Dexdor

Dexdor (dexmedetomidine hydrochloride) injection is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride. Dexdor has a molecular weight of 236.7 and the empirical formula is C₁₃H₁₆N₂ HCl.
Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89.
Each mL contains 118 mcg of dexmedetomidine hydrochloride equivalent to 100 mcg (0.1 mg) of dexmedetomidine and 9 mg of sodium chloride in water and is to be used after dilution. The solution is preservative free and contains no additives or chemical stabilizers.

PHARMACOLOGY: Mechanism of Action: Dexdor is a relatively selective 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 (≥1000 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 Dexdor was administered by intravenous infusion at doses within the dose range of 0.2 - 0.7 mcg/kg/hr.
Pharmacokinetics: Following intravenous administration, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t_½) of approximately 6 minutes; a terminal elimination half-life (t_½) 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 1 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 1.)

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The loading doses for each of the previously mentioned 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 PK parameters after dexmedetomidine maintenance dosing for <24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t_½ 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 Dexdor 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 Dexdor were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by Dexdor was explored in vitro and none of these compounds appeared to be significantly displaced by Dexdor.
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-hydroxydexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxydexmedetomidine; and N methylation of dexmedetomidine to generate 3-hydroxy N-methyldexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O glucuronide.
Elimination: The terminal elimination half-life (t_½) 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.
Gender: There was no observed difference in Dexdor pharmacokinetics due to gender.
Geriatrics: The pharmacokinetic profile of Dexdor was not altered by age. There were no differences in the pharmacokinetics of Dexdor in young (18 - 40 years), middle age (41 - 65 years), and elderly (>65 years) subjects.
Hepatic Impairment: In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for Dexdor 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 Dexdor is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see Dosage Information under Dosage & Administration and Hepatic Impairment under Precautions].
Renal Impairment: Dexdor pharmacokinetics (C_max, T_max, AUC, t_½, CL, and V_ss) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects.
Drug Interactions: 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.
NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, Impairment of Fertility: Animal carcinogenicity studies have not been performed with Dexdor.
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.
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 Pharmacology and/or Toxicology: 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 Dexdor 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.
CLINICAL STUDIES: The safety and efficacy of Dexdor has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1185 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 2. (See Table 2.)

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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 3).
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 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 (0.47 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 4).
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 4).

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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 Studies Experience under Adverse Reactions].
In two randomized, double-blind, parallel-group, comparator-controlled multicenter clinical trials 1000 adult patients were randomized to either continue the current sedative agent or be switched to dexmedetomidine. The two trials evaluated dexmedetomidine compared to propofol or midazolam for sedation in intubated and mechanically ventilated ICU patients, who required sedation over 24 hours. The first hierarchical primary objective was to demonstrate that dexmedetomidine is at least as effective as sedation with midazolam or propofol in maintaining a target depth of sedation. The dose range of dexmedetomidine was 0.2-1.4 mcg/kg/h, and the length of sedation was up to 14 days. The target sedation range was light to moderate, corresponding to Richmond Agitation Sedation Scale 0 to -3. The Richmond Agitation Sedation Scale is displayed in Table 5. (See Table 5.)

