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Dexmedetomidine

Pronunciation

(deks MED e toe mi deen)

Index Terms

  • Dexmedetomidine HCl
  • Dexmedetomidine Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous:

Generic: 400 mcg/4 mL (4 mL); 1000 mcg/10 mL (10 mL)

Solution, Intravenous [preservative free]:

Precedex: 400 mcg/100 mL (100 mL); 200 mcg/2 mL (2 mL) [additive free, latex free]

Precedex: 200 mcg/50 mL (50 mL) [latex free]

Precedex: 80 mcg/20 mL (20 mL)

Generic: 200 mcg/2 mL (2 mL)

Brand Names: U.S.

  • Precedex

Pharmacologic Category

  • Alpha2-Adrenergic Agonist
  • Sedative

Pharmacology

Selective alpha2-adrenoceptor agonist with anesthetic and sedative properties thought to be due to activation of G-proteins by alpha2a-adrenoceptors in the brainstem resulting in inhibition of norepinephrine release; peripheral alpha2b-adrenoceptors are activated at high doses or with rapid IV administration resulting in vasoconstriction.

Distribution

Vss: ~118 L; rapid

Metabolism

Hepatic via N-glucuronidation, N-methylation, and CYP2A6

Excretion

Urine (95%); feces (4%)

Clearance: Adults: 39 L/hour; hepatic impairment (Child-Pugh class A, B, or C): mean clearance values were 74%, 64%, and 53% respectively, of those observed in healthy adults; clearance at birth is approximately 30% of adults, reaching adult values between 6-12 months of age

Onset of Action

IV Bolus: 5 to 10 minutes; Peak effect: 15 to 30 minutes

Duration of Action

Dose dependent: 60 to 120 minutes

Half-Life Elimination

Distribution: ~6 minutes; Terminal: ~up to 3 hours (Venn 2002); significantly prolonged in patients with severe hepatic impairment (Cunningham, 1999)

Protein Binding

~94%

Special Populations: Hepatic Function Impairment

Clearance and plasma protein binding are decreased in patients with hepatic impairment.

Use: Labeled Indications

Intensive care unit sedation: Sedation of initially-intubated and mechanically-ventilated patients during treatment in an intensive care setting

Procedural sedation: Procedural sedation prior to and/or during awake fiberoptic intubation; sedation prior to and/or during surgical or other procedures of nonintubated patients

Use: Unlabeled

Awake craniotomy; procedural sedation in children (MRI, CT, EEG; with or without ketamine); treatment of shivering

Contraindications

There are no contraindications listed in the U.S. manufacturer's labeling.

Canadian labeling: Hypersensitivity to dexmedetomidine or any component of the formulation.

Dosing: Adult

Note: Errors have occurred due to misinterpretation of dosing information. Maintenance dose expressed as mcg/kg/hour. Individualized and titrated to desired clinical effect. At recommended doses, dexmedetomidine does not provide adequate and reliable amnesia (when necessary); therefore, use of additional agents with amnestic properties (eg, benzodiazepines) may be necessary (Ebert 2000).

ICU sedation: IV: Initial: Loading infusion (optional; see "Note" below) of 1 mcg/kg over 10 minutes (US labeling) or 20 minutes (Canadian labeling), followed by a maintenance infusion (see "Note" below) of 0.2 to 0.7 mcg/kg/hour; adjust rate to desired level of sedation; titration no more frequently than every 30 minutes may reduce the incidence of hypotension (Gerlach 2009)

Note: Loading infusion: The loading dose may be omitted for this indication if patient is either being converted from another sedative and patient is adequately sedated or there are concerns for hemodynamic compromise. Maintenance infusion: Dosing ranges between 0.2 to 1.5 mcg/kg/hour have been reported during randomized controlled clinical trials (Pandharipande 2007; Riker 2009). Although infusion rates as high as 2.5 mcg/kg/hour have been used, it is thought that doses >1.5 mcg/kg/hour do not add to clinical efficacy (Venn 2003). Manufacturer recommends duration of infusion should not exceed 24 hours; however, randomized clinical trials have demonstrated efficacy and safety comparable to lorazepam and midazolam with longer-term infusions of up to ~5 days (Pandharipande 2007; Riker 2009).

Procedural sedation: IV: Initial: Loading infusion of 1 mcg/kg (or 0.5 mcg/kg for less invasive procedures [eg, ophthalmic]) over 10 minutes, followed by a maintenance infusion of 0.6 mcg/kg/hour, titrate to desired effect; usual range: 0.2 to 1 mcg/kg/hour

Fiberoptic intubation (awake): IV: Initial: Loading infusion of 1 mcg/kg over 10 minutes, followed by a maintenance infusion of 0.7 mcg/kg/hour until endotracheal tube is secured (Bergese 2010).

