With administration up to 7 days, regardless of dose, 12 (5%) dexmedetomidine injection adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) dexmedetomidine 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 injection supportive therapy is indicated.
Adverse reaction information is derived from the continuous infusion trials of dexmedetomidine injection for sedation in the Intensive Care Unit setting in which 1,007 adult patients received dexmedetomidine 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 hours26 subjects in the all dexmedetomidine injection group and 10 subjects in the randomized dexmedetomidine injection group had exposure for greater than 24 hours
Adverse Event | All Dexmedetomidine Injection
(N = 1007)
(%) | Randomized Dexmedetomidine 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% |
Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of dexmedetomidine injection for sedation in the surgical intensive care unit setting in which 387 adult patients received dexmedetomidine 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 StudiesAdverse 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 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 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 StudyAdverse Event | Dexmedetomidine (N = 244) | Midazolam (N = 122) |
Hypotension 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 | 56% | 56% |
Hypotension Requiring Intervention | 28% | 27% |
Bradycardia Bradycardia was defined in absolute terms as < 40 bpm or in relative terms as ≤ 30% lower than pre-study drug infusion value | 42% | 19% |
Bradycardia Requiring Intervention | 5% | 1% |
Systolic Hypertension 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 | 28% | 42% |
Tachycardia Tachycardia was defined in absolute terms as > 120 bpm or in relative terms as ≥ 30% greater than pre-study drug infusion value | 25% | 44% |
Tachycardia Requiring Intervention | 10% | 10% |
Diastolic Hypertension | 12% | 15% |
Hypertension | 11% | 15% |
Hypertension Requiring Intervention Includes any type of hypertension | 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% |
The following adverse events occurred between 2 and 5% for dexmedetomidine 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 Injection GroupDexmedetomidine Injection (mcg/kg/hr) |
Adverse Event | ≤ 0.7 Average maintenance dose over the entire study drug administration (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% |
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 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)].
