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Hycamtin

Novartis

Kapsel, hård 0,25 mg
(Kapslarna är ogenomskinliga, vita till gulvita och märkta med HYCAMTIN och 0,25 mg.)

Andra antineoplastiska medel

Aktiv substans:
ATC-kod: L01CE01
Utbytbarhet: Ej utbytbar
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  • Vad är miljöinformation?

Miljöinformation

Miljöpåverkan

Topotekan

Miljörisk: Risk för miljöpåverkan av topotekan kan inte uteslutas då det inte finns tillräckliga ekotoxikologiska data.
Nedbrytning: Topotekan är potentiellt persistent.
Bioackumulering: Topotekan har låg potential att bioackumuleras.


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Detaljerad miljöinformation


Environmental Risk Classification


According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00 corr 2), use of topotecan is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit 0.01 μg/L.


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) = 1.5*10-6 * 0.00397 * 100

PEC = 0.0000006 μg/L

Where:

A = 0.00397 kg (total sold amount API in Sweden year 2018, data from IQVIA).

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:

No data (not possible due to rapid photolysis)


Water flea (Daphnia magna):

Acute toxicity

EC50 48 h (immobility) = 61,800 μg/L (OECD 202) (Reference 3)


Water flea:

Chronic toxicity

No data


Rainbow Trout (Oncorhyncus mykiss):

Acute toxicity

LC50 96 h (immobility) = 45,700 μg/L (OECD 203) (Reference 3)


Fathead minnow:

Chronic toxicity

No data


Other ecotoxicity data:

Microorganisms in activated sludge

EC50 3 hours (Inhibition) =102,000 μg/L (OECD 209) (Reference 3)


PNEC cannot be calculated because data is not available for all three (algae, crustacean and fish) of the short-term toxicity endpoints.


Environmental risk classification (PEC/PNEC ratio)

Risk of environmental impact of topotecan cannot be excluded, since there is not sufficient ecotoxicity data available.


Degradation

Biotic degradation

Ready degradability:

0% degradation in 28 days (OECD 301B) (Reference 3)

Inherent degradability:

No data


Abiotic degradation

Hydrolysis:

Half-life, pH 7 = 35 years (TAD 3.09) (Reference 3)

Photolysis:

Half-life, pH 7 = 2.51m (TAD 3.10) (Reference 3)


Justification of chosen degradation phrase:

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


Bioaccumulation

Partitioning coefficient:

Log Dow = 0.80 at pH7. (TAD 3.02) (Reference 4)


Justification of chosen bioaccumulation phrase:

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


Excretion (metabolism)

Metabolism accounts for < 10% of the elimination of topotecan. An N-desmethyl metabolite, which was shown to have similar or less activity than the parent in a cell-based assay, was found in urine, plasma, and faeces. The mean metabolite:parent AUC ratio was less than 10 % for both total topotecan and topotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine.

Overall recovery of medicinal product-related material following five daily doses of topotecan was 71 to 76 % of the administered IV dose. Approximately 51 % was excreted as total topotecan and 3 % was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted for 18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall, the N-desmethyl metabolite contributed a mean of less than 7% (range 4-9 %) of the total medicinal product related material accounted for in the urine and faeces. The topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide in the urine were less than 2.0 %. (Reference 2)


PBT/vPvB assessment

Topotecan 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). Topotecan does not fulfil the criteria for PBT and/or vBvP based on a log Dow < 4.


References

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

  • Pharmacokinetic properties: Metabolism and Elimination. Summary of Product Characteristics Hycamtin (Topotecan) Solution for Infusion. GlaxoSmithKline, November 2010.

  • Ziegenfuss P. Hycamtin, SK&F 104864, topotecan, environmental risk assessment, ERA, Phase I, environmental fate, environmental effects. Report No. ERL 9809. SmithKline Beecham Environmental Research Laboratory, June 1998.

  • ACD /LogD. June 2012. Advanced Chemistry Development, Inc.