Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) > 6,430 μg/L (OECD 202) (Reference 6)


Water flea (Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) = 834 μg/L (OECD 211) (Reference 7)


Rainbow Trout:

Acute toxicity

No data


Fathead minnow (Juvenile Pimephales promelas):

Chronic toxicity

NOEC 28 days (mortality) = 220 μg/L (OECD 210) (Reference 8)


Other ecotoxicity data:


Chironomid (Chironomus riparius)

NOEC 28 days (reproduction) = 858,000 μg/kg (OECD 218) (Reference 9)


Microorganisms in activated sludge

EC50 3 hours (Inhibition) = 24,000 μg/L (OECD 209) (Reference 3)


Terrestrial toxicity


Earthworm (Eisenia foetida)

LC50 14 days (mortality) > 1,000,000 μg/kg (OECD 207) (Reference 12)

NOEC = 1,000,000 μg/kg


Collembola (Folsomia candida)

NOEC 28 days (reproduction) = 29,000 μg/kg (ISO 11267:1999) (Reference 13)


Soil microorganisms

NOEC = 984,000 μg/kg (OECD 216) (Reference 14)


Onion (Allium cepa), Pea (Pisum sativum)

NOEC 23 days (emergence) = 12,000 μg/kg (OECD208) (Reference 15)


PNEC = 95/10 = 9.50 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for green alga (= 95 ug/L) has been used for this calculation since it is the most sensitive of the three tested species.


Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 3.63 x 10- 3/9.5 = 3.82 x 10-4, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of dolutegravir has been considered to result in insignificant environmental risk.”


Degradation

Biotic degradation


Ready degradability:

No data


Inherent degradability:

0% degradation in 28 days (OECD 302B) (Reference 10)

18% primary degradation of parent in 28 days

This substance is not inherently biodegradable.


Simulation studies:


Water-sediment study:

50% (DT50) degradation in > 1,000 days (OECD 308) (Reference 11)

Non-extractable residue = 8.70% - 9.30%


Soil Degradation:

Aerobic transformation in soil (OECD 307) (Reference 16)


Degradation rates

DT50 = 1,000 days

DT90 = 1,000 days

Non-extractable residue < 10%


Abiotic degradation


Hydrolysis:

No data


Photolysis:

No data


Justification of chosen degradation phrase:

Dolutegravir is not readily biodegradable nor inherently biodegradable. This substance is predicted to degrade in water sediment systems ≥ 120 days. Non-extractable residues represent < 10% of the total material. The phrase “Dolutegravir is potentially persistent” is thus chosen.


Bioaccumulation


Partitioning coefficient:

Log Dow < 1 at pH 7 (OECD 107) (Reference 4)

Log Dow at pH 5 = -2.28

Log Dow at pH 7 = -2.45

Log Dow at pH 9 = -3.21


Justification of chosen bioaccumulation phrase:


Since log Dow < 4, the substance has low potential for bioaccumulation.


Excretion (metabolism)

Dolutegravir is primarily metabolized through glucuronidation via UGT1A1 with a minor CYP3A component. Dolutegravir is the predominant circulating compound in plasma; renal elimination of unchanged active substance is low (< 1% of the dose). Fifty-three percent of total oral dose is excreted unchanged in the faeces. It is unknown if all or part of this is due to unabsorbed active substance or biliary excretion of the glucuronidate conjugate, which can be further degraded to form the parent compound in the gut lumen. Thirty-two percent of the total oral dose is excreted in the urine, represented by ether glucuronide of dolutegravir (18.9% of total dose), N-dealkylation metabolite (3.6% of total dose), and a metabolite formed by oxidation at the benzylic carbon (3.0% of total dose) (Reference 2).


PBT/vPvB assessment

Dolutegravir does not fulfil the criteria for PBT and/or vBvP.

All three properties, i.e. ‘P’, ‘B’ and ‘T’ are required in order to classify a compound as PBT (Reference 1). Dolutegravir does not fulfil the criteria for PBT and/or vBvP based on log Dow < 4.


Please, also see Safety data sheets on http://www.msds-gsk.com/ExtMSDSlist.asp


References


  1. ECHA, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.

  2. Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics Tivicay (Dolutegravir sodium) 50mg film coated tablets. GlaxoSmithKline, January 2014.

  3. Graham R and Alderman D. GSK1349572: Activated Sludge Respiration Inhibition Test. Report No. 8236109. Covance Laboratories Limited, January 2010.

  4. Moseley RH. GSK1349572A: Determination of the n-octanol: water partition coefficient. Report No. 8240319. Covance Laboratories Limited, October 2011.

  5. Last G, Flenely A and Goodband T. GSK1349572A: Inhibition of Growth to the Alga Pseudokirchneriella subcapitata. Report No. 8240286. Covance Laboratories Limited, November 2012.

  6. Burke J and Scholey A. GSK1349572A: GSK 1349572A: Acute toxicity to Daphnia magna. Report No. 8204501. Covance Laboratories Limited, November 2010.

