Dexmedetomidine Hydrochloride

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a relatively selective alpha
₂-adrenergic agonist indicated for:

• Sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Administer dexmedetomidine hydrochloride in 0.9% sodium chloride injection by continuous infusion not to exceed 24 hours. (
  
  1.1 Intensive Care Unit Sedation

  Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be administered by continuous infusion not to exceed 24 hours.

  
  
  

  Dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue dexmedetomidine hydrochloride in 0.9% sodium chloride injection prior to extubation.
  ).
  

• Sedation of non-intubated patients prior to and/or during surgical and other procedures. (
  
  1.2 Procedural Sedation

  
  
  

  Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures.
  )
  

• Individualize and titrate dexmedetomidine hydrochloride in 0.9% sodium chloride injection dosing to desired clinical effect. (
  
  
  
  2.1 Dosing Guidelines

  • Dexmedetomidine hydrochloride in 0.9% sodium chloride injection dosing should be individualized and titrated to desired clinical response.
  • Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is not indicated for infusions lasting longer than 24 hours.
  • Dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be administered using a controlled infusion device.
  ) 
  
  
• Administer dexmedetomidine hydrochloride in 0.9% sodium chloride injection using a controlled infusion device. (
  
  
  
  2.1 Dosing Guidelines

  • Dexmedetomidine hydrochloride in 0.9% sodium chloride injection dosing should be individualized and titrated to desired clinical response.
  • Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is not indicated for infusions lasting longer than 24 hours.
  • Dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be administered using a controlled infusion device.
  ) 
  
  
• The 200 mcg/50mL and 400 mcg/100 mL single-dose Vials, do not require further dilution prior to administration. (
  
  
  
  2.4 Preparation of Solution

  
  
  

  Strict aseptic technique must always be maintained during handling of dexmedetomidine hydrochloride in 0.9% sodium chloride injection.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
  
  
  
  

  Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection, 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL).
  
  
  
  

  Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection is supplied in glass containers containing a premixed, ready to use dexmedetomidine hydrochloride solution in 0.9% sodium chloride in water. No further dilution of these preparations are necessary.
  )
  
  

Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection is clear and colorless and is available as follows.

• Pregnancy: Based on animal data, may cause fetal harm. (
  
  
  
  8.1 Pregnancy

  
  
  

  Pregnancy Category C
  
  

  There are no adequate and well-controlled studies of dexmedetomidine hydrochloride in 0.9% sodium chloride injection use in pregnant women. In an

  in vitro

  human placenta study, placental transfer of dexmedetomidine occurred. In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously. Thus, fetal exposure should be expected in humans, and dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.
  
  Teratogenic effects were not observed in rats following subcutaneous administration of dexmedetomidine during the period of fetal organogenesis (from gestation day 5 to 16) with doses up to 200 mcg/kg (representing a dose approximately equal to the maximum recommended human intravenous dose based on body surface area) or in rabbits following intravenous administration of dexmedetomidine during the period of fetal organogenesis (from gestation day 6 to 18) with doses up to 96 mcg/kg (representing approximately half the human exposure at the maximum recommended dose based on plasma area under the time-curve comparison). However, fetal toxicity, as evidenced by increased post-implantation losses and reduced live pups, was observed in rats at a subcutaneous dose of 200 mcg/kg. The no-effect dose in rats was 20 mcg/kg (representing a dose less than the maximum recommended human intravenous dose based on a body surface area comparison). In another reproductive toxicity study when dexmedetomidine was administered subcutaneously to pregnant rats at 8 and 32 mcg/kg (representing a dose less than the maximum recommended human intravenous dose based on a body surface area comparison) from gestation day 16 through weaning, lower offspring weights were observed. Additionally, when offspring of the 32 mcg/kg group were allowed to mate, elevated fetal and embryocidal toxicity and delayed motor development was observed in second generation offspring.
  )
  
  
• Nursing Mothers: Caution should be exercised when administered to a nursing woman. (
  
  
  
  8.3 Nursing Mothers

  
  
  

  It is not known whether dexmedetomidine is excreted in human milk. Radio-labeled dexmedetomidine administered subcutaneously to lactating female rats was excreted in milk. Because many drugs are excreted in human milk, caution should be exercised when dexmedetomidine hydrochloride in 0.9% sodium chloride injection is administered to a nursing woman.
  )
  
  
• Geriatric Patients: Dose reduction should be considered. (
  
  
  
  2.2 Dosage Information

  
  
  

  Table1: Dosage Information

  
  
  

