Dexmedetomidine HCl Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Dexmedetomidine HCl Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Sedation
Class: Miscellaneous anxiolytics, sedatives and hypnotics
Form: Liquid solution, Intravenous (IV)
Ingredients: Dexmedetomidine

Description

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, and the structural formula is:


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. Dexmedetomidine Hydrochloride Injection is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7.0.

Each mL contains 118 mcg of dexmedetomidine hydrochloride equivalent to 100 mcg (0.1 mg) of dexmedetomidine, 9 mg of sodium chloride, 597 mcg of sodium acetate trihydrate and 27 mcg of glacial acetic acid in water. The solution is preservative-free.

Clinical Pharmacology

Mechanism of Action

Dexmedetomidine Hydrochloride Injection 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 to 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 Hydrochloride Injection was administered by intravenous infusion at doses within the recommended dose range (0.2 to 0.7 mcg/kg/hr).

Pharmacokinetics

Following intravenous administration, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t1/2) of approximately 6 minutes; a terminal elimination half-life (t1/2) of approximately 2 hours; and steady-state volume of distribution (Vss) 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 Hydrochloride Injection 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.

Table 1: Mean ± SD Pharmacokinetic Parameters
Parameter Loading Infusion (min)/Total Infusion Duration (hrs)
10 min/12 hrs 10 min/24 hrs 10 min/24 hrs 5 min/24 hrs
Dexmedetomidine Hydrochloride Injection Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr)
0.3/0.17 0.3/0.17 0.6/0.33 1.25/0.70
t1/2 *, hour

 
1.78 ± 0.30

 
2.22 ± 0.59

 
2.23 ± 0.21

 
2.50 ± 0.61

 
CL, liter/hour 46.3 ± 8.3 43.1 ± 6.5 35.3 ± 6.8 36.5 ± 7.5
Vss , literAvg 88.7 ± 22.9 102.4 ± 20.3 93.6 ± 17 99.6 ± 17.8
Css# , ng/mL 0.27 ± 0.05 0.27 ± 0.05 0.67 ± 0.10 1.37 ± 0.20

* Presented as harmonic mean and pseudo standard deviation.

# Mean Css = Average steady-state concentration of Dexmedetomidine Hydrochloride Injection. The mean Csswas calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions.

The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively.

Dexmedetomidine pharmacokinetic parameters after Dexmedetomidine Hydrochloride Injection maintenance doses of 0.2 to 1.4 mcg/kg/hr for > 24 hours were similar to the PK parameters after Dexmedetomidine Hydrochloride Injection maintenance dosing for < 24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively.

Distribution

The steady-state volume of distribution (Vss) 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 Hydrochloride Injection 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 Hydrochloride Injection were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by Dexmedetomidine Hydrochloride Injection was explored in vitro and none of these compounds appeared to be significantly displaced by Dexmedetomidine Hydrochloride Injection.

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) 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.

Elimination

The terminal elimination half-life (t1/2) 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.

Gender

There was no observed difference in Dexmedetomidine Hydrochloride Injection pharmacokinetics due to gender.

Geriatrics

The pharmacokinetic profile of Dexmedetomidine Hydrochloride Injection was not altered by age. There were no differences in the pharmacokinetics of Dexmedetomidine Hydrochloride Injection in young (18 to 40 years), middle age (41 to 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 Dexmedetomidine Hydrochloride Injection 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 Hydrochloride Injection is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment.

Renal Impairment

Dexmedetomidine Hydrochloride Injection pharmacokinetics (Cmax, Tmax, AUC, t1/2, CL, and Vss) 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 dexmedetomidine.

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 invitro 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 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.

Clinical Studies

The safety and efficacy of dexmedetomidine hydrochloride injection has been evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials in 431 adult patients.

Procedural Sedation

The safety and efficacy of Dexmedetomidine Hydrochloride Injection 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 Hydrochloride Injection in patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated Dexmedetomidine Hydrochloride Injection in patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.

In Study 1, the sedative properties of Dexmedetomidine Hydrochloride Injection 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 2).

Table 2: Observer’s Assessment of Alertness/Sedation
Assessment Categories
Responsiveness Speech FacialExpression Eyes Composite Score
Responds readily to name spoken in normal tone Normal Normal Clear, no ptosis 5 (alert)
Lethargic response to name spoken in normal tone Mild slowing or thickening Mild relaxation Glazed or mild ptosis (less than half the eye) 4
Responds only after name is called loudly and/or repeatedly Slurring or prominent slowing Marked relaxation (slack jaw) Glazed and marked ptosis (half the eye or more) 3
Responds only after mild prodding or shaking Few recognizable words 2
Does not respond to mild prodding or shaking 1 (deep sleep)

Patients were randomized to receive a loading infusion of either Dexmedetomidine Hydrochloride Injection 1 mcg/kg, Dexmedetomidine Hydrochloride Injection 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 Hydrochloride Injection and comparator groups. Efficacy results showed that Dexmedetomidine Hydrochloride Injection 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 3).

In Study 2, the sedative properties of Dexmedetomidine Hydrochloride Injection 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. Patients were randomized to receive a loading infusion of Dexmedetomidine Hydrochloride Injection 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 Hydrochloride Injection and comparator groups. For efficacy results see Table 3.

Study Loading Infusion Treatment Arm Number of Patients Enrolleda % Not Requiring Midazolam Rescue ConfidenceInterval on the Difference vs. Placebo Mean (SD) Total Dose (mg) of Rescue Midazolam Required ConfidenceIntervals of the Mean Rescue Dose
Study 1 Dexmedetomidine Hydrochloride Injection 0.5 mcg/kg 134 40 37 (27, 48) 1.4 (1.7) -2.7 (-3.4, -2)
Dexmedetomidine Hydrochloride Injection 1 mcg/kg 129 54 51 (40, 62) 0.9 (1.5) -3.1 (-3.8, -2.5)
placebo 63 3 4.1 (3)
Study 2 Dexmedetomidine Hydrochloride Injection 1 mcg/kg 55 53 39 (20, 57) 1.1 (1.5) -1.8 (-2.7, -0.9)
placebo 50 14 2.9 (3)

a Based on ITT population defined as all randomized and treated patients.

b Normal approximation to the binomial with continuity correction.