  7. Burke J. Chronic effects of GSK1349572A to Daphnia magna. Report No. 8236107. Covance Laboratories Limited, April 2012.

  8. Burke J, Jakes M and Goodband T. Fish Early Life Stage Test (Pimephales promelas) with GSK1349572A. Report No. 8240288. Smithers Viscient Limited, November 2012.

  9. Last G and Goodband T. GSK1349572A: Sediment-Water Chironomus riparius Toxicity Test using Spiked Sediment. Report No. 8252363. Smithers Viscient Limited, November 2012.

  10. Graham R and Alderman D. GSK1349572A: Assessment of Inherent Biodegradability by Measurement of Carbon Dioxide Evolution with Specific Analysis. Report No. 8204497. Covance Laboratories Limited, October 2010.

  11. Dixon K and Fletcher T. [14C]-GSK1349572A: Degradation in Water-Sediment Systems under Aerobic Conditions. Report No. 8240289. Smithers Viscient Limited, June 2012.

  12. Muddiman KJ. GSK1349572A: Acute toxicity to the earthworm Eisenia fetida. Report No. 8252367. Smithers Viscient Limited, July 2012.

  13. Muddiman KJ. GSK1349572A: Determination of the Effects on Reproduction of the Collembolan Folsomia candida. Report No. 8252368. Smithers Viscient Limited, November 2012.

  14. Schöbinger U. Effects of GSK1349572A on the Activity of the Soil Microflora - Nitrogen Transformation Test. Report No. S11-03815. Eurofins Agricultural Services, November 2012.

  15. Muddiman KJ. GSK1349572A: Seedling Emergence and GrowthTest. Report No. 8252366. Smithers Viscient Limited, November 2012.

  16. Dixon K and Fletcher T. [14C]-GSK1349572A: Aerobic Soil Metabolism and Degradation. Report No. 8252364. Smithers Viscient Limited, September 2012.

Miljöinformationen för rilpivirin är framtagen av företaget Janssen för EDURANT

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


Läs mer

Detaljerad miljöinformation

1. PREDICTED ENVIRONMENTAL CONCENTRATION (PEC):

The Predicted Environmental Concentration is calculated according to the following formula:

PEC (µg/L)

=

A x 109 x (100 - R) / 365 x P x V x D x 100

Where:

A (kg/year)

=

6.863175 kg (total sold amount API in the most recent sales data for Sweden (2016) was distributed by QuintilesIMS in summer 2017)

R (%)

=

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

 

=

0% (worst-case scenario: no removal)

P

=

number of inhabitants in Sweden (9 x 106)

V (L/day)

=

volume of waste water per capita and day

 

=

200 (ECHA default) [1]

D

=

factor for dilution of waste water by surface water flow

 

=

10 (ECHA default) [1]

PEC (µg/L)

=

0.001044623 µg/L

2. PREDICTED NO EFFECT CONCENTRATION (PNEC)

2.1 Ecotoxicological studies

2.1.1 Algae

Algal growth inhibition test with the green alga (Scenedesmus subspicatus) (OECD 201) [2]:

EγC50 72 h (yield) =

> 0.022 mg/L

NOECγ (yield) =

> 0.022 mg/L

ErC50 72 h (growth) =

> 0.022 mg/L

NOECr (growth) =

> 0.022 mg/L


The 72-hour NOEC was determined to be > 22 μg/L, since up to and including this test concentration the growth rate and yield of the algae after 72 hours were not significantly lower than in the solvent control.


2.1.2 Crustacean


Acute

No data available


Chronic

Reproduction test with water-flea (Daphnia Magna) (OECD 211) [3]:

NOEC 21 days = > 0.032 mg/L


Rilpivirine had no toxic effects on survival and reproduction of Daphnia magna after the exposure period of 21 days up to the highest test concentration.


2.1.3 Fish


Acute

No data available


Chronic

Fish early life stage test with Zebra fish (Brachydanio rerio) (OECD 210) [4]:

NOEC 28 days = > 0.020 mg/L


The NOEC was determined to be the test concentration of 20 μg/L, since up to and including this test concentration no toxic effect was observed on the eggs, larvae or fish. The overall LOEC was determined to be >20 μg/L. Thus Rilpivirine had no toxic effects on the early life stages of zebra fish up to its water solubility under the conditions of the test.


2.14 Other ecotoxicity data

Activated sludge respiration inhibition test (OECD 209) [5]:


EC50 3h = could not be calculated but were clearly higher than 1000 mg/L

NOEC 3h = > 1000 mg/L


Rilpivirine had no significant inhibitory effect (≤15%) on the respiration rate of activated sludge after the incubation period of 3 hours at the limit test concentration of 1000 mg/L.


2.2 Calculation of Predicted No Effect Concentration (PNEC)

PNEC (µg/l) = lowest NOEC/10, where 10 is the assessment factor used. NOEC for the species Zebra fish (Brachydanio rerio) of > 20 µg/L has been used for this calculation since it is the most sensitive of the three tested species.


