DEXMEDETOMIDINE HCL (Generic for PRECEDEX)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Dexmedetomidine solution is clear and colorless.
Intravenous Administration
-Only experienced clinicians, skilled in the management of patients in the intensive care or operating room setting, should administer or supervise the use of dexmedetomidine.
-Dexmedetomidine has the potential to adhere to some types of natural rubber; it is advisable to use administration components made with synthetic or coated natural rubber gaskets.
-Dexmedetomidine is compatible with 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Lactated Ringer's Injection, 20% mannitol, 0.3% potassium chloride solution, and 100 mg/mL magnesium sulfate solution.

Dilution
-Dilute the 200 mcg/2 mL (100 mcg/mL) vial with 48 mL of 0.9% Sodium Chloride Injection to provide a final concentration of 4 mcg/mL.
--Dexmedetomidine diluted to a final concentration of 8, 12, and 20 mcg/mL with 0.9% Sodium Chloride Injection is stable for up to 48 hours, despite a slight decrease in solution pH seen with increasing concentrations. NOTE: This is stability data; administration data regarding these concentrations in pediatric patients are not available.

-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 4 mcg/mL.
-Shake gently to mix well.
-Storage: Prior to use, diluted dexmedetomidine admixed from a multi-dose vial may be stored for up to 4 hours at room temperature or up to 24 hours at 2 to 8 degrees C. Dexmedetomidine 4 mcg/mL in 0.9% Sodium Chloride Injection is stable for at least 48 hours at room temperature (20 to 25 degrees C) and at least 14 days refrigerated (5 degrees C) when stored in polypropylene syringes. Concentrated solutions (8, 12, and 20 mcg/mL) stored in PVC bags at 23 +/- 2 degrees C are stable for 48 hours.

Continuous IV Infusion
-Administer using a controlled infusion device.
-Loading dose: Infuse over 10 minutes. Serious adverse events have occurred after rapid administration; do not administer via IV push.
-Do not coadminister dexmedetomidine through the same IV catheter with blood, serum, or plasma because physical compatibility has not been established.
-Carefully monitor blood pressure and heart rate.



Other Administration Route(s)
Intranasal Administration
NOTE: Dexmedetomidine is not FDA-approved for intranasal administration.
-Dexmedetomidine injection (100 mcg/mL) has been administered intranasally in pediatric patients requiring both procedural and preanesthesia sedation.
-Small studies have administered doses as undiluted or diluted drug in small volumes of normal saline (total volumes ranged from 0.4 to 1.5 mL/dose).
-Using a small syringe, drip the solution into both nostrils with the child in a recumbent position 30 to 60 minutes before optimal sedation is required. Alternatively, dexmedetomidine may be administered via a nasal atomizer, which may improve bioavailability.

Dexmedetomidine is associated with dose-related hypotension and bradycardia. Bradycardia (62%) and hypotension (25%) were frequently reported in pediatric patients receiving dexmedetomidine (0.5 to 1.5 mcg/kg/hour continuous IV infusion) for procedural sedation in clinical studies (n = 122). In the combined age group and in each age group, an increased incidence in bradycardia was observed with increasing dexmedetomidine dose. In other pediatric studies with dexmedetomidine (n = 219), clinically significant hypotension (9% to 16%) and bradycardia (3% to 12%) have been reported. A neonatal study (n = 42; gestational age: 28 to 44 weeks) reported a mean decrease in heart rate and blood pressure of 12% and 14%, respectively, with dexmedetomidine at loading doses 0.2 mcg/kg IV or less and infusion rates 0.2 mcg/kg/hour IV or less; no hemodynamic changes required intervention. Transient hypertension may also occur due to stimulation of alpha2-receptors on arterial and venous smooth muscle. In pediatric clinical trials, hypertension has been reported in 8% to 38% of patients and an increased incidence in hypertension was observed with increasing dexmedetomidine dose. Hemodynamic instability is more likely with bolus dosing; for this reason, loading doses of dexmedetomidine are often bypassed in critical care patients. If hypotension or bradycardia occur and require intervention, decrease or stop the IV infusion, increase the rate of IV fluids, elevate lower extremities, or use vasopressor as indicated. Consider an anticholinergic (e.g., glycopyrrolate, atropine) to modify vagal tone. Treatment of hypertension is not usually necessary, but administering loading doses over a longer period (e.g., 20 minutes) may minimize risk.

