Detaljerad miljöinformation

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 authorisation

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)

(Note: The factor 10⁹ converts the quantity sold from kg to μg).

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)

Dexmedetomidine is a potent and highly selective alpha2-adenoreceptor agonist with a broad range of pharmacological properties (ref 2). It is intended for sedation of adult ICU (Intensive Care Unit) patients (hospital use only) as well as recently also for sedation of non-intubated adult patients prior to and/or during diagnostic or surgical procedues requiring sedation. Dexmedetomidine is administered as a diluted infusion by healthcare professionals skilled in the management of patients requiring intensive care, or in the anaesthetic management of patients in the operating room or during diagnostic procedures. The dose given to each patient is low (a maximum of 1.4 μg/kg*h for a maximum of 14 days, but more frequently for no longer than 4 to 7 days). Both for the use at the ICU as well as prior to and during diagnostic or surgical procedures the number of patients treated/year will also be limited. Therefore the default value of 1% of population clearly overestimates the actual use of dexmedetomidine. (ref 3).

Dexmedetomidine HCl as the product ”Dexdor” gained marketing authorisation approval in the EU in September 2011, and was launched on the market in Sweden soon thereafter. The total amount of the API dexmedetomidine sold in Sweden in 2019 was about 33 g (data from Orion Sweden Marketing Department). In order to count for potential increase in use of dexmedetomidine in Sweden, the amount of API sold/year in Sweden has been set to 50 g for the ”worst case” calculation of the PEC value.

PEC (μg/L) = 1.5 x 10^-6 x (50 x 10^-3) x (100-R) = 75 x 10^-9 x (100-R)

Dexmedetomidine has been shown to be extensively metabolised by the liver. The elimination of the parent drug via the urine is minimal, while urinary excretion of the metabolites is the dominant route (refs 4-7). The 4 most abundant circulating metabolites in humans are 2 isomeric glucuronides (G-Dex-1 and G-Dex-2), a product formed by oxidation in the imidazole ring (H-3), and a product of successive N-methylation, methyl group hydroxylation and o-glucuronidation (H-1) (refs 4-7). The metabolites G-Dex-1, G-Dex-2 and H-3 are well established as being pharmacologically inactive (refs 8-11), and it is expected that the conjugated H-1 metabolite (in similarity to G-Dex) will also be pharmacologically inactive. This results in a very small amount of the active parent compound that will be released into the environment. However, as the amount of API used/year is already so low, the parameter R in the above equation has been set to 0 for the sake of simplicity.

Thus, the PEC value for dexmedetomidine has been calculated to 0.0000075 μg/L.

PNEC (Predicted No Effect Concentration)

The PEC value for dexmedetomidine is far below the EMA action limit of 0.01 μg/L, above which level studies for environmental risk assessment must be performed. There are therefore almost no ecotoxicity data available for this compound, and only a single study for the determination of microbial growth inhibition has been performed using dexmedetomidine (study G005/3, ref 12).

In this study, the minimum inhibitory concentration (MIC) for the heterotrophic microorganisms Aspergillus niger, Trichoderma viride, Clostridium perfringens and Bacillus subtilis was shown to be >100 mg/L, while the autotrophic cyanobacterium Nostoc sp. was more sensitive, showing an inhibitory effect on growth down to 56 mg/L. This study had a design similar to that of the current OECD 201 test (Freshwater Alga and Cyanobacteria, Growth Inhibition Test), although the species of microorganisms to be used according to the current Guidelines are different. This is most probably due to development of the accepted study design after the Study G005/3 was performed in 1996, as the current Guidelines were adopted in 2006.

Thus, as a result of the near complete lack of ecotoxicity data available for dexmedetomidine 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 dexmedetomidine.

The relevant environmental text in English is therefore -

“Environmental risk: Risk of environmental impact of dexmedetomidine cannot be excluded, since there is not sufficient ecotoxicity data available.

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

And in Swedish – ”Miljörisk: Risk för miljöpåverkan av dexmedetomidin kan inte uteslutas då det inte finns tillräckliga ekotoxikologiska data.

