Dexdor

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. Sedation of adult ICU (Intensive Care Unit) patients 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. Procedural/awake sedation 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. ▪ Study 1 randomised patients undergoing elective surgeries/procedures under monitored anaesthesia care and local/regional anaesthesia to receive a loading infusion of dexmedetomidine either 1 µg/kg (n=129) or 0.5 µg/kg (n=134), or placebo (normal saline; n=63) given over 10 minutes and followed by a maintenance infusion started at 0.6 µg/kg/h. The maintenance infusion of study drug could be titrated from 0.2 µg/kg/h to 1 µg/kg/h. The proportion of patients that achieved the targeted sedation level (Observer's Assessment of Alertness/Sedation Scale ≤4) without need for rescue midazolam was 54% of the patients receiving dexmedetomidine 1 µg/kg and 40% of the patients receiving dexmedetomidine 0.5 µg/kg compared to 3% of patients receiving the placebo.The risk difference in proportion of subjects randomised to dexmedetomidine 1 µg/kg group and dexmedetomidine 0.5 µg/kg group not requiring rescue midazolam was 48% (95% CI: 37 % - 57%) and 40% (95% CI: 28 % - 48%), respectively compared placebo. The median (range) midazolam rescue dose was 1.5 (0.5-7.0) mg in the dexmedetomidine1.0 µg/kg group, 2.0 (0.5-8.0) mg in the dexmedetomidine 0.5 µg/kg group, and 4.0 (0.5-14.0) mg in the placebo group. The difference in means in dose of rescue midazolam in dexmedetomidine 1 µg/kg and dexmedetomidine 0.5 µg/kg group compared to placebo was -3.1 mg (95% CI: -3.8 - -2.5) and -2.7 mg (95% CI: -3.3 - -2.1), respectively favouring dexmedetomidine.The median time to first rescue dose was 114 minutes in the dexmedetomidine 1.0 µg/kg group, 40 minutes in the dexmedetomidine 0.5 µg/kg group, and 20 minutes in the placebo group. ▪ Study 2 randomised patients undergoing awake fibreoptic intubation under topical anaesthesia to receive a loading infusion of dexmedetomidine 1 µg/kg (n=55) or placebo (normal saline) (n=50) given over 10 minutes and followed by a fixed maintenance infusion of 0.7 µg/kg/h. To maintain a Ramsay Sedation Scale ≥2 53% of the patients receiving dexmedetomidine did not require midazoloam rescue vs. 14% of patients receiving placebo. The risk difference in proportion of subjects randomised to dexmedetomidine not requiring rescue midazolam was 43% (95% CI: 23 % - 57%) compared placebo. The mean midazolam rescue dose was 1.1 mg in the dexmedetomidine group, and 2.8 mg in the placebo group. The difference in means in dose of rescue midazolam was -1.8 mg (95% CI: -2.7 - -0.86) favouring dexmedetomidine.