Sinus tachycardia occurred in 4% of pediatric patients receiving dexmedetomidine (0.5 to 1.5 mcg/kg/hour continuous IV infusion) for procedural sedation in clinical trials (n = 122). Atrial fibrillation (4%) and ventricular tachycardia (less than 1%) have been reported in adults receiving IV dexmedetomidine during clinical trials. Arrhythmia exacerbation, AV block, cardiac arrest, unspecified cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia (SVT), ventricular arrhythmia, T-wave inversion, and QT prolongation have been reported during postmarketing use of IV dexmedetomidine.

Acute renal failure (unspecified) (2% to 2.5%), oliguria (2%), and decreased urine output (1%) have been reported during adult clinical trials of intravenous dexmedetomidine. Polyuria has been observed during postmarketing use of dexmedetomidine.

Dexmedetomidine has induced fever (4% to 7%), hyperpyrexia (2%), and hyperthermia (2%), which may be resistant to traditional cooling methods including cooled IV fluids and antipyretic medications, in adults. Discontinue dexmedetomidine if drug-related hyperthermia or fever is suspected and monitor the patient until the body temperature normalizes. Chills (2%), rigors (2%), hypovolemia (3%), generalized edema (2%), and pain (unspecified) (2%) have also been reported in adults during clinical trials of IV dexmedetomidine. Peripheral edema rarely occurred during these clinical trials and was dose-related, occurring in 3% of adults who received an average infusion rate of less than 0.7 mcg/kg/hour IV and 7% of adults who received an average rate of more than 1.1 mcg/kg/hour IV. Bleeding, including post-procedure bleeding, was noted in 2% to 3% of patients.
Agitation (2% to 7%) and anxiety have been reported during adult intensive care sedation trials of dexmedetomidine. These effects appear to be dose-related; average infusion rates less than 0.7 mcg/kg/hour were associated with agitation or anxiety in 5% of adult patients, while infusion rates more than 1.1 mcg/kg/hour were associated with agitation or anxiety in 14% and 9% of patients, respectively. Seizures, confusion, delirium, dizziness, hallucinations or illusions, headache, speech disorders (dysarthria or dysphasia, unspecified), neuralgia, neuritis, and light anesthesia have been reported during postmarketing use of intravenous dexmedetomidine. Patients may be arousable and alert when stimulated; this alone should not be considered as a lack of efficacy in the absence of other clinical signs and symptoms. Drowsiness is commonly reported in ambulatory adults receiving dexmedetomidine sublingual film for acute agitation associated with schizophrenia or bipolar disorder.

Nausea (3% to 11%), vomiting (3% to 4%), constipation (6%), xerostomia (3% to 4%), and polydipsia (2%) have been reported in adults during clinical trials of intravenous dexmedetomidine. Constipation was dose-related, occurring in 6% of patients who received an average infusion rate of less than 0.7 mcg/kg/hour and 14% of patients who received an average rate of more than 1.1 mcg/kg/hour. Abdominal pain and diarrhea have been reported during postmarketing use of dexmedetomidine. Abdominal discomfort, including dyspepsia and gastroesophageal reflux, xerostomia, and nausea have been reported in ambulatory adults receiving dexmedetomidine sublingual film for acute agitation associated with schizophrenia or bipolar disorder.

Hyperglycemia (2% to 7%), hypoglycemia (5%), hypocalcemia (1%), hypomagnesemia (1%), hypokalemia (9%), anemia (2% to 3%), and metabolic acidosis (1% to 2%) have been reported in adults receiving intravenous dexmedetomidine during clinical trials. Respiratory acidosis, elevated hepatic enzymes (i.e., GGT, AST, ALT, and alkaline phosphatase), hyperbilirubinemia, abnormal liver function, elevated BUN, hyperkalemia, and hypernatremia have been reported during postmarketing use.