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In the first study, 249 adult patients were randomized to receive propofol and 251 to receive dexmedetomidine by intravenous infusion. Loading doses were not used, the starting infusion dose for the first hour was between 0.2 and 0.7 mcg/kg/h then titrated between 0.2 and 1.4 mcg/kg/h to maintain RASS scores between 0 and -3. The first-line rescue medication for inadequate sedation was midazolam, for analgesia fentanyl was used. The co-primary efficacy end points were 1. the proportion of time in target sedation range without use of rescue therapy, 2. the duration of mechanical ventilation. Secondary efficacy outcomes were length of ICU stay and nurses' assessment of arousal, ability to cooperate with care, and ability to communicate pain using visual analogue scales (VAS). The mean percentage of time at target sedation level without use of rescue medication was 64.6% and 64.7% for dexmedetomidine and propofol, respectively, dexmedetomidine was demonstrated to be as effective as propofol. The median duration of mechanical ventilation was 96.5 and 117.5 hours in the dexmedetomidine and propofol groups, respectively (p=0.240). Subjects on dexmedetomidine were significantly (p < 0.001) more arousable, cooperative and better able to communicate whether they had pain than those on propofol. The median length of ICU stay was 6.8 and 7.7 days for dexmedetomidine and propofol, respectively (p = 0.535). 72.5% of subjects in the dexmedetomidine than 64.4% of subjects in the propofol group used the first-line (i.e. midazolam) rescue treatment for inadequate sedation (p = 0.054). The mean total dose (32.9 vs. 22.8 mg, p=0.024) of midazolam was higher for dexmedetomidine.
In the second study, 251 adult patients were randomized to receive midazolam and 249 to receive dexmedetomidine by intravenous infusion. Loading doses were not used, the starting infusion dose for the first hour was between 0.2 and 0.7 mcg/kg/h then titrated between 0.2 and 1.4 mcg/kg/h to maintain RASS scores between 0 and -3. The first-line rescue medication for inadequate sedation was propofol, for analgesia fentanyl was used. The co-primary efficacy end points and the secondary efficacy outcomes were identical than in the first study. The mean percentage of time at target sedation level without use of rescue medication was 60.7% and 56.6% for dexmedetomidine and midazolam, respectively, dexmedetomidine was demonstrated to be as effective as midazolam. The median duration of mechanical ventilation was 123.0 and 164.0 hours in the dexmedetomidine and midazolam groups, respectively (p = 0.033 Gehan-Wilcoxon; p = 0.265, Cox's proportional-hazards regression). Subjects on dexmedetomidine were significantly (p < 0.001) more arousable, cooperative and better able to communicate whether they had pain than those on midazolam. The median length of ICU stay was 8.8 and 10.1 days for dexmedetomidine and midazolam, respectively (p = 0.269). A similar percentage of dexmedetomidine (43.8%) and midazolam subjects (45.4%) used the first-line rescue treatment (propofol) for inadequate sedation. Similarly, no difference between groups in the mean total dose of propofol used (360 vs. 299 mg, p = 0.317) was observed.
Procedural Sedation: The safety and efficacy of dexmedetomidine for sedation of non-intubated patients prior to and/or during surgical and other procedures was evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials. Study 1 evaluated the sedative properties of dexmedetomidine in patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated dexmedetomidine in patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.
In Study 1, the sedative properties of dexmedetomidine were evaluated by comparing the percent of patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer's Assessment of Alertness/Sedation Scale (see Table 6).

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Patients were randomized to receive a loading infusion of either dexmedetomidine 1 mcg/kg, dexmedetomidine 0.5 mcg/kg, or placebo (normal saline) given over 10 minutes and followed by a maintenance infusion started at 0.6 mcg/kg/hr. The maintenance infusion of study drug could be titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr to achieve the targeted sedation score (Observer's Assessment of Alertness/Sedation Scale ≤4). Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain an Observer's Assessment of Alertness/Sedation Scale ≤4. After achieving the desired level of sedation, a local or regional anesthetic block was performed. Demographic characteristics were similar between the dexmedetomidine and comparator groups. Efficacy results showed that dexmedetomidine was more effective than the comparator group when used to sedate non-intubated patients requiring monitored anesthesia care during surgical and other procedures (see Table 7).
In Study 2, the sedative properties of dexmedetomidine were evaluated by comparing the percent of patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see Table 2). Patients were randomized to receive a loading infusion of dexmedetomidine 1 mcg/kg or placebo (normal saline) given over 10 minutes and followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired level of sedation, topicalization of the airway occurred. Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay Sedation Scale ≥2. Demographic characteristics were similar between the dexmedetomidine and comparator groups. For efficacy results see Table 7.

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Intensive Care Unit Sedation: For sedation of adult ICU (Intensive Care Unit) patients requiring a sedation level not deeper than arousal in response to verbal stimulation (corresponding to Richmond Agitation-Sedation Scale (RASS) 0 to -3).
Dexdor has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue Dexdor prior to extubation.
Procedural Sedation: Dexdor is indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures.

Dosing Guidelines: Dexdor dosing should be individualized and titrated to desired clinical response.
There is no experience in the use of Dexdor for more than 14 days. The use of Dexdor for longer than this period should be regularly reassessed.
Dexdor should be administered using a controlled infusion device.
Dosage Information: See Table 8.

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Dosage Adjustment: Due to possible pharmacodynamic interactions, a reduction in dosage of Dexdor or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered. [see Anesthetics, Sedatives, Hypnotics, Opioids under Interactions].
Dosage reductions may need to be considered for patients with renal or hepatic impairment, and geriatric patients [see Hepatic Impairment under Precautions and PHARMACOLOGY: Pharmacokinetics under Actions].
Preparation of Solution: Dexdor can be diluted in glucose 50 mg/ml (5%), Ringers, mannitol or sodium chloride 9 mg/ml (0.9%) solution for injection to achieve the required concentration of either 4 micrograms/ml or 8 micrograms/ml prior to administration. See tabulated form the volumes needed to prepare the infusion as follows. (See Table 9.)

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The solution should be shaken gently to mix well.
Strict aseptic technique must always be maintained during handling of Dexdor.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Administration with Other Fluids: Dexdor infusion should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established.
Dexdor has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam.
Dexdor has been shown to be compatible when administered with the following intravenous fluids: 0.9% sodium chloride in water, 5% dextrose in water, 20% mannitol, lactated ringer's solution, 100 mg/mL magnesium sulfate solution and 0.3% potassium chloride solution.

