DEXMEDETOMIDINE HYDROCHLORIDE: Package Insert and Label Information

DEXMEDETOMIDINE HYDROCHLORIDE — dexmedetomidine hydrochloride injection
Slayback Pharma LLC

1 INDICATIONS & USAGE

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.

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.

2 DOSAGE & ADMINISTRATION

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.

2.2 Dosage Information

Table 1: 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 [see Dosage and Administration (2.2) ].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 beconsidered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3) ].
Maintenance of Procedural Sedation For adult patients: the maintenance infusion is generally initiated at0.6 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 of0.7 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)].

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, 80 mcg/20 mL (4 mcg/mL), 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 single-dose 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.

2.5 Administration with Other Fluids

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection infusion should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established.
Dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam.
Dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been shown to be compatible when administered with the following intravenous fluids:
• 0.9% sodium chloride in water
• 5% dextrose in water
• 20% mannitol
• Lactated Ringer’s solution
• 100 mg/mL magnesium sulfate solution
• 0.3% potassium chloride solution

2.6 Compatibility with Natural Rubber

Compatibility studies have demonstrated the potential for absorption of dexmedetomidine hydrochloride in 0.9% sodium chloride injection to some types of natural rubber. Although dexmedetomidine hydrochloride in 0.9% sodium chloride injection is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.

3 DOSAGE FORMS & STRENGTHS

Dexmedetomidine hydrochloride in 0.9% Sodium Chloride Injection
Dexmedetomidine hydrochloride in 0.9% Sodium Chloride Injection, 80 mcg dexmedetomidine/20 mL (4 mcg/mL) dexmedetomidine in a 20 mL single-dose vial. Ready to use.
Dexmedetomidine hydrochloride in 0.9% Sodium Chloride Injection, 200 mcg dexmedetomidine/50 mL (4 mcg/mL) dexmedetomidine in a 50 mL single-dose bottle. Ready to use.
Dexmedetomidine hydrochloride in 0.9% Sodium Chloride Injection, 400 mcg dexmedetomidine/100 mL (4 mcg/mL) dexmedetomidine in a 100 mL single-dose bottle. Ready to use.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

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 hydrochloride in 0.9% sodium chloride injection, patients should be continuously monitored while receiving dexmedetomidine hydrochloride in 0.9% sodium chloride injection.

5.2 Hypotension, Bradycardia, and Sinus Arrest

Clinically significant episodes of bradycardia and sinus arrest have been reported with dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 hydrochloride in 0.9% sodium chloride injection 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 hydrochloride in 0.9% sodium chloride injection 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 hydrochloride ­ 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 hydrochloride in 0.9% sodium chloride injection 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.

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.

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.

5.5 Withdrawal

Intensive Care Unit Sedation
With administration up to 7 days, regardless of dose, 12 (5%) dexmedetomidine hydrochloride in 0.9% sodium chloride injection adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) dexmedetomidine hydrochloride in 0.9% sodium chloride injection adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events were nausea, vomiting, and agitation.
In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after discontinuation of dexmedetomidine hydrochloride in 0.9% sodium chloride injection supportive therapy is indicated.

Procedural Sedation
In adult subjects, withdrawal symptoms were not seen after discontinuation of short term infusions of dexmedetomidine hydrochloride in 0.9% sodium chloride injection (<6 hours).

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) ].

5.7 Hepatic Impairment

Since dexmedetomidine hydrochloride in 0.9% sodium chloride injection clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration (2.2)].

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

Use of dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been associated with the following serious adverse reactions:

  • Hypotension, bradycardia and sinus arrest [see Warnings and Precautions (5.2) ]
  • Transient hypertension [see Warnings and Precautions (5.3) ]

Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia and dry mouth.

Intensive Care Unit Sedation

Adverse reaction information is derived from the continuous infusion trials of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for sedation in the Intensive Care Unit setting in which 1007 adult patients received dexmedetomidine hydrochloride in 0.9% sodium chloride injection. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% ≥65 years of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 2. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see Warnings and Precautions (5.2) ].

Table 2: Adverse Reactions with an Incidence >2%—Adult Intensive Care Unit Sedation Population <24 hours*

Adverse Event All Dexmedetomidine Hydrochloride in 0.9% sodium chloride Injection (N = 1007) (%) Randomized Dexmedetomidine Hydrochloride in 0.9% sodium chloride Injection (N = 798) (%) Placebo (N = 400) (%) Propofol (N = 188) (%)
Hypotension 25% 24% 12% 13%
Hypertension 12% 13% 19% 4%
Nausea 9% 9% 9% 11%
Bradycardia 5% 5% 3% 0
Atrial Fibrillation 4% 5% 3% 7%
Pyrexia 4% 4% 4% 4%
Dry Mouth 4% 3% 1% 1%
Vomiting 3% 3% 5% 3%
Hypovolemia 3% 3% 2% 5%
Atelectasis 3% 3% 3% 6%
Pleural Effusion 2% 2% 1% 6%
Agitation 2% 2% 3% 1%
Tachycardia 2% 2% 4% 1%
Anemia 2% 2% 2% 2%
Hyperthermia 2% 2% 3% 0
Chills 2% 2% 3% 2%
Hyperglycemia 2% 2% 2% 3%
Hypoxia 2% 2% 2% 3%
Post-procedural Hemorrhage 2% 2% 3% 4%
Pulmonary Edema 1% 1% 1% 3%
Hypocalcemia 1% 1% 0 2%
Acidosis 1% 1% 1% 2%
Urine Output Decreased 1% 1% 0 2%
Sinus Tachycardia 1% 1% 1% 2%
Ventricular Tachycardia <1% 1% 1% 5%
Wheezing <1% 1% 0 2%
Edema Peripheral <1% 0 1% 2%

* 26 subjects in the all dexmedetomidine hydrochloride in 0.9% sodium chloride injection group and 10 subjects in the randomized dexmedetomidine hydrochloride in 0.9% sodium chloride injection group had exposure for greater than 24 hours.

Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for sedation in the surgical intensive care unit setting in which 387 adult patients received dexmedetomidine hydrochloride in 0.9% sodium chloride injection for less than 24 hours. The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 3).

Table 3: Treatment-Emergent Adverse Events Occurring in >1% Of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion <24 Hours ICU Sedation Studies

Adverse Event Randomized Dexmedetomidine (N = 387) Placebo (N = 379)
Hypotension 28% 13%
Hypertension 16% 18%
Nausea 11% 9%
Bradycardia 7% 3%
Fever 5% 4%
Vomiting 4% 6%
Atrial Fibrillation 4% 3%
Hypoxia 4% 4%
Tachycardia 3% 5%
Hemorrhage 3% 4%
Anemia 3% 2%
Dry Mouth 3% 1%
Rigors 2% 3%
Agitation 2% 3%
Hyperpyrexia 2% 3%
Pain 2% 2%
Hyperglycemia 2% 2%
Acidosis 2% 2%
Pleural Effusion 2% 1%
Oliguria 2% <1%
Thirst 2% <1%

In a controlled clinical trial, dexmedetomidine hydrochloride in 0.9% sodium chloride injection was compared to midazolam for ICU sedation exceeding 24 hours duration in adult patients. Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 4. The number (%) of subjects who had a dose-related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection group is provided in Table 5.

Table 4: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation Study

Adverse Event Dexmedetomidine (N = 244) Midazolam (N = 122)
Hypotension1 56% 56%
Hypotension Requiring Intervention 28% 27%
Bradycardia2 42% 19%
Bradycardia Requiring Intervention 5% 1%
Systolic Hypertension3 28% 42%
Tachycardia4 25% 44%
Tachycardia Requiring Intervention 10% 10%
Diastolic Hypertension3 12% 15%
Hypertension3 11% 15%
Hypertension Requiring Intervention 19% 30%
Hypokalemia 9% 13%
Pyrexia 7% 2%
Agitation 7% 6%
Hyperglycemia 7% 2%
Constipation 6% 6%
Hypoglycemia 5% 6%
Respiratory Failure 5% 3%
Renal Failure Acute 2% 1%
Acute Respiratory Distress Syndrome 2% 1%
Generalized Edema 2% 6%
Hypomagnesemia 1% 7%

† Includes any type of hypertension.

1 Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value.
2 Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value.

3 Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value.4 Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.

The following adverse events occurred between 2 and 5% for dexmedetomidine hydrochloride in 0.9% sodium chloride injection and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%).

Table 5. Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Dexmedetomidine Hydrochloride in 0.9% sodium chloride Injection Group

Dexmedetomidine Hydrochloride in 0.9% sodium chloride Injection mcg/kg/hr
Adverse Event ≤0.7* (N = 95) >0.7 to ≤1.1* (N = 78) >1.1* (N = 71)
Constipation 6% 5% 14%
Agitation 5% 8% 14%
Anxiety 5% 5% 9%
Edema Peripheral 3% 5% 7%
Atrial Fibrillation 2% 4% 9%
Respiratory Failure 2% 6% 10%
Acute Respiratory Distress Syndrome 1% 3% 9%

* Average maintenance dose over the entire study drug administration

Procedural Sedation

Adverse reaction information is derived from the two trials for procedural sedation [see Clinical Studies (14.2) ] in which 318 adult patients received dexmedetomidine hydrochloride in 0.9% sodium chloride injection. The mean total dose was 1.6 mcg/kg (range: 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of infusion of 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93 years of age, ASA I-IV, 30% ≥65 years of age, 52% male and 61% Caucasian.

Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 6. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [see Warnings and Precautions (5.2) ]. Pre-specified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. The decrease in respiratory rate and hypoxia was similar between dexmedetomidine hydrochloride in 0.9% sodium chloride injection and comparator groups in both studies.

Table 6: Adverse Reactions with an Incidence > 2%—Procedural Sedation Population

Adverse Event Dexmedetomidine Hydrochloride in 0.9% sodium chloride Injection (N = 318) (%) Placebo (N = 113) (%)
Hypotension1 54% 30%
Respiratory Depression2 37% 32%
Bradycardia3 14% 4%
Hypertension4 13% 24%
Tachycardia5 5% 17%
Nausea 3% 2%
Dry Mouth 3% 1%
Hypoxia6 2% 3%
Bradypnea 2% 4%

1 Hypotension was defined in absolute and relative terms as Systolic blood pressure of <80 mmHg or ≤30% lower than pre- study drug infusion value, or Diastolic blood pressure of <50 mmHg.

2 Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or > 25% decrease from baseline.

3 Bradycardia was defined in absolute and relative terms as <40 beats per minute or ≤30% lower than pre-study drug infusion value.

4 Hypertension was defined in absolute and relative terms as Systolic blood pressure >180 mmHg or ≥30% higher than pre- study drug infusion value or Diastolic blood pressure of >100 mmHg.
5 Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value.6 Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline.

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