PNEC = 20 µg/L / 10 = 2 µg/L


2.3 Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.001044623 / 2 = 0.000522312 i.e. PEC/PNEC ≤ 0.1


Conclusion for environmental risk:

Use of Rilpivirine has been considered to result in insignificant environmental risk.


3. DEGREDATION

3.1 Biotic degradation

3.1.1 Ready biodegradation

No data available


3.1.2 Simulation study: Aerobic degradation in aquatic sediment systems:

Rilpivirine was investigated for its aerobic degradation in a 100-day aquatic sediment test, according to OECD 308 [8]:


The route and rate of degradation of Rilpivirine in two aquatic systems (river and pond) under aerobic conditions were investigated at 20 °C in the dark.


The rates of dissipation (DT50, DT90) of Rilpivirine from the water phase and the entire system were calculated using first order kinetics and the Origin calculation software. All calculated DT50 and DT90 values are summarised in the following table:

Table

The majority of the radioactivity found in the sediments was extractable, with values up to 90.0% of applied radioactivity for the river and 89.7% for the pond system. Non-extractable residues accounted for up to 12.7% of applied radioactivity for the river and 14.4% for the pond system throughout the study. Organic matter fractionation of the bound residues showed that the majority of the radioactivity was associated with the insoluble fraction (humin).


Radioactive carbon dioxide increased slightly from day 28 onwards but not exceed a mean amount of 1.2% in both systems. No other organic volatile compounds were formed at any time point during the study (<0.1% of applied).


A few minor metabolites were formed in the sediments, but none individually exceeded 3% of the applied radioactivity in either aquatic system.


In aerobic aquatic systems, Rilpivirine rapidly dissipated from the water phase by adsorption to the sediment. Once in the sediment, Rilpivirine was only slowly degraded. Some 14CO2 production and the formation of bound residues were observed.


Conclusion for degradation:

Rilpivirine is potentially persistent.


4. BIOACCUMULATION

4.1 Partition coefficient octanol/water

The partition coefficient octanol/water was determined using guideline OECD 123. [6]

Log Pow= 4.66 at 25°C using the slow stirring method.

pH = min/6.98 – max 8.76


4.2 Bioconcentration

The bioconcentration and depuration characteristics of Rilpivirine in the Rainbow trout (Oncorhynchus mykiss) in a flow through system were examined according to OECD 305 [7].


BCFlow dose = 137.2

BCFhigh dose = 125.6

The BCF –values indicate that Rilpivirine did not bioaccumulate in the rainbow trout.


Conclusion for bioaccumulation:

Rilpivirine has low potential for bioaccumulation.


5. PBT-ASSESSMENT


PBT-criteria

Results for Rilpivirine

Persistence

Half-life in freshwater: DT50 > 40 days
Half-life in sediment: DT50 > 120 days

DT50 total system
- river 307 days
- pond 321 days

Bioaccumulation

BCF > 2000

BCFlow dose = 137.2

BCFhigh dose = 125.6

Toxicity

Chronic NOEC < 10 µg/L

NOEC algae = > 0.022 mg/L

NOEC daphnia = > 0.032 mg/L

NOEC fish = > 0,020 mg/l 

Conclusion for PBT-assessment:

Rilpivirine should not be regarded as PBT/vPvB substance.


6. 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. Höger S., TMC 278 (R278474): Toxicity to Scenedesmus subspicatus in a 72-Hour Algal Growth Inhibition Test (OECD 201); Harlan Laboratories Study B79356; JNJ Study RMD1020; December 10, 2008.

  3. Höger S., TMC 278 (R278474): Effect on Survival and Reproduction of Daphnia magna in a Semi-Static Test iver Three Weeks (OECD 211); Harlan Laboratories Study B79378; JNJ Study RMD1021; December 10, 2008.

  4. Peither A., TMC 278 (R278474): Toxic Effects to Zebra fish (Brachydanio rerio) in an Early Life Stage Toxicity Test (OECD 210); Harlan Laboratories Study B79391; JNJ Study RMD1022; January 9, 2009.

  5. Seyfried B., TMC 278 (R278474): Toxicity to Activated Sludge in a Respiration Inhibition Test (OECD 209); RCC Study Number B79345; JNJ Study RMD1019; October 20, 2008.

  6. Weissenfeld M., TMC278: Slow Stirring Method for the Determination of the Partition Coefficient (1-Octanol / Water) (OECD 123); Harlan Laboratories Study D29255; JNJ Study RMD1149; July 19, 2011.

  7. Burri R., Bioconcentration: flow-through fish test in the Rainbow trout (Oncorhynchus mykiss) (OECD 305); Harlan Laboratories Study B79413; JNJ Study RMD1023; February 20, 2009.

  8. Fahrbach M., Route and Rate of Degradation in Aerobic Aquatic Sediment Systems (OECD 308); Harlan Laboratories Study B79323; JNJ Study RMD1017; September 30, 2009.