Dexmedetomidine

5.4 Arousability Some patients receiving dexmedetomidine 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 adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) dexmedetomidine 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 [see Adverse Reactions ( 6.1 )]. In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%. Procedural Sedation In adult subjects, withdrawal symptoms were not seen after discontinuation of short-term infusions of dexmedetomidine (<6 hours). In pediatric patients, mild transient withdrawal symptoms of emergence delirium or agitation were seen after discontinuation of short-term infusions of dexmedetomidine (<2 hours) [see Adverse Reactions ( 6.1 )] .

5.6 Diabetes Insipidus Cases of diabetes insipidus (DI) have been reported with use of dexmedetomidine in the setting of sedation. Signs of DI in this setting include polyuria (output >125 mL/hr), diluted urine (osmolality <300 mOsm/kg), and hypernatremia (serum sodium >145 mmol/L). If unrecognized, this condition can lead to hemodynamic instability including unstable blood pressure and increased risk of other cardiovascular sequelae. In reported cases, signs of DI have spontaneously resolved following discontinuation of dexmedetomidine, with resolution often occurring after 24 hours. Monitor urine output and laboratory data for signs of DI during and after dexmedetomidine administration. If DI is suspected, adjust fluid management, provide supportive care, and consider discontinuing dexmedetomidine. If such care is insufficient, or in a setting where dexmedetomidine is used for an extended treatment period, consider expert consultation to assist with patient management.

5.7 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 )].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypotension, bradycardia and sinus arrest [see Warnings and Precautions ( 5.2 )] Transient hypertension [see Warnings and Precautions ( 5.3 )] The most common adverse reactions (incidence >2%) in adults are hypotension, bradycardia, and dry mouth. (6.1) The most common adverse reactions (incidence >5%) in pediatric patients aged 1 month to less than 17 years are bradypnea, bradycardia, hypertension, and hypotension. (6.1) Adverse reactions in adults, associated with infusions >24 hours in duration include ARDS, respiratory failure, and agitation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Piramal Critical Care at 1-800-414-1901, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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 the clinical trials of another drug and may not reflect the rates observed in practice. Most common treatment-emergent adverse reactions, occurring in greater than 2% of adult 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 for sedation in the Intensive Care Unit setting in which 1,007 adult patients received dexmedetomidine. 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 3. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see Warnings and Precautions (5.2)] . Table 3: Adverse Reactions with an Incidence >2%-Adult Intensive Care Unit Sedation Population <24 hours* Adverse Event All Dexmedetomidine (N = 1,007) (%) Randomized Dexmedetomidine (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 group and 10 subjects in the randomized dexmedetomidine group had exposure for greater than 24 hours. Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of dexmedetomidine for sedation in the surgical intensive care unit setting in which 387 adult patients received dexmedetomidine 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 4). Table 4: 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 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 adult patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 5. The number (%) of adult subjects who had a dose-related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the dexmedetomidine group is provided in Table 6. Table 5: 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) Hypotension 1 56% 56% Hypotension Requiring Intervention 28% 27% Bradycardia 2 42% 19% Bradycardia Requiring Intervention 5% 1% Systolic Hypertension 3 28% 42% Tachycardia 4 25% 44% Tachycardia Requiring Intervention 10% 10% Diastolic Hypertension 3 12% 15% Hypertension 3 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 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 6: Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Dexmedetomidine Group Dexmedetomidine (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. Adult Procedural Sedation Adverse reaction information is derived from the two trials for adult procedural sedation [see Clinical Studies (14.2)] in which 318 adult patients received dexmedetomidine. 