Bradypnea or respiratory depression (67%) and hypoxia (8%) were reported in pediatric patients receiving dexmedetomidine (0.5 to 1.5 mcg/kg/hour continuous IV infusion) for procedural sedation in clinical trials (n = 122). In another study of 30 children (1 to 7 years) receiving dexmedetomidine 1 mcg/kg IV over 10 minutes followed by a continuous IV infusion of 0.5 mcg/kg/hour, mean respiratory rate fell from 25 +/- 3.96 breaths/minute to 24 +/- 3.29 breaths/minute at 50 minutes after drug initiation. Oxygen saturation below 93% for at least 30 seconds did not occur in any of the 30 children. Respiratory failure and acute respiratory distress syndrome (ARDS) occurred in 5% and 2.5% of adults during clinical trials of long-term (more than 24 hours) dexmedetomidine continuous infusion sedation. Both were dose-related events, with incidence rates increasing to 10% and 9% for respiratory failure and ARDS, respectively, in patients who received average maintenance doses more than 1.1 mcg/kg/hour. Other respiratory-related adverse reactions reported in adult clinical trials with dexmedetomidine include atelectasis (3%), pleural effusion (2%), pulmonary edema (1%), and wheezing (less than 1%). Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, and pulmonary congestion have been reported during postmarketing use of dexmedetomidine.

Photopsia and visual impairment have been reported during postmarketing use of intravenous dexmedetomidine.

Use of dexmedetomidine beyond 24 hours has been associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events. Physiological dependence may occur.

Dexmedetomidine continuous infusion may cause adrenocortical insufficiency because it is structurally similar to etomidate. While in vivo and in vitro animal studies have demonstrated decreased cortisol concentrations and blunted cortisol response to adrenocorticotrophic hormone (ACTH) stimulation after dexmedetomidine administration, human studies have shown mixed results. Transient adrenocortical insufficiency has been described in a single case report. A 1-year-old, 10 kg, previously healthy boy presenting to the hospital with 24% total body surface area second degree burns was emergently intubated. Initially, the patient required a combination of sedative and analgesic medications including fentanyl, morphine, and ketamine infusions, as well as scheduled lorazepam and methadone. In order to wean his sedation regimen, dexmedetomidine was initiated at a rate of 0.5 mcg/kg/hour on hospital day 8; the infusion was eventually titrated up to 2.7 mcg/kg/hour on day 10, and clonidine was added. The dexmedetomidine infusion was discontinued on hospital day 15 after 6.5 days of continuous infusion. On hospital day 18, the patient was diagnosed with adrenocortical insufficiency, presenting with lethargy, hypotension, tachycardia, low cortisol (0.4 mcg/dL), and blunted cortisol response. A septic workup was unremarkable. Hydrocortisone was initiated and the patient was discharged after 23 days of hospitalization. Repeat cortisol and ACTH stimulation test 2 months after discharge showed a complete resolution of adrenal insufficiency.

Mild transient withdrawal symptoms of emergence delirium or agitation occurred in 3 pediatric patients after discontinuation of short-term (less than 2 hours) dexmedetomidine infusions (0.5 to 1.5 mcg/kg/hour) in procedural sedation clinical studies (n = 122). Other withdrawal symptoms including nervousness, sleeplessness, headache, tremor, nausea, vomiting, diarrhea, tachycardia, and hypertension can occur with discontinuation of dexmedetomidine continuous infusion. Additional signs of withdrawal specific to neonates and infants include high-pitched crying, an exaggerated Moro reflex, and feeding intolerance. The primary manifestations of dexmedetomidine withdrawal involve the central nervous system (e.g., agitation, hypertonicity, tonic-clonic movements). Monitor for withdrawal symptoms after the infusion is discontinued. If dexmedetomidine has been infused for more than 6 hours, monitor for at least 48 hours after infusion discontinuation. Gradual tapering of the infusion or transitioning to oral or transdermal clonidine may aid in the prevention of withdrawal after prolonged infusion. Initiate supportive care if withdrawal symptoms occur.

