Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Orion Corporation, Orionintie 1, FI-02200 Espoo, Finland
Pharmacotherapeutic group: Psycholeptics, other hypnotics and sedatives
ATC code: N05CM18
Dexmedetomidine is a selective alpha-2 receptor agonist with a broad range of pharmacological properties. It has a sympatholytic effect through decrease of the release of noradrenaline in sympathetic nerve endings. The sedative effects are mediated through decreased firing of locus coeruleus, the predominant noradrenergic nucleus, situated in the brainstem. Dexmedetomidine has analgesic and anaesthetic/analgesic-sparing effects. The cardiovascular effects depend on the dose; with lower infusion rates the central effects dominate leading to decrease in heart rate and blood pressure. With higher doses, peripheral vasoconstricting effects prevail leading to an increase in systemic vascular resistance and blood pressure, while the bradycardic effect is further emphasised. Dexmedetomidine is relatively free from respiratory depressive effects when given as monotherapy to healthy subjects.
In placebo controlled trials in a post-operative ICU population previously intubated and sedated with midazolam or propofol, Dexdor significantly reduced the requirement for both rescue sedative (midazolam or propofol) and opioids during sedation for up to 24 hours. Most dexmedetomidine patients required no additional sedative treatment. Patients could be successfully extubated without stopping the Dexdor infusion. Studies from outside the ICU have confirmed that Dexdor can be administered safely to patients without endotracheal intubation provided adequate monitoring is in place.
Dexmedetomidine was similar to midazolam (Ratio 1.07; 95% CI 0.971, 1.176) and propofol (Ratio 1.00; 95% CI 0.922, 1.075) on the time in target sedation range in a predominently medical population requiring prolonged light to moderate sedation (RASS 0 to 3) in the ICU for up to 14 days, reduced the duration of mechanical ventilation compared to midazolam and reduced the time to extubation compared to midazolam and propofol. Compared to both propofol and midazolam, patients were more easily roused, more cooperative and better able to communicate whether or not they had pain. Dexmedetomidine treated patients had more frequent hypotension and bradycardia but less tachycardia than those receiving midazolam and more frequent tachycardia but similar hypotension to propofol treated patients. Delirium measured by the CAM-ICU scale was reduced in a study compared to midazolam and delirium-related adverse events were lower on dexmedetomidine compared to propofol. Those patients who withdrew due to insufficient sedation were switched to either propofol or midazolam. The risk of insufficient sedation was increased in patients who were difficult to sedate with standard care immediately prior to switching.
Evidence of paediatric efficacy was seen in a dose-controlled ICU study in a largely post-operative population aged 1 month to ≤17 years. Approximately 50% of patients treated with dexmedetomidine did not require rescue addition of midazolam during a median treatment period of 20.3 hours, not exceeding 24 hours. Data on treatment for >24 hours is not available. Data in new-born infants (28–44 weeks gestation) is very limited and restricted to low doses (≤0.2 mcg/kg/h) (see sections 5.2 and 4.4). New-born infants may be particularly sensitive to the bradycardic effects of Dexdor in the presence of hypothermia and in conditions of heart rate-dependent cardiac output.
In double blind comparator controlled ICU studies the incidence of cortisol suppression in patients treated with dexmedetomidine (n=778) was 0.5% compared with 0% in patients treated with either midazolam (n=338) or propofol (n=275). The event was reported as mild in 1 and moderate in 3 cases.
The safety and efficacy of dexmedetomidine for sedation of non-intubated patients prior to and/or during surgical and diagnostic procedures was evaluated in two randomised, double-blind, placebo-controlled multicentre clinical trials.
The pharmacokinetics of dexmedetomidine has been assessed following short term IV administration in healthy volunteers and long term infusion in ICU population.
Dexmedetomidine exhibits a two-compartment disposition model. In healthy volunteers it exhibits a rapid distribution phase with a central estimate of the distribution half-life (t1/2α) of about 6 minutes. The mean estimate of the terminal elimination half-life (t½) is approximately 1.9 to 2.5 h (min 1.35, max 3.68 h) and the mean estimate of the steady-state volume of distribution (Vss) is approximately 1.16 to 2.16 l/kg (90 to 151 litres). Plasma clearance (Cl) has a mean estimated value of 0.46 to 0.73 l/h/kg (35.7 to 51.1 l/h). The mean body weight associated with these Vss and Cl estimates was 69 kg. Plasma pharmacokinetics of dexmedetomidine is similar in the ICU population following infusion >24 h. The estimated pharmacokinetic parameters are: t½ approximately 1.5 hours, Vss approximately 93 litres and Cl approximately 43 l/h. The pharmacokinetics of dexmedetomidine is linear in the dosing range from 0.2 to 1.4 μg/kg/h and it does not accumulate in treatments lasting up to 14 days. Dexmedetomidine is 94% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.85 to 85 ng/ml. Dexmedetomidine binds to both human serum albumin and Alpha-1-acid glycoprotein with serum albumin as the major binding protein of dexmedetomidine in plasma.