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 in adults at an incidence of >2% are provided in Table 7. 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 and comparator groups in both studies. Table 7: Adverse Reactions with an Incidence >2% - Adult Procedural Sedation Population Adverse Event Dexmedetomidine (N = 318) (%) Placebo (N = 113) (%) Hypotension 1 54% 30% Respiratory Depression 2 37% 32% Bradycardia 3 14% 4% Hypertension 4 13% 24% Tachycardia 5 5% 17% Nausea 3% 2% Dry Mouth 3% 1% Hypoxia 6 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. Subjects in Study 2 were pretreated with glycopyrrolate 0.1 mg intravenously before receiving study drug [see Clinical Studies (14.2)]. 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 SpO 2 <90% or 10% decrease from baseline. Pediatric Sedation for Magnetic Resonance Imaging Adverse reaction information is derived from a trial for sedation of pediatric procedural during a non-invasive procedure [see Clinical Studies (14.2)] in which 122 pediatric patients aged 1 month to less than 17 years undergoing magnetic resonance imaging (MRI) scans received dexmedetomidine. In pediatric patients 1 month to less than 2 years old, the median total dose for the dexmedetomidine low, middle, and high dose treatment groups was 8.30, 18.90, and 22.75 mcg, respectively. The median duration of treatment ranged from 52.5 to 69 minutes across treatment groups. In pediatric patients 2 to less than 17 years old, the median total dose for the dexmedetomidine low, middle, and high dose treatment groups was 21.30, 43.90, and 80.25 mcg, respectively. The median duration of treatment ranged from 56.5 to 66 minutes across treatment groups. All-causality treatment-emergent adverse reactions occurring in the combined age group of pediatric patients during the procedure at an incidence of >5% are provided in Table 8. The most frequent treatment-emergent adverse events were bradypnea, bradycardia, hypertension, and hypotension [see Warnings and Precautions (5.2, 5.3)] . In the combined age group and in each age group, increased incidence in bradycardia and hypertension was observed with increasing dexmedetomidine dose. Mild transient withdrawal symptoms of emergence delirium or agitation occurred in 3 of 122 patients after discontinuation of dexmedetomidine infusion [see Warnings and Precautions (5.5)] . All reported treatment-emergent adverse reactions were mild to moderate in severity and the majority resolved without medical intervention. No subject in the study required airway intervention, including a jaw thrust or insertion of a nasal or oral airway. A similar profile was observed in the pediatric patients 1 month to less than 2 years old and in pediatric patients 2 to less than 17 years old. Pre-specified criteria for the vital signs to be reported as adverse events are footnoted below the table. Table 8: Treatment-Emergent Adverse Events with Incidence >5% — Pediatric Patients During Non-invasive Procedure Dexmedetomidine Low Dose (N = 42) Dexmedetomidine Middle Dose (N = 42) Dexmedetomidine High Dose (N = 38) Total (N = 122) Number (%) of Pediatric Patients n (%) n (%) n (%) n (%) Adverse Event Bradypnea 1 33 (79) 27 (64) 22 (58) 82 (67) Bradycardia 2 24 (57) 24 (57) 27 (71) 75 (62) Hypertension 3 11 (26) 17 (41) 18 (47) 46 (38) Hypotension 4 13 (31) 11 (26) 6 (16) 30 (25) Hypoxia 5 6 (14) 3 (7) 1 (3) 10 (8) Diastolic Hypertension 3 3 (7) 3 (7) 4 (11) 10 (8) Systolic Hypertension 3 1 (2) 5 (12) 3 (8) 9 (7) Tachycardia 3 (7) 1 (2) 1 (3) 5 (4) N = Number of pediatric patients evaluable for adverse events. 1 Bradypnea was defined as respiratory rate <1 st centile of the age adjusted normal range. 2 Bradycardia was defined as a decrease in HR of 30% from baseline or absolute HR ≤1 st centile of the age adjusted normal range. 3 For pediatric patients 1 month to less than 1 year old, hypertension was defined as supine systolic blood pressure ≥104 mm/Hg and/or diastolic blood pressure ≥56 mmHg measurements. For pediatric patients 1 to less than 17 years old: hypertension was defined as supine systolic blood pressure and/or diastolic blood pressure measurements ≥95 th percentile for gender, age, and height. 4 Hypotension was defined as a decrease in systolic blood pressure ≥30% from baseline. 5 Hypoxia was defined as oxygen saturation <90% for any duration. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of dexmedetomidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypotension and bradycardia were the most common adverse reactions associated with the use of dexmedetomidine during post-approval use of the drug. Table 9: Adverse Reactions Experienced During Post-Approval Use of Dexmedetomidine System Organ Class Preferred Term Blood and Lymphatic System Disorders Anemia Cardiac Disorders Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia Eye Disorders Photopsia, visual impairment Gastrointestinal Disorders Abdominal pain, diarrhea, nausea, vomiting General Disorders and Administration Site Conditions Chills, hyperpyrexia, pain, pyrexia, thirst Hepatobiliary Disorders Hepatic function abnormal, hyperbilirubinemia Investigations Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged Metabolism and Nutrition Disorders Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia, diabetes insipidus (Cases of diabetes insipidus, with associated polyuria, dilute urine, and hypernatremia, have been reported) Nervous System Disorders Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder Psychiatric Disorders Agitation, confusional state, delirium, hallucination, illusion Renal and Urinary Disorders Oliguria, polyuria Respiratory, Thoracic and Mediastinal Disorders Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis Skin and Subcutaneous Tissue Disorders Hyperhidrosis, pruritus, rash, urticaria Surgical and Medical Procedures Light anesthesia Vascular Disorders Blood pressure fluctuation, hemorrhage, hypertension, hypotension

6.1 Clinical Trials 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 the clinical trials of another drug and may not reflect the rates observed in practice. Most common treatment-emergent adverse reactions, occurring in greater than 2% of adult 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 for sedation in the Intensive Care Unit setting in which 1,007 adult patients received dexmedetomidine. 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 3. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see Warnings and Precautions (5.2)] . Table 3: Adverse Reactions with an Incidence >2%-Adult Intensive Care Unit Sedation Population <24 hours* Adverse Event All Dexmedetomidine (N = 1,007) (%) Randomized Dexmedetomidine (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 group and 10 subjects in the randomized dexmedetomidine group had exposure for greater than 24 hours. Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of dexmedetomidine for sedation in the surgical intensive care unit setting in which 387 adult patients received dexmedetomidine 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 4). Table 4: 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 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 adult patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 5. The number (%) of adult subjects who had a dose-related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the dexmedetomidine group is provided in Table 6. Table 5: 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) Hypotension 1 56% 56% Hypotension Requiring Intervention 28% 27% Bradycardia 2 42% 19% Bradycardia Requiring Intervention 5% 1% Systolic Hypertension 3 28% 42% Tachycardia 4 25% 44% Tachycardia Requiring Intervention 10% 10% Diastolic Hypertension 3 12% 15% Hypertension 3 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 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 6: Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Dexmedetomidine Group Dexmedetomidine (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. Adult Procedural Sedation Adverse reaction information is derived from the two trials for adult procedural sedation [see Clinical Studies (14.2)] in which 318 adult patients received dexmedetomidine. 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 in adults at an incidence of >2% are provided in Table 7. 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 and comparator groups in both studies. Table 7: Adverse Reactions with an Incidence >2% - Adult Procedural Sedation Population Adverse Event Dexmedetomidine (N = 318) (%) Placebo (N = 113) (%) Hypotension 1 54% 30% Respiratory Depression 2 37% 32% Bradycardia 3 14% 4% Hypertension 4 13% 24% Tachycardia 5 5% 17% Nausea 3% 2% Dry Mouth 3% 1% Hypoxia 6 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. Subjects in Study 2 were pretreated with glycopyrrolate 0.1 mg intravenously before receiving study drug [see Clinical Studies (14.2)]. 