Hyperhidrosis, pruritus, rash, and urticaria have been reported with postmarketing use of intravenous dexmedetomidine.

Oral paresthesias or oral hypoesthesia were commonly reported in ambulatory adults receiving dexmedetomidine sublingual film.

Intravenous dexmedetomidine is associated with dose-related hypotension and bradycardia. Because dexmedetomidine decreases sympathetic nervous system activity, these effects may be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension. Use intravenous dexmedetomidine with caution in patients with advanced AV block and/or severe ventricular dysfunction. If used in patients at risk for heart block or symptomatic bradycardia, ensure pacing capabilities are available. Clinically significant episodes of bradycardia and sinus arrest have been reported in healthy adults with high vagal tone and with rapid intravenous or bolus administration. If hypotension or bradycardia occur and require intervention, decrease or stop the infusion, increase the rate of intravenous fluids, elevate lower extremities, or use vasopressor as indicated. Consider an anticholinergic (e.g., glycopyrrolate, atropine) to modify vagal tone. More advanced resuscitative measures may be required in patients with significant cardiac disease. The sublingual film indicated in adults for agitation associated with schizophrenia or bipolar disorder should also be avoided in those with hypotension, orthostatic hypotension, advanced AV block, severe ventricular dysfunction, or a history of syncope.

Use of IV dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions. Abrupt discontinuation of IV dexmedetomidine may produce a clonidine-like withdrawal syndrome. Monitor for withdrawal symptoms after the infusion is discontinued. If dexmedetomidine has been infused for more than 6 hours, monitor for at least 48 hours after infusion discontinuation. Gradual tapering of the infusion or transitioning to oral or transdermal clonidine may aid in the prevention of withdrawal after prolonged infusion. Initiate supportive care if withdrawal symptoms occur.

Consider dose reduction in patients with hepatic disease as dexmedetomidine clearance decreases with severity of hepatic impairment.

Dexmedetomidine administration for sedation requires a specialized care setting and requires an experienced clinician skilled in the management of patients in the intensive care unit or operating room. Monitor patients continuously while receiving dexmedetomidine. Some patients receiving dexmedetomidine may be arousable and alert when stimulated; this alone should not be considered as a lack of efficacy in the absence of other clinical signs and symptoms.

Dexmedetomidine may prolong the QT interval. Avoid use of dexmedetomidine film in patients at risk of torsade de pointes or sudden death including those with known QT prolongation, a history of other cardiac arrhythmias, symptomatic bradycardia, hypokalemia or hypomagnesemia, and in patients receiving other drugs known to prolong the QT interval. Use dexmedetomidine injection with caution in these patients. Additionally, use dexmedetomidine with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypocalcemia, or in patients receiving medications known to cause an electrolyte imbalance. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Description: Dexmedetomidine is a relatively selective alpha2-adrenergic agonist with centrally mediated sedative, analgesic/opioid-sparing, and sympatholytic properties. Dexmedetomidine injection is used in pediatric patients for procedural and intensive care sedation. Dexmedetomidine has similar pharmacological effects to clonidine, with a greater affinity for the alpha2-receptor. Sedation from dexmedetomidine often results in a patient who is tranquil yet easily aroused, making it an ideal sedative agent when neurologic examination is required. Short half-life, limited effects on respiratory drive, and reduced analgesic and anesthetic requirements with dexmedetomidine use make it an attractive agent in many clinical situations. Dexmedetomidine is a useful sedative agent in multiple pediatric critical care subpopulations (e.g., cardiac and burn patients) and may have a place in treatment and prevention of drug withdrawal, anesthesia-induced emergence delirium, post anesthesia shivering, cyclic vomiting syndrome, and tachyarrhythmias. There is also evidence suggesting dexmedetomidine diminishes inflammatory processes, which may provide additional benefit in patients with sepsis and those who are mechanically ventilated. Dexmedetomidine is associated with dose-related hypotension and bradycardia that is more likely to occur during the intravenous loading phase. Abrupt discontinuation can result in withdrawal symptoms. In addition, unlike benzodiazepines, dexmedetomidine does not possess amnestic properties and should not be used as the sole sedative agent in paralyzed patients. Dexmedetomidine injection is FDA-approved for pediatric patients as young as infants, and is used off-label in pediatric patients as young as neonates.

