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Ketek®

Sanofi AB

Filmdragerad tablett 400 mg
Avregistreringsdatum: 2019-06-06 (Tillhandahålls ej) (ljusorange, avlång, bikonvex och filmdragerad, märkt med H3647 på ena sidan och 400 på den andra)

Antibakteriellt medel för systemiskt bruk

Aktiv substans:
ATC-kod: J01FA15
För information om det avregistrerade läkemedlet omfattas av Läkemedelsförsäkringen, kontakta Läkemedelsförsäkringen.
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Miljöinformation

Miljöpåverkan (Läs mer om miljöpåverkan)

Telitromycin

Miljörisk: Användning av telitromycin har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Telitromycin är potentiellt persistent.
Bioackumulering: Telitromycin 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)


PEC =1.2*10-6 µg/L


Where:

A = 0.008 kg (total sold amount API in Sweden year 2016, data from Quintiles IMS)

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) (Ref I).

D = factor of dilution of waste water by surface water flow = 10 (ECHA default) (Ref I).


Predicted No Effect Concentration (PNEC)

Ecotoxicological studies

Algae (Selenastrum capricornutum):

MIC (growth inhibition) = 5.45 μg/L

NOEC 12 days (growth inhibition) = 2.38 μg/L

MIC (µ-max) = 17.3 μg/L

NOEC (µ-max) = 8.21 μg/L

The maximum standing crop was attained on day 10, the µ-max (the largest specific growth rate) was reached between days 2 and 4.

(Protocol: FDA 4.01)

(Ref II)


Crustacean (Daphnia magna):

EC50 48 h (immobilization) = 35,100 μg/L

NOEC 48 h (immobilization) = 4,940 μg/L

(Protocol: FDA 4.08)

(Ref III)


Fish (Oncorhynchus mykiss):

LC50 48 h (mortality) > 308,000 μg/L

NOEC 48 h (mortality) = 308,000 μg/L

(Protocol: FDA 4.11)

(Ref IV)


Other ecotoxicity data:

PNEC = 0.0024 µg/L


PNEC (µg/L) = lowest EC50/1,000. The PNEC was calculated using results from the most sensitive toxicity endpoint and an assessment factor of 1,000 (At least one short-term L(E)C50 from each of three trophic levels of the base set), to add a safety margin to the toxicity endpoint. The most sensitive species was Selenastrum capricornutum for which the NOEC 12 days was 2.38 μg/L.


Environmental Risk Classification (PEC/PNEC ratio)

PEC/PNEC=1.2*10-6 / 0.0024 = 0.0005, i.e. PEC/PNEC ≤ 0.1 which justifies the phrase “Use of telithromycin has been considered to result in insignificant environmental risk”.

However, according to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of telithromycin is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit 0.01 μg/L.


Degradation

Biotic degradation

Ready biodegradation:

Test results showed 10.7% degradation in 28 days (FDA 3.11) (Ref V)


Abiotic degradation

Hydrolysis:

Test showed < 10% degradation in 5 days (FDA 3.09) (Ref VI)


Justification of chosen degradation phrase:

Telithromycin fails to pass the criteria for ready biodegradability which justifies the phrase “Telithromycin is potentially persistent”.


Bioaccumulation

Partitioning coefficient:

Log Kow = 3.53 at pH 7 (estimated by unknown method) (Ref VII)


Justification of chosen bioaccumulation phrase:

Since Log Kow < 4 at pH 7, telithromycin has low potential for bioaccumulation.


Excretion (metabolism)

The substance is excreted as 34% as parent compound and 13% as metabolites.

Metabolites identified are RU 76363, an alcohol resulting from the loss of aryl rings; RU 78849, an acid resulting from oxidation of RU 76363; RU 72365, N‑desmethyl‑desosamine; and RU 584, Noxide‑pyridine (Ref VIII).

The pharmacological activity of metabolites is 4 to 16 times less active compared to the parent compound (Ref IX).


References

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

  2. Sanofi, internal report: Toxicity of HMR 3647 to the unicellular green alga, Selenastrum capricornutum, determined under static test conditions. FDA 4.01. Report #46433. May 2001.

  3. Sanofi, internal report: Acute toxicity of HMR 3647 to the water flea, Daphnia magna, determined under static test conditions. FDA 4.08. Report #46432. April 2001.

  4. Sanofi, internal report: Acute toxicity of HMR 3647 to the rainbow trout, Oncorhynchus mykiss, determined under static test conditions. FDA 4.11. Report #46431. April 2001.

  5. Sanofi, internal report: Determination of the aerobic biodegradation in water for HMR 3647. FDA 3.11. Report #46429. May 2001.

  6. Sanofi, internal report: Hydrolysis determination for HMR 3647. FDA 3.09. Report #46427. May 2001.

  7. DrungBank, MSDS, online consultation, March 2014: http://www.drugbank.ca/system/msds/DB00976.pdf?1265922744

  8. Shain CS, Amsden GW. 2002. Telithromycin: The First of the Ketolides. The Annals of Pharmacotherapy. 36(3): 452-464.

  9. Cantalloube C, Bhargava V, Sultan E, Vacheron F, Batista I, Montay G. 2003. Pharmacokinetics of the ketolide telithromycin after single and repeated doses in patients with hepatic impairment. International Journal of Antimicrobial Agents. 22: 112-121.