  INDICATION	DOSAGE AND ADMINISTRATION
  Initiation of Intensive Care Unit Sedation	For adult patients: a loading infusion of one mcg/kg over 10 minutes . For adult patients being converted from alternate sedative therapy: a loading dose may not be required. For patients over 65 years of age: a dose reduction should be considered [ see Use in Specific Populations (8.5) ]. For adult patients with impaired hepatic function: a dose reduction should be considered [ see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].
  Maintenance of Intensive Care Unit Sedation	For adult patients: a maintenance infusion of 0.2 to 0.7 mcg/kg/ hour . The rate of the maintenance infusion should be adjusted to achieve the desired level of sedation. For patients over 65 years of age: a dose reduction should be considered [ see Use in Specific Populations (8.5) ] . For adult patients with impaired hepatic function: a dose reduction should be considered [ see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].
  Initiation of Procedural Sedation	For adult patients: a loading infusion of one mcg/kg over 10 minutes . For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable. For awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes . For patients over 65 years of age: a loading infusion of 0.5 mcg/kg over 10 minutes [ see Use in Specific Populations (8.5) ] . For adult patients with impaired hepatic function: a dose reduction should be considered [ see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].
  Maintenance of Procedural Sedation	For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/ hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/ hour . The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation. For awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/ hour is recommended until the endotracheal tube is secured. For patients over 65 years of age: a dose reduction should be considered [ see Use in Specific Populations (8.5) ] . For adult patients with impaired hepatic function: a dose reduction should be considered [ see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].
  ,
  
  
  
  2.3 Dosage Adjustment

  Due to possible pharmacodynamic interactions, a reduction in dosage of dexmedetomidine hydrochloride in 0.9% sodium chloride injection or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered [

  see Drug Interactions (7.1)

  ].

  
  
  

  Dosage reductions may need to be considered for

  adult

  patients with hepatic impairment and geriatric patients [

  see Warnings and Precautions (5.7), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)

  ].
  ,
  
  
  
  5.2 Hypotension, Bradycardia, and Sinus Arrest

  
  
  

  Clinically significant episodes of bradycardia and sinus arrest have been reported with dexmedetomidine administration in young, healthy adult volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration.
  
  
  
  Reports of hypotension and bradycardia have been associated with dexmedetomidine infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine hydrochloride in 0.9% sodium chloride  injection, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because dexmedetomidine has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of dexmedetomidine-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.
  
  
  
  Caution should be exercised when administering dexmedetomidine hydrochloride in 0.9% sodium chloride injection to patients with advanced heart block and/or severe ventricular dysfunction. Because dexmedetomidine decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients.
  
  
  
  In clinical trials where other vasodilators or negative chronotropic agents were co-administered with dexmedetomidine hydrochloride in 0.9% sodium chloride injection an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine hydrochloride in 0.9% sodium chloride injection.
  ,
  
  
  
  8.5 Geriatric Use

  
  
  

  Intensive Care Unit Sedation

  A total of 729 patients in the clinical studies were 65 years of age and over. A total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection [

  see Warnings and Precautions (5.2)

  ]. Therefore, a dose reduction may be considered in patients over 65 years of age [

  see Dosage and Administration (2.2, 2.3) and Clinical Pharmacology (12.3)

  ]

  .

  
  
  

  Procedural Sedation

  
  
  
  
  A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in dexmedetomidine-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age.
  )
  
  
• Hepatic Impairment: Dose reduction should be considered. (
  
  
  
  2.2 Dosage Information

  
  
  

  Table1: Dosage Information

  
  
  

  INDICATION	DOSAGE AND ADMINISTRATION
  Initiation of Intensive Care Unit Sedation	For adult patients: a loading infusion of one mcg/kg over 10 minutes . For adult patients being converted from alternate sedative therapy: a loading dose may not be required. For patients over 65 years of age: a dose reduction should be considered [ see Use in Specific Populations (8.5) ]. For adult patients with impaired hepatic function: a dose reduction should be considered [ see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].
  Maintenance of Intensive Care Unit Sedation	For adult patients: a maintenance infusion of 0.2 to 0.7 mcg/kg/ hour . The rate of the maintenance infusion should be adjusted to achieve the desired level of sedation. For patients over 65 years of age: a dose reduction should be considered [ see Use in Specific Populations (8.5) ] . For adult patients with impaired hepatic function: a dose reduction should be considered [ see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].
  Initiation of Procedural Sedation	For adult patients: a loading infusion of one mcg/kg over 10 minutes . For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable. For awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes . For patients over 65 years of age: a loading infusion of 0.5 mcg/kg over 10 minutes [ see Use in Specific Populations (8.5) ] . For adult patients with impaired hepatic function: a dose reduction should be considered [ see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].
  Maintenance of Procedural Sedation	For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/ hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/ hour . The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation. For awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/ hour is recommended until the endotracheal tube is secured. For patients over 65 years of age: a dose reduction should be considered [ see Use in Specific Populations (8.5) ] . For adult patients with impaired hepatic function: a dose reduction should be considered [ see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].
  ,
  
  
  
  2.3 Dosage Adjustment

  Due to possible pharmacodynamic interactions, a reduction in dosage of dexmedetomidine hydrochloride in 0.9% sodium chloride injection or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered [

  see Drug Interactions (7.1)

  ].