General dosing information:
-Hemodynamic instability is more likely with bolus dosing; for this reason, loading doses of dexmedetomidine are often bypassed in critical care patients. If a loading dose is used, it must be administered over a minimum of 10 minutes.
-Dexmedetomidine does not provide deep sedation and patients may be arousable and alert when stimulated; this should not be considered lack of efficacy in the absence of other clinical signs and symptoms. Dexmedetomidine does not produce amnesia and is not appropriate in clinical situations where amnesia is required (e.g., during neuromuscular blockade).
-Dexmedetomidine is not indicated for infusions lasting longer than 24 hours; however, longer infusions are commonly used in clinical practice.

For sedation induction* and sedation maintenance* of mechanically ventilated intensive care patients:
Continuous Intravenous Infusion dosage:
Premature Neonates: Limited data available. 0.05 to 0.5 mcg/kg/dose IV loading dose, followed by 0.05 to 0.3 mcg/kg/hour continuous IV infusion, initially. Adjust dose by 0.1 mcg/kg/hour gradually to achieve target level of sedation. Loading doses are often bypassed due to their association with bradycardia and hypotension. Mean infusion rate was 0.6 mcg/kg/hour (range: 0.3 to 1.2 mcg/kg/hour) and mean duration of infusion was 12 days in a retrospective case-control study (n = 24; mean gestational age: 25 weeks). Decreased clearance and prolonged half-life may warrant relatively lower doses compared to older populations. Wean by 0.1 mcg/kg/hour every 12 to 24 hours, as tolerated, upon discontinuation.
Term Neonates: 0.05 to 0.5 mcg/kg/dose IV loading dose, followed by 0.05 to 0.6 mcg/kg/hour continuous IV infusion, initially. Adjust dose as needed to achieve target level of sedation. Loading doses are often bypassed due to their association with bradycardia and hypotension. Infusion rates comparable to those used in older populations have been reported in neonates (mean infusion rate: 0.4 mcg/kg/hour); however, decreased clearance and prolonged half-life may warrant relatively lower doses. Max: 2.5 mcg/kg/hour.
Infants: 0.5 to 1 mcg/kg IV, then 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate by 0.1 to 0.2 mcg/kg/hour every 20 to 30 minutes until target level of sedation is attained. Loading doses are often bypassed due to their association with bradycardia and hypotension. Usual maintenance dose: 0.3 to 0.7 mcg/kg/hour. Max: 2.5 mcg/kg/hour. Infants may require higher infusion rates than older patients; in a retrospective case series of 38 patients, the average infusion rate was 0.4 mcg/kg/hour in infants and 0.29 mcg/kg/hour in children and adolescents.
Children and Adolescents: 0.5 to 1 mcg/kg IV, then 0.1 to 0.5 mcg/kg/hour continuous IV infusion, initially. Titrate by 0.1 to 0.2 mcg/kg/hour every 20 to 30 minutes until target level of sedation is attained. Loading doses are often bypassed due to their association with bradycardia and hypotension. Usual maintenance dose: 0.3 to 0.7 mcg/kg/hour. Max: 2.5 mcg/kg/hour.

For procedural sedation of non-intubated patients prior to and/or during non-invasive procedures:
Continuous Intravenous Infusion dosage:
Infants and Children 1 month to 1 year: 1.5 mcg/kg IV loading dose over 10 minutes, followed by 1.5 mcg/kg/hour continuous IV infusion initially. Titrate until desired level of sedation is attained. Dose range: 0.5 to 2 mcg/kg/hour. Some studies have used repeat boluses if sedation was inadequate prior to beginning the infusion.
Children and Adolescents 2 to 17 years: 2 mcg/kg IV loading dose over 10 minutes, followed by 1.5 mcg/kg/hour continuous IV infusion initially. Titrate until desired level of sedation is attained. Dose range: 0.5 to 2 mcg/kg/hour. Some studies have used repeat boluses if sedation was inadequate prior to beginning the infusion.
Intranasal dosage*:
Infants 1 to 5 months: 2 to 3 mcg/kg intranasally (divided and given in both nostrils) as a single dose 30 minutes before the nonpainful procedure.
Infants, Children, and Adolescents 6 months to 17 years: 1 to 4 mcg/kg (Max: 200 mcg) intranasally (divided and given in both nostrils) as a single dose 30 to 60 minutes before the nonpainful procedure.