Craniotomy (awake) (off-label use): IV: Initial: Loading infusion of 1 mcg/kg over 10 minutes, followed by a maintenance infusion of 0.5 mcg/kg/hour, titrate to desired effect (Bekker 2008); usual range: 0.1 to 0.7 mcg/kg/hour (Piccioni 2008)

Dosing: Geriatric

ICU sedation: IV: Refer to adult dosing. Consider dosage reduction. No specific guidelines available. Dose selections should be cautious, at the low end of dosage range; titration should be slower, allowing adequate time to evaluate response.

Procedural sedation: IV: Refer to adult dosing: Initial: Loading infusion of 0.5 mcg/kg over 10 minutes; Maintenance infusion: Dosage reduction should be considered.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; however, pharmacokinetics were not significantly different in patients with severe renal impairment (CrCl <30 mL/minute).

Dosing: Hepatic Impairment

There are no specific dosage adjustments provided in the manufacturer’s labeling; however, consider a dose reduction. Clearance is reduced in varying degrees based on the level of impairment.

Reconstitution

Concentrated solution (100 mcg/mL): Must dilute in NS to achieve the required concentration (4 mcg/mL) prior to administration. Add 2 mL (200 mcg) of dexmedetomidine to 48 mL of NS for a total volume of 50 mL (4 mcg/mL) or 4 mL (400 mcg) of dexmedetomidine to 96 mL of NS for a total volume of 100 mL. Shake gently to mix.

Administration

Administer using a controlled infusion device. Advisable to use administration components made with synthetic or coated natural rubber gaskets. If loading dose used, administer over 10 minutes; may extend to 20 minutes to further reduce vasoconstrictive effects. Titration no more frequently than every 30 minutes may reduce the incidence of hypotension when used for ICU sedation (Gerlach 2009).

Compatibility

Stable in D5W, LR, NS, mannitol 20%, plasma substitute.

Y-site administration: Incompatible with amphotericin B, diazepam.

May adsorb to certain types of natural rubber; use components made with synthetic or coated natural rubber gaskets whenever possible.

Storage

Store at room temperature. May store diluted solution up to 4 hours at room temperature or up to 24 hours at 2°C to 8°C (35°F to 46°F).

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta-Blockers: Alpha2-Agonists may enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Levobunolol; Metipranolol. Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Monitor therapy

CYP2A6 Inhibitors (Moderate): May decrease the metabolism of CYP2A6 Substrates. Monitor therapy

CYP2A6 Inhibitors (Strong): May decrease the metabolism of CYP2A6 Substrates. Consider therapy modification

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Iobenguane I 123: Alpha2-Agonists may diminish the therapeutic effect of Iobenguane I 123. Avoid combination

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Mirtazapine: May diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding concurrent use. If the combination cannot be avoided, monitor for decreased effects of alpha2-agonists if mirtazapine is initiated/dose increased, or increased effects if mirtazapine is discontinued/dose decreased. Consider therapy modification

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May diminish the antihypertensive effect of Alpha2-Agonists. Monitor therapy

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy

Tricyclic Antidepressants: May diminish the antihypertensive effect of Alpha2-Agonists. Consider therapy modification

Adverse Reactions

Frequency dependent upon dose, duration, and indication.

>10%:

Cardiovascular: Hypotension (24% to 56%), bradycardia (5% to 42%), systolic hypertension (28%), tachycardia (25%), hypertension (diastolic; 12%), hypertension (11%)

Central nervous system: Agitation (5% to 14%)

Gastrointestinal: Constipation (6% to 14%), nausea (3% to 11%)

Respiratory: Respiratory depression (37%; placebo 32%)

1% to 10%:

Cardiovascular: Atrial fibrillation (2% to 9%), peripheral edema (3% to 7%), hypovolemia (3%), edema (2%)

Central nervous system: Anxiety (5% to 9%)

Endocrine & metabolic: Hypokalemia (9%), hyperglycemia (7%), hypoglycemia (5%), increased thirst (2%), hypocalcemia (1%), hypomagnesemia (1%)

Gastrointestinal: Xerostomia (3% to 4%)

Genitourinary: Oliguria (2%)

Hematologic & oncologic: Anemia (3%)

Renal: Acute renal failure (2% to 3%), decreased urine output (1%)