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 SpO 2 <90% or 10% decrease from baseline. Pediatric Sedation for Magnetic Resonance Imaging Adverse reaction information is derived from a trial for sedation of pediatric procedural during a non-invasive procedure [see Clinical Studies (14.2)] in which 122 pediatric patients aged 1 month to less than 17 years undergoing magnetic resonance imaging (MRI) scans received dexmedetomidine. In pediatric patients 1 month to less than 2 years old, the median total dose for the dexmedetomidine low, middle, and high dose treatment groups was 8.30, 18.90, and 22.75 mcg, respectively. The median duration of treatment ranged from 52.5 to 69 minutes across treatment groups. In pediatric patients 2 to less than 17 years old, the median total dose for the dexmedetomidine low, middle, and high dose treatment groups was 21.30, 43.90, and 80.25 mcg, respectively. The median duration of treatment ranged from 56.5 to 66 minutes across treatment groups. All-causality treatment-emergent adverse reactions occurring in the combined age group of pediatric patients during the procedure at an incidence of >5% are provided in Table 8. The most frequent treatment-emergent adverse events were bradypnea, bradycardia, hypertension, and hypotension [see Warnings and Precautions (5.2, 5.3)] . In the combined age group and in each age group, increased incidence in bradycardia and hypertension was observed with increasing dexmedetomidine dose. Mild transient withdrawal symptoms of emergence delirium or agitation occurred in 3 of 122 patients after discontinuation of dexmedetomidine infusion [see Warnings and Precautions (5.5)] . All reported treatment-emergent adverse reactions were mild to moderate in severity and the majority resolved without medical intervention. No subject in the study required airway intervention, including a jaw thrust or insertion of a nasal or oral airway. A similar profile was observed in the pediatric patients 1 month to less than 2 years old and in pediatric patients 2 to less than 17 years old. Pre-specified criteria for the vital signs to be reported as adverse events are footnoted below the table. Table 8: Treatment-Emergent Adverse Events with Incidence >5% — Pediatric Patients During Non-invasive Procedure Dexmedetomidine Low Dose (N = 42) Dexmedetomidine Middle Dose (N = 42) Dexmedetomidine High Dose (N = 38) Total (N = 122) Number (%) of Pediatric Patients n (%) n (%) n (%) n (%) Adverse Event Bradypnea 1 33 (79) 27 (64) 22 (58) 82 (67) Bradycardia 2 24 (57) 24 (57) 27 (71) 75 (62) Hypertension 3 11 (26) 17 (41) 18 (47) 46 (38) Hypotension 4 13 (31) 11 (26) 6 (16) 30 (25) Hypoxia 5 6 (14) 3 (7) 1 (3) 10 (8) Diastolic Hypertension 3 3 (7) 3 (7) 4 (11) 10 (8) Systolic Hypertension 3 1 (2) 5 (12) 3 (8) 9 (7) Tachycardia 3 (7) 1 (2) 1 (3) 5 (4) N = Number of pediatric patients evaluable for adverse events. 1 Bradypnea was defined as respiratory rate <1 st centile of the age adjusted normal range. 2 Bradycardia was defined as a decrease in HR of 30% from baseline or absolute HR ≤1 st centile of the age adjusted normal range. 3 For pediatric patients 1 month to less than 1 year old, hypertension was defined as supine systolic blood pressure ≥104 mm/Hg and/or diastolic blood pressure ≥56 mmHg measurements. For pediatric patients 1 to less than 17 years old: hypertension was defined as supine systolic blood pressure and/or diastolic blood pressure measurements ≥95 th percentile for gender, age, and height. 4 Hypotension was defined as a decrease in systolic blood pressure ≥30% from baseline. 5 Hypoxia was defined as oxygen saturation <90% for any duration.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of dexmedetomidine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypotension and bradycardia were the most common adverse reactions associated with the use of dexmedetomidine during post-approval use of the drug. Table 9: Adverse Reactions Experienced During Post-Approval Use of Dexmedetomidine System Organ Class Preferred Term Blood and Lymphatic System Disorders Anemia Cardiac Disorders Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia Eye Disorders Photopsia, visual impairment Gastrointestinal Disorders Abdominal pain, diarrhea, nausea, vomiting General Disorders and Administration Site Conditions Chills, hyperpyrexia, pain, pyrexia, thirst Hepatobiliary Disorders Hepatic function abnormal, hyperbilirubinemia Investigations Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged Metabolism and Nutrition Disorders Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia, diabetes insipidus (Cases of diabetes insipidus, with associated polyuria, dilute urine, and hypernatremia, have been reported) Nervous System Disorders Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder Psychiatric Disorders Agitation, confusional state, delirium, hallucination, illusion Renal and Urinary Disorders Oliguria, polyuria Respiratory, Thoracic and Mediastinal Disorders Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis Skin and Subcutaneous Tissue Disorders Hyperhidrosis, pruritus, rash, urticaria Surgical and Medical Procedures Light anesthesia Vascular Disorders Blood pressure fluctuation, hemorrhage, hypertension, hypotension

