Dexmedetomidine

N05C - Hypnotics and sedatives ATC N05CM18 Small molecule approved 1999 Parenteral Topical Natural product

JFDA label: Precedex Vial

Mechanism of Action

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.

Indications

Approved

Intensive care unit sedation
Procedural sedation

Off-label

Sedation during awake craniotomy
Treatment of shivering

Contraindications

Source: Lexicomp

Hypersensitivity to dexmedetomidine or any component of the formulation Absolute
There are no contraindications listed in the U.S. manufacturer's labeling Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (9)

Very Common bradycardia · hypertension · Hypotension · systolic hypertension · tachycardia

Common Atrial fibrillation · edema · hypovolemia · peripheral edema

Nervous system disorders (2)

Very Common Agitation

Common Anxiety

Renal and urinary disorders (3)

Common Acute renal failure · decreased urine output · Oliguria

Blood and lymphatic system disorders (1)

Common Anemia

Metabolism and nutrition disorders (6)

Common hyperglycemia · hypocalcemia · hypoglycemia · Hypokalemia · hypomagnesemia · increased thirst

Gastrointestinal disorders (3)

Very Common Constipation · nausea

Common Xerostomia

General disorders and administration site conditions (2)

Common Fever · withdrawal syndrome

Respiratory, thoracic and mediastinal disorders (5)

Very Common Respiratory depression

Common adult respiratory distress syndrome · pleural effusion · Respiratory failure · wheezing

Other (57)

Not Known 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

Dosing

Source: Lexicomp

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, 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 0.5 to 1 mcg/kg over 10 to 20 minutes, followed by a maintenance infusion of 0.5 mcg/kg/hour, titrate to desired effect (Bekker 2001; Bekker, 2008; Piccioni 2008; Shen 2013); usual range: 0.1 to 0.7 mcg/kg/hour (Piccioni 2008)

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.

There are no dosage adjustments provided in the manufacturer’s labeling; however, pharmacokinetics were not significantly different in patients with severe renal impairment (CrCl

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.

Warnings & Precautions

Source: Lexicomp

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.

Pregnancy & Lactation

Pregnancy

FDA category C

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).

Lactation

It is not known if dexmedetomidine is excreted in breast milk. According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of infant exposure, the benefits of breast-feeding to the infant, and benefits of treatment to the mother.

Monitoring

Clinical pearl	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)

Chemistry & Properties

Formula	C13H16N2
Molecular weight	200.28 g/mol
IUPAC name	5-[(1S)-1-(2,3-dimethylphenyl)ethyl]-1H-imidazole
CAS	113775-47-6
PubChem CID	5311068
InChIKey	`CUHVIMMYOGQXCV-NSHDSACASA-N`
logP	3.18 (XLogP 3.1)
Polar surface area	28.68 Å²
H-bond acceptors / donors	1 / 1
Drug-likeness (QED)	0.79
Lipinski violations	0

SMILES

Cc1cccc([C@H](C)c2c[nH]cn2)c1C

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	1.655 h
Volume of distribution	1.15 L/kg
Protein binding	93.5%
BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	—
CYP2B6	Inhibitor	—
CYP2C19	Inhibitor	—
CYP2C8	Inhibitor	—
CYP2C9	Inhibitor	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 6)

Target	Action	Affinity
α2B-adrenoceptor (ADRA2B)	Agonist	pIC50 10.9
α2B-adrenoceptor (ADRA2B)	Agonist	pEC50 9.9
α2C-adrenoceptor (ADRA2C)	Agonist	pEC50 9.6
α2A-adrenoceptor (ADRA2A)	Agonist	pIC50 9.3
α2C-adrenoceptor (ADRA2C)	Agonist	pIC50 9.2
α2A-adrenoceptor (ADRA2A)	Agonist	pEC50 7.6

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)P-gp (Substrate)

Drug–drug interactions (44, DDInter)

Interacting drug	Severity	Management
Aldesleukin	moderate
Amyl Nitrite	moderate
Azatadine	moderate
Brimonidine (ophthalmic)	moderate
Brimonidine (topical)	moderate
Carbinoxamine	moderate
Cetirizine	moderate
Chlorphenesin	moderate
Chlorpheniramine	moderate
Clemastine	moderate
Clofedanol	moderate
Codeine	moderate
Cyclizine	moderate
Cyproheptadine	moderate
Dexbrompheniramine	moderate
Dextromethorphan	moderate
Diazoxide	moderate
Diphenhydramine	moderate
Diphenoxylate	moderate
Doxepin	moderate
Doxepin (topical)	moderate
Doxylamine	moderate
Dronabinol	moderate
Ethanol	moderate
Hydrocodone	moderate
Ifosfamide	moderate
Levocetirizine	moderate
Meclizine	moderate
Mepyramine	moderate
Minoxidil	moderate
Morphine	moderate
Morphine (liposomal)	moderate
Nabilone	moderate
Olopatadine (nasal)	moderate
Opium	moderate
Papaverine	moderate
Pentoxyverine	moderate
Phentolamine	moderate
Promethazine	moderate
Sibutramine	moderate

Showing 40 of 44.

Registered Products (9)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Desedate 0.2mg/2ml solution for infusion	Infusion 0.2 mg	1 vial	MS Pharma Jordan	—
Dexmedetomidine Ever Pharma	Vial ( as Hcl) 200 mcg/2 ml	2 ml	Sabbagh Drug Store	—
Dexmedetomidine Ever Pharma	Vial ( as Hcl) 400 mcg/4 ml	4 ml	Sabbagh Drug Store	—
Dexmedetomidine Ever Pharma	Vial (as Hcl) 1000 mcg/10 ml	10 ml	Sabbagh Drug Store	—
Dexmedetomidine Pharmidea 100 Micogram/ml concentrate for solution for inf	Solution 100 mcg/1 ml	25 vial	شركة مستودع ادوية جرينلاند	—
Precedex Vial	Vial 100 mcg/ml	25 vial	Khoury Drug Store	—
Primidex	Vial 4 mcg/1 ml	1 vial pack varies	Pharma International Company/ Jordan	—
Primidex	Vial 4 mcg/1 ml	10 vial pack varies	Pharma International Company/ Jordan	—
Proxida	Vial 200 mcg/2 ml	2 ml	Hikma Pharmaceuticals Co.Ltd/Jordan	—