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AstraZeneca

Filmdragerad tablett 500 mikrog
(Gul, 9 mm stor, D-formad filmdragerad tablett, med "D" präglat på ena sidan)

Övriga systemiska medel för obstruktiva lungsjukdomar

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ATC-kod: R03DX07
Läkemedel från AstraZeneca omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Roflumilast

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


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Detaljerad miljöinformation

PEC/PNEC = 0.0044 µg/L /0.084 µg/L = 0.052


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) = 1.5*10-6*A*(100-R)


Where:

A  (kg/year) = 29.0362 kg = total sold amount API in Sweden year 2015, data from IMS Health.

R  (%) = removal rate (due to loss by adsorption to sludge particles, by volatilisation, hydrolysis or biodegradation). R = 0, no data is available.

P  = number of inhabitants in Sweden =9*106

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

D  = factor for dilution of waste water by surface water flow = 10 (ECHA default) (Ref.1) (Note: The factor 109 converts the quantity used from kg to μg)


PEC = 1.5 * 10-6 * 29.0362 *(100-R) = 0.0044 µg/L


Metabolism and excretion

In a human pharmacokinetics study with radiolabelled roflumilast, total recovery of radioactivity amounted to 90 % of the dose, 70 % being excreted in urine and about 20 % in faeces (Ref 3). Roflumilast itself is not detectable in urine, and its active metabolite roflumilast N-oxide is detected only in small amounts (1%). Instead, 4 inactive metabolites, each about 10 – 15 % were found in urine. The origin of radioactivity in faeces was not investigated.


Ecotoxicity Data

Study Type

Method

Result

Reference

Toxicity to green algae, Desmodesmus subspicatus, growth inhibition test (Note 1)

OECD201

72 hour NOEC (growth rate) =0.024 mg/l

72 hour LOEC (growth rate) =0.043 mg/l

72 hour EC50 (growth rate) = 0.084 mg/l

72 hour NOEC (biomass) =0.024 mg/l

72 hour LOEC (biomass) =0.043 mg/l

72 hour EC50 (biomass) =0.043 mg/l

4

Acute toxicity to Daphnia magna (Note 1)

OECD202

48 hour EC50 (immobility) > 0.430 mg/L

48 hour NOEC (immobility) = 0.430 mg/L 

5

Acute toxicity to Zebra fish, Brachydanio rerio (Note 1)

OECD203

96 hour LC50 (mortality) > 0.295

96 hour NOEC (mortality) = 0.295

6

NOEC No Observed Effect Concentration

LOEC Lowest Observed Effect Concentration

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

LC50 the concentration of the test substance that results in a 50% mortality


Predicted No Effect Concentration (PNEC)


Short-term tests have been undertaken for species from three trophic levels. Therefore, the PNEC is based on the EC50 value for growth rate inhibition for green algae, 0.084 mg/L (equivalent to 84 µg/L), and an assessment factor of 1000 is applied, in accordance with ECHA guidance (Ref.2)


PNEC = 84 µg/L /1000 = 0.084 µg/L


Environmental Risk Classification (PEC/PNEC ratio)


PEC/PNEC = 0.0044 µg/L /0.084 µg/L


PEC/PNEC = 0.052


PEC/PNEC ≤ 0.1 which justifies the phrase: “Use of Roflumilast has been considered to result in insignificant environmental risk.”


In Swedish: Användning av Roflumilast har bedömts medföra försumbar risk för miljöpåverkan.


Environmental Fate Data

Study Type

Method

Result

Reference

Determination of ready biodegradability

OECD 301D

Degradation after 21 days <11.6%

Not readily biodegradable

7

Biodegradation

The potential for Roflumilast to rapidly biodegrade during sewage treatment was investigated in an OECD 301D “Closed bottle test”; Roflumilast cannot be considered readily biodegradable. Due to lack of data, the phrase ‘Roflumilast is potentially persistent’ is assigned.

In Swedish: Roflumilast är potentiellt persistent.


 Physical Chemistry Data

Study Type

Method

Result

Reference

Disassociation constant

Not stated

pKa = 8.74.

8

Solubility

Not stated

Water (21 – 22°C) 0.52 – 0.56 mg/L

8

Octanol-water partition coefficient

Not stated

logP at pH 7.4 = 3.99.

8


Roflumilast is a weak acid with a pKa of 8.74, as such aqueous solubility increases from about 0.8 mg/L under neutral conditions to about 35.8 mg/L at pH 10. Based on the octanol-water partition coefficient; Roflumilast has a low potential for bioaccumulation

In Swedish: Roflumilast har låg potential att bioackumulera.


References

  1. [ECHA] European Chemicals Agency. 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

  2. ECHA, European Chemicals Agency. May 2008. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment

    http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf

  3. 223/2001 A study to investigate the distribution, metabolism and excretion (mass balance) and pharmacokinetics of [14C]-B9302-107 after oral and intravenous administration to six healthy male volunteers. Atlanta Pharma 2001

  4. 204/2007 Algae growth inhibition test with Roflumilast on Desmodesmus subspicatus. BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007

  5. 211/2007 Acute toxicity of Roflumilast to Daphnia magna. BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007

  6. 214/2007 Acute toxicity of Roflumilast to the zebra-fish, Brachydanio rerio. BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007

  7. 116/2007 Determination of ready biodegradability of Roflumilast “Closed bottle test”. BioChem, Labor für biologische und chemische Analytik GmbH, Daimlerstraße 5b, D-76185 Karlsruhe, 2007

  8. Internal Report, 3.2.S.1.3 General Properties (Roflumilast), 2009