For preanesthesia sedation*:
Intranasal dosage:
Children: 1 to 2 mcg/kg intranasally (divided and given into both nostrils) as a single dose 30 to 60 minutes before anesthesia induction.

Maximum Dosage Limits:
-Neonates
Premature Neonates: Safety and efficacy have not been established; however, loading doses up to 0.5 mcg/kg IV and continuous infusions up to 1.2 mcg/kg/hour IV have been used off-label.
Term Neonates: Safety and efficacy have not been established; however, loading doses up to 0.5 mcg/kg IV and continuous infusions up to 2.5 mcg/kg/hour IV have been used off-label.
-Infants
1 to 5 months: 1.5 mcg/kg IV loading dose and 1.5 mcg/kg/hour continuous IV infusion are FDA-approved maximums; however, doses up to 2.5 mcg/kg/hour continuous IV infusion have been used off-label. Doses up to 3 mcg/kg/dose intranasally used off-label for procedural sedation.
6 to 11 months: 1.5 mcg/kg IV loading dose and 1.5 mcg/kg/hour continuous IV infusion are FDA-approved maximums; however, doses up to 2.5 mcg/kg/hour continuous IV infusion have been used off-label. Doses up to 4 mcg/kg/dose intranasally used off-label for procedural sedation.
-Children
1 year: 1.5 mcg/kg IV loading dose and 1.5 mcg/kg/hour continuous IV infusion are FDA-approved maximums; however, doses up to 2.5 mcg/kg/hour continuous IV infusion have been used off-label. Doses up to 4 mcg/kg/dose intranasally used off-label for procedural sedation.
2 to 12 years: 2 mcg/kg IV loading dose and 1.5 mcg/kg/hour continuous IV infusion are FDA-approved maximums; however, doses up to 2.5 mcg/kg/hour continuous IV infusion have been used off-label. Doses up to 4 mcg/kg/dose intranasally used off-label for procedural sedation.
-Adolescents
2 mcg/kg IV loading dose and 1.5 mcg/kg/hour continuous IV infusion are FDA-approved maximums; however, doses up to 2.5 mcg/kg/hour continuous IV infusion have been used off-label. Doses up to 4 mcg/kg/dose intranasally used off-label for procedural sedation.

Patients with Hepatic Impairment Dosing
Consider initial dosage reduction in patients with hepatic impairment; titrate to effect.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Dexmedetomidine is a relatively selective, centrally-acting, alpha2-adrenergic agonist with sedative, analgesic, and sympatholytic properties but without significant ventilatory effects. Selectivity for the alpha2-receptors is observed in animals after slow intravenous (IV) infusion of dosages ranging from 10 to 300 mcg/kg. Both alpha1 and alpha2 activity is observed after slow IV infusion of very high doses (1,000 mcg/kg or more) or with rapid IV administration. Dexmedetomidine is 8 times more specific for alpha2-receptors than clonidine; activity ratios of alpha2:alpha1 activity are 1,620:1 and 220:1 for dexmedetomidine and clonidine, respectively.

In general, presynaptic activation of alpha2-receptors inhibits the release of norepinephrine and terminates the propagation of pain signals. Postsynaptic activation of alpha2-receptors in the central nervous system (CNS) inhibits sympathetic activity and therefore decreases blood pressure and heart rate. Together, the presynaptic and postsynaptic actions produce sedation, analgesia, and anxiolysis. The analgesic effect of dexmedetomidine is not clearly understood. It is believed that the drug may somehow regulate the transmission of nociceptive signals at both CNS and peripheral sites. In addition, it is known that alpha2-agonism activates G1-protein-gated potassium channels, preventing neuronal firing, and reduces G0-protein-mediated calcium conductance into the cells, inhibiting neurotransmitter release. High densities of alpha2-receptors are found in the locus coeruleus, a predominate noradrenergic center in the brain, which not only modulates alertness but is the site of origin for the descending medullospinal noradrenergic pathway, an important modulator of nociceptive transmission. Dexmedetomidine also directly stimulates alpha2-receptors in the spinal cord, inhibiting nociceptive neuronal firing and the release of substance P.