Dexmedetomidine is eliminated by extensive metabolism in the liver. There are three types of initial metabolic reactions; direct N-glucuronidation, direct N-methylation and cytochrome P450 catalysed oxidation. The most abundant circulating dexmedetomidine metabolites are two isomeric N-glucuronides. Metabolite H-1, N-methyl 3-hydroxymethyl dexmedetomidine O-glucuronide, is also a major circulating product of dexmedetomidine biotransformation. Cytochrome P-450 catalyses the formation of two minor circulating metabolites, 3-hydroxymethyl dexmedetomidine produced by hydroxylation at the 3-methyl group of dexmedetomidine and H-3 produced by oxidation in the imidazole ring. Available data suggest that the formation of the oxidised metabolites is mediated by several CYP forms (CYP2A6, CYP1A2, CYP2E1, CYP2D6 and CYP2C19). These metabolites have negligible pharmacological activity.
Following IV administration of radiolabeled dexmedetomidine an average 95% of radioactivity was recovered in the urine and 4% in the faeces after nine days. The major urinary metabolites are the two isomeric N-glucuronides, which together accounted for approximately 34% of the dose and N-methyl 3-hydroxymethyl dexmedetomidine O-glucuronide that accounted for 14.51% of the dose. The minor metabolites dexmedetomidine carboxylic acid, 3-hydroxymethyl dexmedetomidine and its O-glucuronide individually comprised 1.11 to 7.66% of the dose. Less than 1% of unchanged parent drug was recovered in the urine. Approximately 28% of the urinary metabolites are unidentified minor metabolites.
No major pharmacokinetic differences have been observed based on gender or age.
Dexmedetomidine plasma protein binding is decreased in subjects with hepatic impairment compared with healthy subjects. The mean percentage of unbound dexmedetomidine in plasma ranged from 8.5% in healthy subjects to 17.9% in subjects with severe hepatic impairment. Subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C) had decreased hepatic clearance of dexmedetomidine and prolonged plasma elimination t½. The mean plasma clearance values of unbound dexmedetomidine for subjects with mild, moderate, and severe hepatic impairment were 59%, 51% and 32% of those observed in the normal healthy subjects, respectively. The mean t½ for the subjects with mild, moderate or severe hepatic impairment was prolonged to 3.9, 5.4, and 7.4 hours, respectively. Although dexmedetomidine is administered to effect, it may be necessary to consider initial/maintenance dose reduction in patients with hepatic impairment depending on the degree of impairment and the response.
The pharmacokinetics of dexmedetomidine in subjects with severe renal impairment (creatinine clearance <30 ml/min) is not altered relative to healthy subjects.
Data in new-born infants (28-44 weeks gestation) to children 17 years of age are limited. Dexmedetomidine half life in children (1 months to 17 years) appears similar to that seen in adults, but in new-born infants (under 1 month) it appears higher. In the age groups 1 months to 6 years, body weight-adjusted plasma clearance appeared higher but decreased in older children. Body weight-adjusted plasma clearance in new-born infants (under 1 month) appeared lower (0.9 l/h/kg) than in the older groups due to immaturity.
The available data is summarised in the following table:
| Mean (95% CI) | |||
|---|---|---|---|
| Age | N | Cl (l/h/kg) | t1/2 (h) |
| Under 1 month | 28 | 0,93 (0,76, 1,14) | 4,47 (3,81, 5,25) |
| 1 to <6 months | 14 | 1,21 (0,99, 1,48) | 2,05 (1,59, 2,65) |
| 6 to <12 months | 15 | 1,11 (0,94, 1,31) | 2,01 (1,81, 2,22) |
| 12 to <24 months | 13 | 1,06 (0,87, 1,29) | 1,97 (1,62, 2,39) |
| 2 to <6 years | 26 | 1,11 (1,00, 1,23) | 1,75 (1,57, 1,96) |
| 6 to <17 years | 28 | 0,80 (0,69, 0,92) | 2,03 (1,78, 2,31) |
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxicity.
In the reproductive toxicity studies, dexmedetomidine had no effect on male or female fertility in the rat, and no teratogenic effects were observed in the rat or rabbit. In the rabbit study intravenous administration of the maximum dose, 96 μg/kg/day, produced exposures that are similar to those observed clinically. In the rat, subcutaneous administration at the maximum dose, 200 μg/kg/day, caused an increase in embryofetal death and reduced the fetal body weight. These effects were associated with clear maternal toxicity. Reduced fetal body weight was noted also in the rat fertility study at dose 18 μg/kg/day and was accompanied with delayed ossification at dose 54 μg/kg/day. The observed exposure levels in the rat are below the clinical exposure range.
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