The tolerability of Precedex was studied in one study in which healthy adult subjects were administered doses at and above the dose of 0.2 to 0.7 mcg/kg/hr. The maximum blood concentration achieved in this study was approximately 13 times the upper boundary of the therapeutic range. The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second-degree heart block. No hemodynamic compromise was noted with the atrioventricular block and the heart block resolved spontaneously within one minute.
The signs and symptoms of dexmedetomidine overdose are exaggerated pharmacology, especially cardiovascular effects. A patient who received a loading bolus dose of undiluted dexmedetomidine (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated. A 20-month-old child received 60 mcg/kg/h (1 mcg/kg/min) for 36 minutes and experienced bradycardia, hypertension and hypoglycemia.

Hypersensitivity to the active substance or to any of the excipients listed in Description; Advanced heart block (grade 2 or 3) unless paced; Uncontrolled hypotension.

Drug Administration: Dexdor should be administered only by persons skilled in the management of patients in the intensive care or operating room setting. Due to the known pharmacological effects of Dexdor, patients should be continuously monitored while receiving Dexdor.
Hypotension, Bradycardia, and Sinus Arrest: Clinically significant episodes of bradycardia and sinus arrest have been reported with Dexdor administration in young, healthy adult volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration.
Reports of hypotension and bradycardia have been associated with Dexdor infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of Dexdor, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because Dexdor has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of Dexdor-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.
Caution should be exercised when administering Dexdor to patients with advanced heart block and/or severe ventricular dysfunction. Because Dexdor decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients.
In clinical trials where other vasodilators or negative chronotropic agents were co-administered with Dexdor an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with Dexdor.
Transient Hypertension: Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of Dexdor. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable.
Arousability: Some patients receiving Dexdor have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms.
Withdrawal Intensive Care Unit Sedation: Alpha-2 agonists have rarely been associated with withdrawal reactions when stopped abruptly after prolonged use. This possibility should be considered if the patient develops agitation and hypertension shortly after stopping dexmedetomidine.
With administration up to 14 days, regardless of dose, 2-7% of Dexdor adult subjects experienced signs of sympathetic activation indicating withdrawal syndrome within the first 48 hours after discontinuing study drug. The most common events were nausea, vomiting, agitation, anxiety and sweating.
In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after discontinuation of Dexdor supportive therapy is indicated.
Procedural Sedation: In adult subjects, withdrawal symptoms were not seen after discontinuation of short term infusions of Dexdor (<6 hours).
Tolerance and Tachyphylaxis: Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions [see Clinical Studies Experience under Adverse Reactions].
Hepatic Impairment: Since Dexdor clearance decreases with increasing severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage Information under Dosage & Administration].
DRUG ABUSE AND DEPENDENCE: Controlled Substance: Dexdor (dexmedetomidine hydrochloride) is not a controlled substance.
Dependence: The dependence potential of Dexdor has not been studied in humans. However, since studies in rodents and primates have demonstrated that Dexdor exhibits pharmacologic actions similar to those of clonidine, it is possible that Dexdor may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [see Withdrawal Intensive Care Unit Sedation as previously mentioned].
Use in Children: Safety and efficacy have not been established for Procedural or ICU Sedation in pediatric patients. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of Dexdor for this patient population. The use of Dexdor for procedural sedation in pediatric patients has not been evaluated.
Use in the Elderly: Intensive Care Unit Sedation: In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of Dexdor [see Hypotension, Bradycardia, and Sinus Arrest as previously mentioned]. Therefore, a dose reduction may be considered in patients over 65 years of age [see Dosage Information under Dosage & Administration and PHARMACOLOGY: Pharmacokinetics under Actions].
Procedural Sedation: A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in Dexdor-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age.

Pregnancy: Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. In an in vitro human placenta study, placental transfer of dexmedetomidine occurred. In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously. Thus, fetal exposure should be expected in humans, and Dexdor should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.
Teratogenic effects were not observed in rats following subcutaneous administration of Dexdor during the period of fetal organogenesis (from gestation day 5 to 16) with doses up to 200 mcg/kg (representing a dose approximately equal to the maximum recommended human intravenous dose based on body surface area) or in rabbits following intravenous administration of dexmedetomidine during the period of fetal organogenesis (from gestation day 6 to 18) with doses up to 96 mcg/kg (representing approximately half the human exposure at the maximum recommended dose based on plasma area under the time-curve comparison). However, fetal toxicity, as evidenced by increased post-implantation losses and reduced live pups, was observed in rats at a subcutaneous dose of 200 mcg/kg. The no-effect dose in rats was 20 mcg/kg (representing a dose less than the maximum recommended human intravenous dose based on a body surface area comparison). In another reproductive toxicity study when Dexdor was administered subcutaneously to pregnant rats at 8 and 32 mcg/kg (representing a dose less than the maximum recommended human intravenous dose based on a body surface area comparison) from gestation day 16 through weaning, lower offspring weights were observed. Additionally, when offspring of the 32 mcg/kg group were allowed to mate, elevated fetal and embryocidal toxicity and delayed motor development was observed in second generation offspring.
Labor and Delivery: The safety of Dexdor during labor and delivery has not been studied.
Nursing Mothers: It is not known whether Dexdor is excreted in human milk. Radio-labeled Dexdor administered subcutaneously to lactating female rats was excreted in milk. Because many drugs are excreted in human milk, caution should be exercised when Dexdor is administered to a nursing woman.

