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Juluca

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 (i bokstavsordning):
ATC-kod: J05AR21
Läkemedel från GlaxoSmithKline omfattas av Läkemedelsförsäkringen.
Läkemedlet distribueras också av företag som inte omfattas av Läkemedelsförsäkringen, se Förpackningar.
  • Vad är miljöinformation?

Miljöinformation

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

PEC = 1.08 x 10-2 μg/L

Where:

A = 78.90 kg (total sold amount API free base in Sweden year 2022, data from IQVIA). Total volume of Dolutegravir sodium 83.05 = 78.90 Dolutegravir free base. Total Dolutegravir = 78.90.


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 = 10 *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 = 1.08 x 10-2/9.5 = 1.14 x 10-3, 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).


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.

Rilpivirin

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

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

PEC = 8.25 x 10-4 μg/L

Where:


A = 6.02 kg (total sold amount API in Sweden year 2022, data from IQVIA). Total volume of Rilpivirine sodium 6.49 = 5.90 sodium free base. Total Rilpivirine = 5.90 + 0.12 = 6.02.


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 = 10 *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):

NOEC 96h (growth ≥ 22 μg/L (OECD 201) (Reference 3)


Water flea (Daphnia magna):

Acute toxicity

No data


Water flea (Daphnia magna):

Chronic toxicity

NOEC 21 days (reproduction) = 32 μg/L (OECD 211) (Reference 4).


Rainbow Trout:

Acute toxicity

No data


Zebra Fish (Brachydanio rerio)

Chronic toxicity

NOEC 28 days (survival) = 20 μg/L (OECD 210) (Reference 5)


Other ecotoxicity data:


Chironomid (Chironomus riparius)

NOEC 28 days (reproduction) = 100,000 μg/kg (OECD 218) (Reference 6)


Microorganisms in activated sludge

EC50 3 hours (Inhibition) > 1,000,000 μg/L (OECD 209) (Reference 7)


Terrestrial toxicity


Earthworm (Eisenia foetida)

LC50 14 days (mortality) > 1,000,000 μg/kg (OECD 207) (Reference 8)

NOEC = 1,000,000 μg/kg


Collembola (Folsomia candida)

NOEC 28 days (reproduction) ≥ 1,000,000 μg/kg (ISO 11267:1999) (Reference 9)


Soil microorganisms

NOEC 28 days (nitrification) > 100,000 μg/kg (OECD 216) (Reference 10)


Plants

NOEC 15-17 days (emergence) = 1,000,000 μg/kg (OECD208) (Reference 11)


PNEC = 20/10 = 2 μg/L

PNEC (μg/L) = lowest NOEC/10, where 10 is the assessment factor applied for three long-term NOECs. NOEC for zebra fish (= 20 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 = 8.25 x 10-4/2 = 4.13 x 10-4, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of rilpivirine has been considered to result in insignificant environmental risk.”


Degradation


Biotic degradation

Ready degradability:

No data


Inherent degradability:

No data


Simulation studies:

Water-sediment study:

Total System: 50% (DT50) dissipation in > 307 - 321 days (OECD 308) (Reference 12)

Non-extractable residue = 12.70% - 14.40%


(Organic matter fractionation of the bound residues showed that the majority of the radioactivity was associated with the insoluble fraction (humin)).


Extraction with acetonitrile/water (4/1; v/v), up to three times (from the start to day 28); acetone/water (4/1; v/v), up to three times (days 58 to 120). Reflux extraction with 0.1 M HCl / acetonitrile (1:1; v/v) at day 120.


Soil Degradation:

Aerobic transformation in soil (OECD 307) (Reference 13)


Degradation rates

DT50 = 71 - 232 days

DT90 > 365 days

Non-extractable residue = 12.5% – 15.1%


(Organic matter fractionation of the bound residues showed that the majority of the radioactivity was associated with the insoluble fraction (humin).