Enligt den europeiska läkemedelsmyndigheten EMA:s riktlinjer för miljöriskbedömning av läkemedelssubstanser (EMA/CHMP/SWP/4447/00), bedöms det vara osannolikt att användningen av dexmedetomidin 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 dexmedetomidine in the environment have been performed, and no other information on biodegradation is available. The chemical stability of the drug substance (dexmedetomidine HCl) 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 (100 μg/mL dexmedetomidine HCl in sterile aqueous solution) has also been shown to be excellent, with negligible degradation of the drug substance when the drug product is stored at 25°C/60%RH over 36 months (CTD module 3.2.P.8.3.1). The stability data also confirm that both drug substance and concentrated drug product show excellent photostability and freeze-thaw stability (CTD modules 3.2.P.8.1.6 and 3.2.P.8.1.7).

The chemical stability of a dilute dexmedetomidine 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 to 48 hours (CTD module 3.2.P.8.1.8). 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. However, no degradation was noted at ambient room temperature over a time period of up to 48 hours.

It can thus be concluded that dexmedetomidine is a very stable molecule in an aqueous solution, and 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 dexmedetomidine administered to patients each year is, in itself, very small, and that in addition, the main part of each dose given will be excreted as pharmacologically inactive human metabolites. Thus the amount of unchanged API 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 dexmedetomidine cannot be excluded, due to lack of data.”

And in Swedish –

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

Bioaccumulation

The most widely accepted measure of bioaccumulation potential is the bioconcentration factor (BCF), e.g., in fish. In the absence of a measured BCF the bioaccumulation potential can instead be evaluated from the log Kow (also called log P) 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 dexmedetomidine, and thus the log P/ log Dow value must be used to assess bioaccumulation potential. Measurement in an n-octanol/0.1 M phosphate buffer system at pH 7.4 gave a log P value of 2.89 for dexmedetomidine (CTD module 3.2.S.1.3.11). This log P value is equivalent to a log Dow value as it was measured at a neutral pH, and as this value is <4 the bioaccumulation potential for dexmedetomidine can be classed as low.

The relevant environmental text in English is therefore –

”Bioaccumulation: Dexmedetomidine has low potential for bioaccumulation.”

And in Swedish –

”Bioackumulering: Dexmedetomidin har låg potential att bioackumuleras.”

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 “PVT”.

A PBT/vPvB assessment is not relevant for dexmedetomidine.

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. Carollo DS, Nossaman BD, Ramadhyani U. Dexmedetomidine: a review of clinical applications. Current Opinion in Anaesthesiology. 2008:21(4);457-61.

3. Dexdor Produktresumé: 2019-01-18
https://www.fass.se/LIF/product?userType=2&nplId=20101005000010&docType=3&scrollPosition=500

4. BA-91-04 (1994). Pharmacokinetics and metabolic profiling of 3H-labelled dexmedetomidine in healthy male volunteers, disposition of parent, unlabelled dexmedetomidine. Clinical study report, Pharma Bio-Research International BV, The Netherlands.

5. R&D/97/457 (1997). Drug metabolism report No. 26: Phase I study of the metabolism and excretion of [3H]dexmedetomidine HCl (Abbott 85499.1) in normal male subjects. Clinical study report, Abbot Laboratories, USA.

6. DEX-96-018 (1998). A phase I, single-center, open-label study evaluating the metabolism and excretion of 3H-dexmedetomidine in healthy, adult volunteers. Clinical study report, Abbot Laboratories, USA.

7. R&D/97/389 (1997) Drug metabolism report No. 23: Metabolism of [3H]dexmedetomidine, [3H]levomedetomidine and [3H]medetomidine by precision-cut human liver slices. Nonclinical study report, Abbot Laboratories, USA.

8. 08000072 (2008). Pharmacological characterization of ORM-14305 on adrenergic alpha-2 and alpha-1 receptor subtypes. Nonclinical study report, Orion Pharma, Finland.

9. 08000278 (2008). Agonism of dexmedetomidine, dexmedetomidine N-glucuronide and clonidine on human adrenergic alpha-1 and alpha-2 receptor subtypes. Nonclinical study report, Orion Pharma, Finland.

10. 09000111 (2009). The cardiovascular effects of ORM-14305 in pithed rats. Nonclinical study report, Orion Pharma, Finland.

11. CNS97122100010 (1997). The effects of dexmedetomidine N-glucuronides on alpha-2 adrenoceptors in vitro and in vivo. Nonclinical study report, Orion Pharma, Finland.

12. NIVA study G005/3 (1996). Microbial Growth Inhibition (Reference US FDA TAD 4.02). Nonclinical study report, Norwegian Institute for Water Research, Norw