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Novartis

Inhalationspulver, hård kapsel 85 mikrogram/43 mikrogram
(Kapslar med transparent, gul överdel och naturell, transparent underdel innehållande ett vitt till nästan vitt pulver, med produktkoden ”IGP110.50” tryckt med blått under två blå streck på underdelen och företagets logotyp tryckt med svart på överdelen.)

Medel vid obstruktiva luftvägssjukdomar, adrenergika i kombination med antikolinergika

ATC-kod: R03AL04
Läkemedel från Novartis omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Glykopyrron

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


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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 * 0.3398 kg (100-R)

PEC = 0.000051 μg/L

Where:

A = 0.3398 kg (total sold amount API in Sweden year 2018, data from IQVIA).

R = 0 % removal rate (due to 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) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Pseudokirchneriella subcapitata) (OECD 201) (Harlan Laboratories Study C13436):

ErC50 72 h (growth rate) > 100 mg/L

NOEC = 7.5 mg/L


Crustacean (Daphnia magna):

Acute toxicity

EC50 48 h (immobilisation) = 33.0 mg/L (OECD 202) (Harlan Laboratories Study C13425)


Fish (Danio rerio):

Acute toxicity

LC50 96 h (lethality) > 100 mg/L (OECD 203) (Harlan Laboratories Study C10040)


PNEC = 33.0 μg/L


PNEC (μg/L) = lowest EC50/1000, where 1000 is the assessment factor used if acute toxicity data for three trophic levels is available. EC50 for Daphnia magna 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 = 0.000051 μg/L / 33.0 µg/L = 0.0000015, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of glycopyrronium bromide has been considered to result in insignificant environmental risk."


Degradation

Biotic degradation

Ready degradability:

0 % degradation in 28 days (OECD 301A) (Harlan Laboratories Study C13447)

Justification of chosen degradation phrase:

Glycopyrronium bromide is not readily biodegradable. The phrase “Glycopyrronium bromide is potentially persistent” is thus chosen.


Bioaccumulation

Partitioning coefficient:

Log Pow = -2.1 (OECD 107). (Harlan Laboratories Study C13403)

Justification of chosen bioaccumulation phrase:

Since log P < 4, glycopyrronium bromide has low potential for bioaccumulation.


Excretion (metabolism)

Following inhalation of single and repeated once-daily doses between 50 and 200 μg glycopyrronium by healthy volunteers and patients with COPD mean renal clearance of glycopyrronium was in the range of 17.4 and 24.4 L/h. Active tubular secretion contributes to the renal elimination of glycopyrronium. Up to 20% of the dose was found in urine as parent drug. (Novartis Core Data Sheet, 2016)


PBT/vPvB assessment

According to the established EU criteria, glycopyrronium bromide cannot be regarded as a PBT/vPvB substance, as it has low potential for bioaccumulation and is not toxic.


References


  • ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment. http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm 

  • Harlan Laboratories Study C13436. Toxicity of NVA237 A5 to Pseudokirchneriella subcapitata in a 72-hour algal growth inhibition test. Final report: 28 January 2009.

  • Harlan Laboratories Study C13425. Acute toxicity of NVA237 A5 to Daphnia magna in a 48-hour immobilization test. Final report: 28 January 2009.

  • Harlan Laboratories Study C10040. Acute toxicity of NVA237 A5 to zebra fish (Brachydanio rerio) in a 96-hour test. Final report: 28 January 2009.

  • Harlan Laboratories Study C13447. Ready biodegradability of NVA237 A5 in a DOC Die-Away test. Final report: 09 February 2009.

  • Harlan Laboratories Study C13403. Determination of the water solubility and the partition coefficient (n-octanol/water). Final report: 15 June 2009.

  • Novartis Core Data Sheet, SEEBRI™ BREEZHALER® (Glycopyrronium bromide, NVA237), Version 2.1, 19 May 2016.

Indakaterol

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


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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) = 1.5 * 10-6 * A * (100-R) = 0.0000972 μg/L

Where:

A = 0.64805 kg indacaterol maleate (total sold amount API in Sweden year 2018, data from IQVIA).