Respiratory: Respiratory failure (2% to 10%), adult respiratory distress syndrome (1% to 9%), pleural effusion (2%), wheezing (≤1%)

Miscellaneous: Fever (5% to 7%), withdrawal syndrome (ICU sedation; 3% to 5%)

Postmarketing and/or case reports (Limited to important or life-threatening): Abdominal pain, acidosis, apnea, atrioventricular block, bronchospasm, cardiac arrhythmia, cardiac disease, chills, confusion, convulsions, decreased visual acuity, delirium, diaphoresis, diarrhea, dizziness, drug tolerance (use >24 hours), dyspnea, extrasystoles, hallucination, headache, heart block, hemorrhage, hepatic insufficiency, hyperbilirubinemia, hypercapnia, hyperkalemia, hypernatremia, hyperpyrexia, hypoventilation, hypoxia, illusion, increased blood urea nitrogen, increased gamma-glutamyl transferase, increased serum alkaline phosphatase, increased serum ALT, increased serum AST, inversion T-wave on ECG, myocardial infarction, neuralgia, neuritis, pain, photopsia, polyuria, prolonged Q-T interval on ECG, pulmonary congestion, respiratory acidosis, rigors, seizure, sinoatrial arrest, speech disturbance, supraventricular tachycardia, tachyphylaxis (use >24 hours), variable blood pressure, ventricular arrhythmia, ventricular tachycardia, visual disturbance, vomiting

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: Episodes of bradycardia, hypotension, and sinus arrest have been associated with rapid IV administration (eg, bolus administration) or when given to patients with high vagal tone. When used for ICU sedation, use of a loading dose is optional; for the maintenance infusion, titration no more frequently than every 30 minutes may reduce the incidence of hypotension (Gerlach 2009). If medical intervention is required, treatment may include stopping or decreasing the infusion, increasing the rate of IV fluid administration, use of pressor agents, and elevation of the lower extremities. At low concentrations, mean arterial pressure (MAP) may be reduced without changes in other hemodynamic parameters (eg, pulmonary artery occlusion pressure [PAOP]); however, at higher concentrations (>1.9 ng/mL), MAP, CVP, PAOP, PVR, and SVR increase (Ebert 2000).

• Transient hypertension: Has been primarily observed during loading dose administration and is associated with the initial peripheral vasoconstrictive effects of dexmedetomidine. Treatment is generally unnecessary; however, reduction of infusion rate may be required.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with heart block, bradycardia, severe ventricular dysfunction, hypovolemia, or chronic hypertension. In a scientific statement from the American Heart Association, dexmedetomidine has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: moderate) (AHA [Page 2016]).

• Diabetes: Use with caution in patients with diabetes mellitus; cardiovascular adverse events (eg, bradycardia, hypotension) may be more pronounced.

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage reductions recommended.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Use with caution in the elderly; cardiovascular events (eg, bradycardia, hypotension) may be more pronounced. Dose reduction may be necessary.

Other warnings/precautions:

• Arousability: Patients may be arousable and alert when stimulated. This alone should not be considered as lack of efficacy in the absence of other clinical signs/symptoms.

• Experienced personnel: Should be administered only by persons skilled in management of patients in intensive care setting or operating room. Patients should be continuously monitored.

• Tolerance and tachyphylaxis: Use of infusions >24 hours has been associated with tolerance and tachyphylaxis and dose-related increase in adverse reactions.

• Withdrawal: When withdrawn abruptly in patients who have received >24 hours of therapy, withdrawal symptoms may result (eg, hypertension, tachycardia, nervousness, nausea, vomiting, agitation, headaches). Use for >24 hours is not recommended by the manufacturer.

Monitoring Parameters

Level of sedation; heart rate, respiration, rhythm, blood pressure; pain control. Note: Dexmedetomidine causes minimal respiratory depression, inhibits salivation, and is analgesic-sparing.

Critically-ill mechanically ventilated patients: Monitor depth of sedation with either the Richmond Agitation-Sedation Scale (RASS) or Sedation-Agitation Scale (SAS) (Barr 2013)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects have been observed in some animal reproduction studies. Dexmedetomidine is expected to cross the placenta. Information related to use during pregnancy is limited (El-Tahan 2012).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea. Have patient report immediately to prescriber severe dizziness, passing out, difficulty breathing, slow breathing, shallow breathing, bradycardia, abnormal heartbeat, agitation, severe anxiety, headache, confusion, constipation, diarrhea, salt cravings, abdominal pain, sweating a lot, weakness, or weight loss (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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