Alpha2-receptor agonists reduce blood pressure, heart rate, and plasma catecholamine concentrations; hypotension and bradycardia occur in a dose-dependent manner. Rapid injection of dexmedetomidine activates alpha2-receptors in peripheral blood vessels, resulting in transient hypertension and significant reflex bradycardia. Dexmedetomidine does not alter respiratory rate or oxygen saturation at the recommended dosage. The sympathetic effects of dexmedetomidine may attenuate myocardial oxygen requirements and myocardial oxygen consumption, as well as increase endocardial/epicardial blood flow ratios. Other physiologic responses to alpha2-receptor activation outside the CNS include decreased salivation, secretion, and bowel motility in the gastrointestinal tract; contraction of vascular and smooth muscle; inhibition of renin release, increased glomerular filtration, and increased sodium and water secretion in the kidney; decreased intraocular pressure; and decreased release of insulin from the pancreas.

Pharmacokinetics: Dexmedetomidine is administered by intravenous infusion in pediatric patients. It is rapidly distributed with a distribution half-life of 6 minutes and a large Vd (118 L in adults). Plasma protein binding is 94%. Dexmedetomidine undergoes almost complete biotransformation with minimal unchanged drug excreted in urine and feces. Biotransformation involves direct N-glucuronidation, aliphatic hydroxylation (mediated primarily by CYP2A6), and N-methylation. Terminal elimination half-life is approximately 2 hours, and clearance is estimated to be approximately 39 L/hour in adults. About 95% of the dose is recovered in the urine (85% within 24 hours) and 4% in the feces. Pharmacokinetic parameters (Vd, half-life, and clearance) are similar between IV continuous infusion dosage ranges of 0.2 to 0.7 mcg/kg/hour for 24 hours or less and 0.2 to 1.4 mcg/kg/hour for more than 24 hours in adults.

Affected cytochrome P450 isoenzymes and drug transporters: CYP2A6
Dexmedetomidine undergoes aliphatic hydroxylation mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6, and CYP2C19; however, clinically significant cytochrome P450-mediated drug interactions are not expected.


-Route-Specific Pharmacokinetics
Intravenous Route
In general, onset of action occurs within 5 to 10 minutes and persists for 60 to 120 minutes. Dexmedetomidine exhibits linear kinetics in the dosage range of 0.2 to 0.7 mcg/kg/hour when administered by continuous IV infusion for up to 24 hours.

Other Route(s)
Intranasal Route
In general, onset of action occurs in 20 to 30 minutes and persists 30 to 45 minutes. In a pharmacokinetic study of 6 healthy adult males, dexmedetomidine 84 mcg administered via nasal spray (1 dose in each nostril) resulted in a median Cmax of 0.34 ng/mL (range: 0.23 to 0.7 ng/mL) within approximately 40 minutes (range: 15 to 60 minutes). The bioavailability of intranasal dexmedetomidine varied, with a median of 65% (range: 35% to 93%).


