Dexmedetomidine B. Braun Concentrate for Solution for Infusion Mechanism of Action

Pharmacology: Mechanism of Action: Dexmedetomidine is a relatively selective centrally acting alpha₂-adrenergic agonist with sedative properties. Alpha₂ selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha₁ and alpha₂ activity is observed following slow intravenous infusion of high doses (≥1,000 mcg/kg) or with rapid intravenous administration.
Pharmacodynamics: In a study in healthy volunteers (N=10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when Dexmedetomidine was administered by intravenous infusion at doses within the recommended dose range (0.2-0.7 mcg/kg/hr).
Clinical Studies: The safety and efficacy of Dexmedetomidine has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1,185 adult patients.
Intensive Care Unit Sedation: Two randomized, double-blind, parallel-group, placebo-controlled multicenter clinical trials included 754 adult patients being treated in a surgical intensive care unit. All patients were initially intubated and received mechanical ventilation. These trials evaluated the sedative properties of Dexmedetomidine by comparing the amount of rescue medication (midazolam in one trial and propofol in the second) required to achieve a specified level of sedation (using the standardized Ramsay Sedation Scale) between Dexmedetomidine and placebo from onset of treatment to extubation or to a total treatment duration of 24 hours. The Ramsay Level of Sedation Scale is displayed in Table 1. (See Table 1.)

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In the first study, 175 adult patients were randomized to receive placebo and 178 to receive Dexmedetomidine by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion rate was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive "rescue" midazolam as needed to augment the study drug infusion. In addition, morphine sulfate was administered for pain as needed. The primary outcome measure for this study was the total amount of rescue medication (midazolam) needed to maintain sedation as specified while intubated. Patients randomized to placebo received significantly more midazolam than patients randomized to Dexmedetomidine (see Table 2).
A second prospective primary analysis assessed the sedative effects of Dexmedetomidine by comparing the percentage of patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of patients in the Dexmedetomidine group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 2).

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A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Dexmedetomidine and placebo groups. On average, Dexmedetomidine-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h). In addition, 44% (79 of 178 patients) of Dexmedetomidine patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group.
In a second study, 198 adult patients were randomized to receive placebo and 203 to receive Dexmedetomidine by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive "rescue" propofol as needed to augment the study drug infusion. In addition, morphine sulfate was administered as needed for pain. The primary outcome measure for this study was the total amount of rescue medication (propofol) needed to maintain sedation as specified while intubated.
Patients randomized to placebo received significantly more propofol than patients randomized to Dexmedetomidine (see Table 3).
A significantly greater percentage of patients in the Dexmedetomidine group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see Table 3).

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A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Dexmedetomidine and placebo groups. On average, Dexmedetomidine-treated patients received less morphine sulfate for pain than placebo-treated patients (0.43 versus 0.89 mg/h). In addition, 41% (83 of 203 patients) of Dexmedetomidine patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.
In a controlled clinical trial, Dexmedetomidine was compared to midazolam for ICU sedation exceeding 24 hours duration. Dexmedetomidine was not shown to be superior to midazolam for the primary efficacy endpoint, the percent of time patients were adequately sedated (81% versus 81%). In addition, administration of Dexmedetomidine for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [see Clinical Trials Experience under Adverse Reactions].
Pharmacokinetics: Following intravenous administration, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t_1/2) of approximately 6 minutes; a terminal elimination half-life (t_1/2) of approximately 2 hours; and steady-state volume of distribution (V_ss) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg.
Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered by intravenous infusion for up to 24 hours. Table 4 shows the main pharmacokinetic parameters when Dexmedetomidine was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/ml) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/ml) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/ml) for 24 hours. (See Table 4.)

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The loading doses for each of the previously indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively.
Dexmedetomidine pharmacokinetic parameters after Dexmedetomidine maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetic (PK) parameters after Dexmedetomidine maintenance dosing for <24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t_1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively.
Distribution: The steady-state volume of distribution (V_ss) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of Dexmedetomidine that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects.
The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro, and negligible changes in the plasma protein binding of Dexmedetomidine were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by Dexmedetomidine was explored in vitro and none of these compounds appeared to be significantly displaced by Dexmedetomidine.
Elimination: Metabolism: Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide.
Excretion: The terminal elimination half-life (t_1/2) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified.
Specific Populations: Male and Female Patients: There was no observed difference in Dexmedetomidine pharmacokinetics due to sex.
Geriatric Patients: The pharmacokinetic profile of Dexmedetomidine was not altered by age. There were no differences in the pharmacokinetics of Dexmedetomidine in young (18-40 years), middle age (41-65 years), and elderly (>65 years) subjects.
Patients with Hepatic Impairment: In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for Dexmedetomidine were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy subjects, respectively.
Although Dexmedetomidine is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see Dosage Information under Dosage & Administration; Hepatic Impairment under Precautions].
Patients with Renal Impairment: Dexmedetomidine pharmacokinetics (C_max, T_max, AUC, t_1/2, CL, and V_ss) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 ml/min) compared to healthy subjects.
Drug Interaction Studies: In vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.
Toxicology: Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Animal carcinogenicity studies have not been performed with dexmedetomidine.
Mutagenesis: Dexmedetomidine was not mutagenic in vitro, in either the bacterial reverse mutation assay (E. coli and Salmonella typhimurium) or the mammalian cell forward mutation assay (mouse lymphoma). Dexmedetomidine was clastogenic in the in vitro human lymphocyte chromosome aberration test with, but not without, rat S9 metabolic activation. In contrast, dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test with or without human S9 metabolic activation. Although dexmedetomidine was clastogenic in an in vivo mouse micronucleus test in NMRI mice, there was no evidence of clastogenicity in CD-1 mice.
Impairment of Fertility: Fertility in male or female rats was not affected after daily subcutaneous injections of dexmedetomidine at doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m² basis) administered from 10 weeks prior to mating in males, and 3 weeks prior to mating and during mating in females.
Animal Toxicology and/or Pharmacology: There were no differences in the adrenocorticotropic hormone (ACTH)-stimulated cortisol response in dogs following a single dose of dexmedetomidine compared to saline control. However, after continuous subcutaneous infusions of dexmedetomidine at 3 mcg/kg/hr and 10 mcg/kg/hr for one week in dogs (exposures estimated to be within the clinical range), the ACTH-stimulated cortisol response was diminished by approximately 27% and 40%, respectively, compared to saline-treated control animals indicating a dose-dependent adrenal suppression.