  
  
  

  Dosage reductions may need to be considered for

  adult

  patients with hepatic impairment and geriatric patients [

  see Warnings and Precautions (5.7), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)

  ].
  ,
  
  
  
  5.7 Hepatic Impairment

  Since dexmedetomidine clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [

  see Dosage and Administration (2.2, 2.3)

  ].
  ,
  
  
  
  8.6 Hepatic Impairment

  Since dexmedetomidine clearance decreases with increasing severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [

  see Dosage and Administration (2.2, 2.3) and Clinical Pharmacology (12.3)

  ].
  )
  
  

• Monitoring: Continuously monitor patients while receiving dexmedetomidine hydrochloride in 0.9% sodium chloride injection. (
  
  
  
  5.1 Drug Administration

  
  
  

  Dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be administered only by persons skilled in the management of patients in the intensive care or operating room setting. Due to the known pharmacological effects of dexmedetomidine, patients should be continuously monitored while receiving dexmedetomidine hydrochloride in 0.9% sodium chloride injection.
  )
  
  
• Bradycardia and Sinus Arrest: Have occurred in young healthy volunteers with high vagal tone or with different routes of administration, e.g., rapid intravenous or bolus administration. (
  
  
  
  5.2 Hypotension, Bradycardia, and Sinus Arrest

  
  
  

  Clinically significant episodes of bradycardia and sinus arrest have been reported with dexmedetomidine administration in young, healthy adult volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration.
  
  
  
  Reports of hypotension and bradycardia have been associated with dexmedetomidine infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine hydrochloride in 0.9% sodium chloride  injection, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because dexmedetomidine has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of dexmedetomidine-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.
  
  
  
  Caution should be exercised when administering dexmedetomidine hydrochloride in 0.9% sodium chloride injection to patients with advanced heart block and/or severe ventricular dysfunction. Because dexmedetomidine decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients.
  
  
  
  In clinical trials where other vasodilators or negative chronotropic agents were co-administered with dexmedetomidine hydrochloride in 0.9% sodium chloride injection an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine hydrochloride in 0.9% sodium chloride injection.
  )
  
  
• Hypotension and Bradycardia: May necessitate medical intervention. May be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension, and in the elderly. Use with caution in patients with advanced heart block or severe ventricular dysfunction. (
  
  
  
  5.2 Hypotension, Bradycardia, and Sinus Arrest

  
  
  

  Clinically significant episodes of bradycardia and sinus arrest have been reported with dexmedetomidine administration in young, healthy adult volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration.
  
  
  
  Reports of hypotension and bradycardia have been associated with dexmedetomidine infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine hydrochloride in 0.9% sodium chloride  injection, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because dexmedetomidine has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of dexmedetomidine-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.
  
  
  
  Caution should be exercised when administering dexmedetomidine hydrochloride in 0.9% sodium chloride injection to patients with advanced heart block and/or severe ventricular dysfunction. Because dexmedetomidine decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients.
  
  
  
  In clinical trials where other vasodilators or negative chronotropic agents were co-administered with dexmedetomidine hydrochloride in 0.9% sodium chloride injection an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine hydrochloride in 0.9% sodium chloride injection.
  )
  
  
• Co-administration with Other Vasodilators or Negative Chronotropic Agents: Use with caution due to additive pharmacodynamic effects. (
  
  
  
  5.2 Hypotension, Bradycardia, and Sinus Arrest

  
  
  

  Clinically significant episodes of bradycardia and sinus arrest have been reported with dexmedetomidine administration in young, healthy adult volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration.
  
  
  
  Reports of hypotension and bradycardia have been associated with dexmedetomidine infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine hydrochloride in 0.9% sodium chloride  injection, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because dexmedetomidine has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of dexmedetomidine-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.
  
  
  
  Caution should be exercised when administering dexmedetomidine hydrochloride in 0.9% sodium chloride injection to patients with advanced heart block and/or severe ventricular dysfunction. Because dexmedetomidine decreases sympathetic nervous system activity, hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients.
  
  
  
  In clinical trials where other vasodilators or negative chronotropic agents were co-administered with dexmedetomidine hydrochloride in 0.9% sodium chloride injection an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine hydrochloride in 0.9% sodium chloride injection.
  )
  
  
• Transient Hypertension: Observed primarily during the loading dose. Consider reduction in loading infusion rate. (
  
  
  
  5.3 Transient Hypertension

  
  
  

  Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of dexmedetomidine hydrochloride in 0.9% sodium chloride injection. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable.
  )
  
  
• Arousability: Patients can become aroused/alert with stimulation; this alone should not be considered as lack of efficacy. (
  
  
  
  5.4 Arousability

  
  
  

  Some patients receiving dexmedetomidine hydrochloride in 0.9% sodium chloride injection have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms.
  )
  
  
• Tolerance and tachyphylaxis: Prolonged exposure to dexmedetomidine beyond 24 hours may be associated with tolerance and tachyphylaxis and a dose-related increase in adverse events. (
  
  
  
  5.6 Tolerance and Tachyphylaxis

  Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions [

  see Adverse Reactions (6.1)

  ].
  )