Detaljerad miljöinformation

Environmental Risk classification

PEC (Predicted Environmental Concentration)

The PEC is obtained by using the following formula, and is based on the total sales of API in Sweden (kg/year):

PEC (μg/L) = [A x 10⁹ x (100-R)] / (365 x P x V x D x 100)

Where:

A (kg/year) = total actual API sales (active moiety) in Sweden for the most recent year and/or predicted sales for the 5 years following marketing authorization.

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

365 = days/year (default)

P = number of inhabitants in Sweden = 9 x 10⁶ (default)

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

D = factor for dilution of waste water by surface water flow = 10 (ECHA default, ref 1)

When all the default values have been added, the formula is as follows:

PEC (μg/L) = 1.5 x 10^-6 x A x (100-R)

Levosimendan (SIMDAX®) is a calcium sensitizer developed for intravenous short-term treatment of acutely decompensated severe chronic heart failure (ADHF) in situations where conventional therapy is not sufficient, and where inotropic support is considered appropriate (SmPC for Simdax, ref 2). Due to the nature of this indication, levosimendan is intended for in-hospital use only and administration is limited to a maximum of 24 hours’ intravenous infusion. The finished product SIMDAX is formulated as a concentrate for solution for infusion containing 2.5 mg/mL of levosimendan dissolved in ethanol. The only vial size of this drug product marketed in Sweden is a vial containing 5 mL concentrate. The concentrate is diluted with glucose 5% shortly prior to use and is administered as a slow infusion.

The intravenous formulation of SIMDAX was granted its first Marketing Authorization in Sweden in September 2000. According to the IQVIA database the total amount of levosimendan API used in Sweden in 2023 was 83.9 g. This amount has been used in the calculation of the PEC value below.

Thus, the PEC value for levosimendan has been calculated as follows:

PEC = 1.5 x 10^-6 x 0.0839 x (100-0) μg/L

         = approximately 0.000013 μg/L

PNEC (Predicted No Effect Concentration)

The PEC value for levosimendan is far below the action limit of 0.01 μg/L, above which level studies for environmental risk assessment must be performed. There are therefore no ecotoxicity data available for this compound. Thus as a result, no PNEC value can be calculated for this compound.

Environmental risk classification (PEC/PNEC ratio)

As no PNEC value is available, the PEC/PNEC ratio cannot be calculated for levosimendan.

The relevant environmental text in English is therefore:

“Environmental risk: Risk of environmental impact of levosimendan cannot be excluded, since no ecotoxicity data are available.

According to the European Medicines Agency guideline on environmental risk assessment of medicinal products (EMA/CHMP/SWP/4447/00), use of levosimendan is unlikely to represent a risk for the environment, because the predicted environmental concentration (PEC) is below the action limit 0.01 μg/L.” (Ref 1)

And in Swedish:

”Miljörisk: Risk för miljöpåverkan av levosimendan kan inte uteslutas då ekotoxikologiska data saknas.

Enligt den europeiska läkemedelsmyndigheten EMA:s riktlinjer för miljöriskbedömning av läkemedelssubstanser (EMA/CHMP/SWP/4447/00), bedöms det vara osannolikt att användningen av levosimendan medför en miljörisk då den förväntade koncentrationen i miljön (PEC) är mindre än tröskelvärdet 0,01 μg/L.”

Degradation

No studies to investigate the ready biodegradability (OECD 301) of levosimendan in the environment have been performed, and no other information on biodegradation is available. The chemical stability of the drug substance (levosimendan) has been shown to be at least 5 years (with negligible degradation) when stored at 25°C/60%RH (CTD module 3.2.S.7.3). That of the concentrated drug product (2.5 μg/mL in ethanol: SIMDAX concentrate for solution for infusion) has also been shown to be good, with low degradation of the drug substance when the drug product is stored at +8 to +15°C over 16 months or at 25°C/60%RH over 6 months (CTD module 3.2.P.8.3). The stability data also confirm that both drug substance and concentrated drug product show excellent photostability (CTD module 3.2.P.8.3). Very little or nothing is known as to the decomposition of the various related substances (degradation products) or metabolites of levosimendan.

The chemical stability of a dilute levosimendan solution (similar to the very low concentrations that may be present in the environment) will probably be lower, but the stability of diluted solutions has not been documented over more than 24 hours (CTD module 3.2.P.8.3). No degradation was noted at ambient room temperature over this time period. A prepared solution for intravenous infusion should not be used for more than 24 hours due to the risk of microbiological growth, and therefore longer investigation of the diluted drug product is not required.

It can thus be concluded that levosimendan is a very stable molecule. In addition it has a very low solubility in an aqueous environment (CTD module 3.2.S.1.3). Thus, the potential for persistence of this molecule in the environment cannot be excluded. However, it should be kept in mind that the total amount of levosimendan administered to patients each year is, in itself, very small, and that majority of each dose given will be excreted as pharmacologically inactive human metabolites. Thus the amount of unchanged API or active metabolites that will be released into the environment each year will be extremely small.

