Prescription Drug Information: DEXMEDETOMIDINE HYDROCHLORIDE (Page 2 of 5)

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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