-Special Populations
Pediatrics
Premature and Term Neonates
Premature neonates and, to a lesser extent, term neonates have decreased protein binding, a larger Vd, decreased clearance, increased half-life, and increased AUC values when compared to older children and adults. Decreased protein binding capacity and an immature hepatic system allow for increased unbound dexmedetomidine in premature neonates; this may contribute significantly to increased half-life and AUC values. Overall, premature neonates (n = 18; gestational age: 28 to 35 weeks) appeared to have lower clearance (0.3 vs. 0.9 L/kg/hour), increased elimination half-life (7.6 vs. 3.2 hours), and increased AUC (2,049 vs. 357 pg x hour/mL per mcg) compared to term neonates (n = 24; gestational age: 36 to 44 weeks) receiving dexmedetomidine for at least 6 hours. Vd was also significantly different, with mean values of 2.7 and 3.8 L/kg for premature and term neonates, respectively. Clearance in term neonates is approximately 42% of adult values. In a phase I pharmacokinetic study (n = 20; postmenstrual age [PMA]: 33 to 61 weeks; weight: 2 to 6 kg) where the median maximum dexmedetomidine infusion rate was 1.8 mcg/kg/hour, the estimated clearance and Vd were 0.87 to 2.65 L/kg/hour and 1.5 L/kg, respectively. Younger PMA was a significant predictor of lower clearance, which increased by 4.5% per 1-week increase in PMA at median PMA (44 weeks). Dexmedetomidine is highly lipid-soluble. The immature blood-brain barrier of the neonate may potentially facilitate higher cerebrospinal fluid drug concentrations, resulting in increased sedative effects. Thus, lower doses than those recommended in other populations should be considered initially.

Infants
The clearance of dexmedetomidine in infants is considerably reduced compared to older populations. This is attributable to immature hepatic microsomal enzyme pathways. Clearance at birth is approximately 42% of adult values, reaching 72% by 6 months, and 85% by 12 months of age. In a phase I pharmacokinetic study (n = 20; postmenstrual age [PMA]: 33 to 61 weeks; weight: 2 to 6 kg) where the median maximum dexmedetomidine infusion rate was 1.8 mcg/kg/hour, the estimated clearance and Vd were 0.87 to 2.65 L/kg/hour and 1.5 L/kg, respectively. In another pooled analysis of 4 pediatric pharmacokinetic studies, clearance estimates were 6.94 and 8.15 L/hour for infants 1 to 5 months and 6 to 11 months, respectively. Corresponding Vd estimates for these populations were 4.34 and 7.29 L, respectively.

Children and Adolescents
A pooled analysis of 4 pediatric pharmacokinetic studies revealed clearance estimates of 10.76, 15.89, and 24.45 L/hour for children 12 to 23 months, 2 to 5 years, and 6 to 16 years, respectively. Corresponding Vd estimates for these populations were 7.35, 13.78, and 24.47 L, respectively.

Hepatic Impairment
Protein binding and clearance values are significantly lower in patients with hepatic impairment. During adult pharmacokinetic studies, mean clearance values for subjects with Child-Pugh Class A, B, or C hepatic impairment were 74%, 64%, and 53% of those observed in the healthy subjects, respectively. Mean clearances for unbound drug were 59%, 51%, and 32% of those observed in healthy subjects, respectively.

Renal Impairment
Dexmedetomidine pharmacokinetics (Cmax, Tmax, AUC, half-life, clearance, Vd) were not significantly different in patients with severe renal dysfunction (CrCl less than 30 mL/minute) compared to healthy subjects in clinical trials. However, in a small study of 12 adults, those with renal failure (mean CrCl 20.9 +/- 9.3 mL/minute) had a significantly shorter half-life and increased sedation scores compared to the control group (mean CrCl 122.1 +/- 30.8 mL/minute). After receipt of dexmedetomidine 0.6 mcg/kg given over 10 minutes, half-life in the renal failure group was 113.4 minutes, compared to 136.5 minutes in the control group. Though protein binding was not specifically measured, decreased protein binding of the drug (as often seen in renal dysfunction) may have resulted in more profound central nervous system effects and increased availability of the drug for elimination.

Other
Congenital Heart Disease
In a pharmacokinetic study of 36 open-heart surgery patients (aged 1 to 24 months), clearance of dexmedetomidine was greater (mean increase 22%, range 1% to 49%) in patients with single-ventricle physiology and inversely related to the duration of cardiopulmonary bypass. In another study (n = 20; postmenstrual age: 33 to 61 weeks) neonates and infants with a recent history of cardiac surgery had approximately 40% lower clearance compared to those without such a history (median clearance 1.01 L/kg/hour vs. 1.6 L/kg/hour, respectively).