Abiotic degradation


Hydrolysis:

No data


Photolysis:

No data


Justification of chosen degradation phrase:

Rilpivirine is not readily biodegradable nor inherently biodegradable. This substance is predicted to degrade in water sediment systems ≥ 120 days. Non-extractable residues represent 12%-14% of the total material. The phrase “Rilpivirine is potentially persistent” is thus chosen.


Bioaccumulation


Partitioning coefficient:

Log Dow = 4.66 (OECD 107) (Reference 14)


Bioconcentration:

BCF = 125.60 – 137.20 (OECD 305) (Reference 15)


Justification of chosen bioaccumulation phrase:

Since BCF is < 500, the substance has low potential for bioaccumulation.


Excretion (metabolism)


In vitro experiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system. The terminal elimination half-life of rilpivirine is approximately 45 hours. After single dose oral administration of 14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in faeces and urine, respectively. In faeces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (< 1% of dose) were detected in urine. (Reference 2).


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 Juluca 50 mg/25 mg film-coated tablets. ViiV Healthcare, September 2020.

  3. Höger S.; TMC278 (R278474) – Toxicity to Scenedesmus subspicatus in a 72-hour Algal Growth Inhibition Test; Harlan Laboratories Study B79356; TMC278-TiDP6-NC322; December 10, 2008.

  4. Höger S.; TMC278 (R278474) – Effect on Survival and Reproduction of Daphnia magna in a Semi-Static Test over Three Weeks; Harlan Laboratories Study B79378; TMC278-TiDP6-NC323; December 10, 2008.

  5. Peither A.; TMC278 (R278474) – Toxic Effects to Zebra Fish (Brachydanio rerio) in an Early Life Stage Toxicity Test; Harlan Laboratories Study B79391; TMC278-TiDP6-NC324; January 09, 2009.

  6. Höger S.; TMC278 (R278474) – Effects in the Development of Sediment Dwelling Larvae of Chironumus riparius in Water-Sediments with Spiked Sediment; Harlan Laboratories Study C83838; 1646_03730; August 17, 2010.

  7. Seyfried B.; TMC278 (R278474) – Toxicity to Activated Sludge in a Respiration Inhibition Test; RCC Study Number B79345; TMC278-TiDP6-NC321; October 20, 2008.

  8. Schmidt T., Acute toxicity of TMC278 (R278474) to the Earthworm Eisenia fetida in a 14-Day Test; Harlan Laboratories Study C29884; TMC278-TiDP6-NC350; December 21, 2009.

  9. Schmidt T., Effects of TMC278 (R278474) on Reproduction of the Springtail Folsomia candida (Collembola); Harlan Laboratories Study C29930; TMC278-TiDP6-NC352; December 11, 2009.

  10. Weber B., Determination of Effects of TMC278 (R278474) on Soil Microflora Activity; Harlan Laboratories Study C29917; TMC278-TiDP6-NC351; September 30, 2009.

  11. Taylor K., TMC278 – Terrestrial (non-target) plant growth test seedling emergence; Huntingdon Life Sciences Study No. TMR0005; TMC278-TiDP6-NC353; January 22, 2010.

  12. Fahrbach M.; 14C-TMC278 (R278474) – Route and Rate of Degradation in Aerobic Aquatic Sediment Systems; Harlan Laboratories Study B79323; TMC278-TiDP6-NC319; September 30, 2009.

  13. Fahrbach M., Degradation and Metabolism of 14C-TMC278 (R278474) in Three Soils Incubated under Aerobic Conditions; Harlan Laboratories Study C29974; TMC278-TiDP6-NC354; December 17, 2009.

  14. Weissenfeld M.; TMC278: Slow Stirring Method for the Determination of the Partition Coefficient octanol/water; Harlan Laboratories Study D29255; 1646_03711; July 19, 2011.

  15. Burri R.; 14C-TMC278 – Bioconcentration: Flow-Through Fish Test in the Rainbow Trout (Oncorhynchus mykiss); Harlan Laboratories Study B79416; TMC278-TiDP6-NC325; February 20, 2009.