Clinical Studies Experience: Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.
Use of Dexdor has been associated with the following serious adverse reactions: Hypotension, bradycardia and sinus arrest [see Hypotension, Bradycardia, and Sinus Arrest under Precautions]; Transient hypertension [see Transient Hypertension under Precautions].
Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia and dry mouth.
Intensive Care Unit Sedation: Adverse reaction information is derived from the continuous infusion trials of dexmedetomidine for sedation in the Intensive Care Unit setting in which 1007 adult patients received dexmedetomidine. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% ≥65 years of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 10. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see Hypotension, Bradycardia, and Sinus Arrest under Precautions]. (See Table 10.)

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Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of dexmedetomidine for sedation in the surgical intensive care unit setting in which 387 adult patients received dexmedetomidine for less than 24 hours. The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 11).

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In a controlled clinical trial, dexmedetomidine was compared to midazolam for ICU sedation exceeding 24 hours duration in adult patients. Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 12. The number (%) of subjects who had a dose related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the dexmedetomidine group is provided in Table 13. (See Table 12.)

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The following adverse events occurred between 2 and 5% for dexmedetomidine and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%). (See Table 13.)

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In a controlled clinical trial 3005012, Dexdor was compared to propofol for continuous sedation of ventilated adult ICU patients needing light to moderate sedation (RASS 0 to -3) for more than 24 hours. Treatment emergent adverse events occurring in at least 2% of the dexmedetomidine treated patients in the study 3005012 are provided in Table 14. (See Table 14.)

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In a controlled clinical trial 3005013, Dexdor was compared to midazolam for continuous sedation of ventilated adult ICU patients needing light to moderate sedation (RASS 0 to -3) for more than 24 hours. Treatment emergent adverse events occurring in at least 2% of the dexmedetomidine treated patients in the study 3005013 are provided in Table 15. (See Table 15.)

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Procedural Sedation: Adverse reaction information is derived from the two trials for procedural sedation [see PHARMACOLOGY: CLINICAL STUDIES: Procedural Sedation under Actions] in which 318 adult patients received dexmedetomidine. The mean total dose was 1.6 mcg/kg (range: 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of infusion of 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93 years of age, ASA I-IV, 30% ≥65 years of age, 52% male and 61% Caucasian.
Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 16. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [see Hypotension, Bradycardia, and Sinus Arrest under Precautions]. Prespecified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. The decrease in respiratory rate and hypoxia was similar between dexmedetomidine and comparator groups in both studies. (See Table 16.)

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Postmarketing Experience: The following adverse reactions have been identified during post approval use of Dexdor. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypotension and bradycardia were the most common adverse reactions associated with the use of Dexdor during post approval use of the drug. (See Table 17.)

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Anesthetics, Sedatives, Hypnotics, Opioids: Co-administration of Dexdor with anesthetics, sedatives, hypnotics, and opioids is likely to lead to an enhancement of effects. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between Dexdor and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with Dexdor a reduction in dosage of Dexdor or the concomitant anesthetic, sedative, hypnotic or opioid may be required.
Neuromuscular Blockers: In one study of 10 healthy adult volunteers, administration of Dexdor for 45 minutes at a plasma concentration of one ng/mL resulted in no clinically meaningful increases in the magnitude of neuromuscular blockade associated with rocuronium administration.

Compatibility with Natural Rubber: Compatibility studies have demonstrated the potential for absorption of Dexdor to some types of natural rubber. Although Dexdor is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.

Store below 30°C.

Dexdor is indicated for intravenous sedation. Dosage must be individualized and titrated to the desired clinical effect. Blood pressure, heart rate and oxygen levels will be monitored both continuously during the infusion of Dexdor and as clinically appropriate after discontinuation.
When Dexdor is infused for more than 6 hours, patients should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours.
Additionally, patients should be informed to report symptoms that may occur within 48 hours after the administration of Dexdor such as: weakness, confusion, excessive sweating, weight loss, abdominal pain, salt cravings, diarrhea, constipation, dizziness or light-headedness.

Hypnotics & Sedatives

N05CM18 - dexmedetomidine ; Belongs to the class of other hypnotics and sedatives.

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