<table cellspacing="0" cellpadding="0" border="1"><tbody><tr><td><paragraph><content styleCode="bold">Adverse Event </content></paragraph></td><td><paragraph><content styleCode="bold">All Dexmedetomidine </content></paragraph><paragraph><content styleCode="bold">(N = 1,007) (%) </content></paragraph></td><td><paragraph><content styleCode="bold">Randomized Dexmedetomidine </content></paragraph><paragraph><content styleCode="bold">(N = 798) (%) </content></paragraph></td><td><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N = 400) (%)</content></paragraph></td><td><paragraph><content styleCode="bold">Propofol</content></paragraph><paragraph><content styleCode="bold">(N = 188) (%)</content></paragraph></td></tr><tr><td><paragraph>Hypotension</paragraph></td><td><paragraph>25%</paragraph></td><td><paragraph>24%</paragraph></td><td><paragraph>12%</paragraph></td><td><paragraph>13%</paragraph></td></tr><tr><td><paragraph>Hypertension</paragraph></td><td><paragraph>12%</paragraph></td><td><paragraph>13%</paragraph></td><td><paragraph>19%</paragraph></td><td><paragraph>4%</paragraph></td></tr><tr><td><paragraph>Nausea</paragraph></td><td><paragraph>9%</paragraph></td><td><paragraph>9%</paragraph></td><td><paragraph>9%</paragraph></td><td><paragraph>11%</paragraph></td></tr><tr><td><paragraph>Bradycardia</paragraph></td><td><paragraph>5%</paragraph></td><td><paragraph>5%</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Atrial Fibrillation</paragraph></td><td><paragraph>4%</paragraph></td><td><paragraph>5%</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>7%</paragraph></td></tr><tr><td><paragraph>Pyrexia</paragraph></td><td><paragraph>4%</paragraph></td><td><paragraph>4%</paragraph></td><td><paragraph>4%</paragraph></td><td><paragraph>4%</paragraph></td></tr><tr><td><paragraph>Dry Mouth</paragraph></td><td><paragraph>4%</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>1%</paragraph></td></tr><tr><td><paragraph>Vomiting</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>5%</paragraph></td><td><paragraph>3%</paragraph></td></tr><tr><td><paragraph>Hypovolemia</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>5%</paragraph></td></tr><tr><td><paragraph>Atelectasis</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>6%</paragraph></td></tr><tr><td><paragraph>Pleural Effusion</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>6%</paragraph></td></tr><tr><td><paragraph>Agitation</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>1%</paragraph></td></tr><tr><td><paragraph>Tachycardia</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>4%</paragraph></td><td><paragraph>1%</paragraph></td></tr><tr><td><paragraph>Anemia</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td></tr><tr><td><paragraph>Hyperthermia</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>0</paragraph></td></tr><tr><td><paragraph>Chills</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>2%</paragraph></td></tr><tr><td><paragraph>Hyperglycemia</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>3%</paragraph></td></tr><tr><td><paragraph>Hypoxia</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>3%</paragraph></td></tr><tr><td><paragraph>Post-procedural Hemorrhage</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>2%</paragraph></td><td><paragraph>3%</paragraph></td><td><paragraph>4%</paragraph></td></tr><tr><td><paragraph>Pulmonary Edema</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>3%</paragraph></td></tr><tr><td><paragraph>Hypocalcemia</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>2%</paragraph></td></tr><tr><td><paragraph>Acidosis</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>2%</paragraph></td></tr><tr><td><paragraph>Urine Output Decreased</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>2%</paragraph></td></tr><tr><td><paragraph>Sinus Tachycardia</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>2%</paragraph></td></tr><tr><td><paragraph>Ventricular Tachycardia</paragraph></td><td><paragraph>&lt;1%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>5%</paragraph></td></tr><tr><td><paragraph>Wheezing</paragraph></td><td><paragraph>&lt;1%</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>2%</paragraph></td></tr><tr><td><paragraph>Edema Peripheral</paragraph></td><td><paragraph>&lt;1%</paragraph></td><td><paragraph>0</paragraph></td><td><paragraph>1%</paragraph></td><td><paragraph>2%</paragraph></td></tr></tbody></table>