R = 0 % removal rate.

P = number of inhabitants in Sweden = 9 *106 

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default) (ECHA 2008)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default) (ECHA 2008)


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Desmodesmus subspicatus) (92/69/EC (L383) C.3) (CETA Study Nr.: 37/02/23, Report Nr. 1803/L):

EC50 72 h (growth rate) > 100.0 mg/L


Crustacean (Daphnia magna, waterflea):

Acute toxicity

EC50 48 h (immobilisation) > 100.0 mg/L (92/69/EEC (L.383) C.2) (CETA Study Nr.: 1/03/22, Report Nr. 2066/L)


Fish:

Acute toxicity (Piecilia reticulata, guppy)

LC50 96 h (mortality) > 100.0 mg/L (OECD203) (CETA Study Nr.: 37/02/21, Report Nr. 1807/L)


Other ecotoxicity data:

Bacterial respiration inhibition

EC50 3 h > 300.0 mg/L (activated sludge respiration inhibition) (87/302/EEC Part C) (ARC Study No.: NOV30)


PNEC derivation:

PNEC = 100.0 μg/L

PNEC (μg/L) = lowest EC50/1000, where 1000 is the assessment factor used, based on the fact that three acute toxicity studies are available, covering three trophic levels. An EC50 of 100 mg/L is used for this calculation, based on the fact that no acute toxic effects were observed in fish, Daphnia and algae at the highest tested concentration of 100.0 mg/L.

Environmental risk classification (PEC/PNEC ratio)

PEC/PNEC = 0.0000972 μg/L / 100.0 μg/L = 0.000000972, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase "Use of indacaterol has been considered to result in insignificant environmental risk."


Degradation 

Biotic degradation

Ready degradability:

0 % degradation in 28 days, not readily biodegradable (OECD301D). (CETA Study Nr.: 37/02/25, Report Nr.: 1811/L)


Justification of chosen degradation phrase:

Indacaterol is not readily biodegradable. Therefore, the phrase “Indacaterol is potentially persistent” is chosen. 


Bioaccumulation

Partitioning coefficient:

Log P = -0.74 at 20.1°C (EC440/2008 A.8 8). (NOTOX Project 491643)

Justification of chosen bioaccumulation phrase:

Since log P < 4, indacaterol has low potential for bioaccumulation.

 

Excretion (metabolism)

In clinical studies which included urine collection, the amount of indacaterol excreted unchanged via urine was generally lower than 2% of the dose. In a human ADME study where indacaterol was given orally, the fecal route of excretion was dominant over the urinary route. Indacaterol was excreted into human feces primarily as unchanged parent drug (54% of the dose) and, to a lesser extent, hydroxylated indacaterol metabolites (23% of the dose). (Novartis Core Data Sheet Onbrez® Breezhaler®).


References

ECHA 2008, European Chemicals Agency. 2008 Guidance on information requirements and chemical safety assessment.http://guidance.echa.europa.eu/docs/guidance_document/information_requirements_en.htm


CETA Study Nr.:37/02/23, Report Nr. 1803/L. QAB149 Alga, growth inhibition test. Final report: 15.09.2004


Study No.: 1/03/22, Report No.: 2066/L. QAB149 Daphnia, acute immobilisation test. Final report: 15.09.2004


CETA Study Nr: 1807/L, Report Nr.: 37/02/21. QAB149 Fish, acute toxicity test. Final report: 15.09.2004


Study project Nr.: NOV30, Report No: ARC- -UL-0561. QAB149 Activated sludge respiration inhibition test. Final report: November 2002.


CETA Study Nr.: 37/02/25, Report Nr.: 1811/L. QAB149 Determination of ready biological degradability - closed bottle test. Final report:15.09.2004.


NOTOX Project 491643. Determination of physico-chemical properties of QAB149 DS / indacatarol maleate. Final report: 21.08.2009.


Novartis Core Data Sheet Onbrez® Breezhaler® and related products (indacaterol maleate). Version 2.1. 30. September 2013.