The relevant environmental text in English is therefore:

”Degradation: The potential for persistence of levosimendan cannot be excluded, due to lack of data.”

And in Swedish:

”Nedbrytning: Det kan inte uteslutas att levosimendan är persistent, då data saknas.”

Bioaccumulation

The most widely accepted measure of bioaccumulation potential is the bioconcentration factor (BCF), in for example fish. In the absence of a measured BCF the bioaccumulation potential can instead be evaluated from the log Kow value, which describes partitioning of the neutral form of the molecule between octanol/water. For complex molecules and ionisable compounds it is more relevant to instead use the log Dow value at pH 7. If this value is <4, a compound is considered to have a low potential for bioaccumulation.

There is no measured BCF for levosimendan, and thus the log Dow value must be used to assess bioaccumulation potential. Measurement in an n-octanol/0.1 M HCl system gave a log D value of 1.7 to 2.2 for levosimendan. Similarly, measurement in an n-octanol/67 mM phosphate buffer system at pH 7.4 gave a log D value of 0.7 to 1.1 (CTD module 3.2.S.1.3). As these values are <4 the bioaccumulation potential for levosimendan can be classified as low.

The relevant environmental text in English is therefore:

”Bioaccumulation: Levosimendan has low potential for bioaccumulation.”

And in Swedish:

”Bioackumulering: Levosimendan har låg potential att bioackumuleras.”

Excretion (metabolism)

Levosimendan is extensively and rapidly metabolised by the liver following intravenous administration, primarily via glutathione conjugation, and only trace amounts of unchanged levosimendan are found in urine and faeces (Orion Pharma studies, refs 3-5). The only significant detectable metabolites in the systemic circulation are OR-1855 and OR-1896. Both these metabolites undergo conjugation or renal filtration, and are excreted predominantly in the urine (Orion Pharma studies, refs 5-6). OR-1855 has only weak pharmacodynamic activity in vitro while that of OR-1896 is very similar to that of levosimendan (Orion Pharma studies, refs7-9). Only a small percentage (about 4 to 7%) of the given dose of levosimendan is converted to OR-1896, although the exposure to this metabolite is significantly greater than to that of the parent drug, due to its long terminal half-life (approximately 70-80 hours). The elimination of OR-1896 has been characterised, and the biotransformation products can be considered as very minor, causing no safety concerns.

This results in a very small amount of the active parent compound and/or active metabolite that will be released into the environment. However, as the amount of API used/year is already so low, the parameter R in the calculation of the PEC has been set to 0 for the sake of simplicity.

PBT/vPvB assessment

If a compound is flagged as potentially persistent (P), bioaccumulative (B) and toxic (T) or very persistent and very bioaccumulative (vPvB), then a PBT/vPvB assessment must be performed. All 3 properties (P + B + T) are required in order to classify a compound as “PBT”, and therefore a PBT/vPvB assessment is not relevant for levosimendan.

References

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

2. Simdax® Produktresumé (SPC), fass.se. http://www.fass.se/LIF/product?7&userType=2&nplId=20000922000137&docType=6

3. Metabolite profiles of intravenous 14C − levosimendan in urine and faeces. Internal report: Orion Pharma; April 2000, Report No. PRE991032.

4. Pharmacokinetics of 24-hour Levosimendan I.V. Infusion in Healthy Volunteers. Internal report: Orion Pharma; April 2000, Report No. 3001053.

5. Excretion balance and pharmacokinetics of radiocarbon after a single intravenous infusion of 14C-labelled levosimendan in healthy subjects (An overview of the excretion and metabolism of 14C-labelled levosimendan including pharmacokinetics and metabolites OR-1855 and OR-1896). Internal report: Orion Pharma; May 2000, Report No. 3001054.

6. Excretion balance and pharmacokinetics of radiocarbon after a single intravenous dose of 14C-labelled OR-1896, a metabolite of levosimendan, in healthy subjects. Overview of excretion balance, metabolism and pharmacokinetics. Internal report: Orion Pharma; February 2003, Report No. 3001070.

7. Szilagyi et al. The effects of levosimendan and OR-1896 on isolated hearts, myocyte-sized preparations and phosphodiesterase enzymes of the guinea pig. Eur J Pharmacol, 2004;486(1):67-74.

8. Inhibition of guinea pig left ventricular phosphodiesterase isoenzymes by OR-1539 and OR-1855. Internal report: Orion Pharma; December 1994, Report No. F94011200526.

9. Inhibition of guinea pig left ventricular phosphodiesterase isoenzymes by OR-1896, (R)-OR-1420 and OR-1746. Internal report: Orion Pharma; May 1995, Report No. F95011200594.