"The U.S. Food and Drug Administration today approved Clinolipid (lipid injectable emulsion, USP) for intravenous feeding (parenteral nutrition) in adult patients, providing a source of calories and essential fatty acids for adult patients who are"...
Mechanism of Action
Precedex 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.
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 Precedex was administered by intravenous infusion at doses within the recommended dose range (0.2–0.7 mcg/kg/hr).
Following intravenous administration, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t½) of approximately 6 minutes; a terminal elimination half-life (t½) 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 8 shows the main pharmacokinetic parameters when Precedex 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 8: Mean ± SD Pharmacokinetic Parameters
|Parameter||Loading Infusion (min)/Total Infusion Duration (hrs)|
|10 min/12 hrs||10 min/24 hrs||10 min/24 hrs||35 min/24 hrs|
|Precedex Target Plasma Concentration (ng/mL)and Dose (mcg/kg/hr)|
|t½*, 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, liter||88.7 ± 22.9||102.4 ± 20.3||93.6 ± 17.0||99.6 ± 17.8|
|Avg 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 Precedex. The mean Css was 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 Precedex maintenance doses of 0.2 to 1.4 mcg/kg/hr for > 24 hours were similar to the PK parameters after Precedex maintenance dosing for < 24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t½ were 39.4 L/hr, 152 L, and 2.67 hours, respectively.
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 Precedex 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 Precedex were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by Precedex was explored in vitro and none of these compounds appeared to be significantly displaced by Precedex.
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-hydroxydexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-Nmethyl O-glucuronide.
The terminal elimination half-life (t½) 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 3hydroxy-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.
There was no observed difference in Precedex pharmacokinetics due to gender.
The pharmacokinetic profile of Precedex was not altered by age. There were no differences in the pharmacokinetics of Precedex in young (18–40 years), middle age (41–65 years), and elderly ( > 65 years) subjects.
In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for Precedex 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.
Precedex pharmacokinetics (Cmax, Tmax, AUC, t½, CL, and Vss) were not significantly different in patients with severe renal impairment (creatinine clearance: < 30 mL/min) compared to healthy subjects.
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.
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.
The safety and efficacy of Precedex 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 Precedex 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 Precedex 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 9.
Table 9: Ramsay Level of
|Clinical Score||Level of Sedation Achieved|
|6||Asleep, no response|
|5||Asleep, sluggish response to light glabellar tap or loud auditory stimulus|
|4||Asleep, but with brisk response to light glabellar tap or loud auditory stimulus|
|3||Patient responds to commands|
|2||Patient cooperative, oriented, and tranquil|
|1||Patient anxious, agitated, or restless|
In the first study, 175 adult patients were randomized to receive placebo and 178 to receive Precedex 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 Precedex (see Table 10).
A second prospective primary analysis assessed the sedative effects of Precedex 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 Precedex group maintained a Ramsay sedation score of ≥ 3 without receiving any midazolam rescue compared to the placebo group (see Table 10).
Table 10: Midazolam Use as
Rescue Medication During Intubation (ITT) Study One
|Placebo N=175||Precedex N=178||p-value|
|Mean Total Dose (mg) of Midazolam||19 mg||5 mg||0.0011*|
|Standard deviation||53 mg||19 mg|
|Categorized Midazolam Use|
|0 mg||43 (25%)||108 (61%)||< 0.001**|
|0-4 mg||34 (19%)||36 (20%)|
|> 4 mg||98 (56%)||34 (19%)|
population includes all randomized patients.
* ANOVA model with treatment center.
A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-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 Precedex 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 Precedex 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 Precedex (see Table 11).
A significantly greater percentage of patients in the Precedex group compared to the placebo group maintained a Ramsay sedation score of ≥ 3 without receiving any propofol rescue (see Table 11).
Table 11: Propofol Use as Rescue Medication During
Intubation (ITT) Study Two
|Placebo N=198||Precedex N=203||p-value|
|Mean Total Dose (mg) of Propofol||513 mg||72 mg||< 0.0001*|
|Standard deviation||782 mg||249 mg|
|Categorized Propofol Use|
|0 mg||47 (24%)||122 (60%)||< 0.001**|
|0-50 mg||30 (15%)||43 (21%)|
|> 50 mg||121 (61%)||38 (19%)|
|* ANOVA model with treatment
A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-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 Precedex patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.
In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration. Precedex 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 Precedex for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [see ADVERSE REACTIONS].
The safety and efficacy of Precedex 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 Precedex in patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated Precedex in patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.
In Study 1, the sedative properties of Precedex 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 12).
Table 12: Observer's Assessment of Alertness/Sedation
|Responsiveness||Speech||Facial Expression||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 Precedex 1 mcg/kg, Precedex 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 Precedex and comparator groups. Efficacy results showed that Precedex 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 13).
In Study 2, the sedative properties of Precedex 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 9). Patients were randomized to receive a loading infusion of Precedex 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 Precedex and comparator groups. For efficacy results see Table 13.
Table 13: Key Efficacy Results of Procedural Sedation
|Study||Loading Infusion Treatment Arm||Number of Patients Enrolleda||% Not Requiring Midazolam Rescue||Confidenceb Interval on the Difference vs. Placebo||Mean (SD) Total Dose (mg) of Rescue Midazolam Required||Confidenceb Intervals of the Mean Rescue Dose|
|Study 1||Precedex 0.5 mcg/kg||134||40||37 (27, 48)||1.4 (1.7)||-2.7 (-3.4, -2.0)|
|Precedex 1 mcg/kg||129||54||51 (40, 62)||0.9 (1.5)||-3.1 (-3.8, -2.5)|
|Study 2||Precedex 1 mcg/kg||55||53||39 (20, 57)||1.1 (1.5)||-1.8 (-2.7, -0.9)|
|aBased on ITT population defined as all randomized and
bNormal approximation to the binomial with continuity correction.
Last reviewed on RxList: 7/2/2013
This monograph has been modified to include the generic and brand name in many instances.
Additional Precedex Information
Report Problems to the Food and Drug Administration
Find out what women really need.