Dexmedetomidine

1 INDICATIONS AND USAGE Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection is a alpha 2 adrenergic receptor agonist indicated for: • Sedation of initially intubated and mechanically ventilated adult patients during treatment in an intensive care setting. Administer Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection by continuous infusion not to exceed 24 hours. (1.1) • Sedation of non-intubated adult patients prior to and/or during surgical and other procedures. (1.2) 1.1 Intensive Care Unit Sedation Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection is indicated for sedation of initially intubated and mechanically ventilated adult patients during treatment in an intensive care setting. Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection should be administered by continuous infusion not to exceed 24 hours. 1.2 Procedural Sedation Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection is indicated for sedation of non-intubated adult patients prior to and/or during surgical and other procedures.

12.1 Mechanism of Action Dexmedetomidine is a relatively selective centrally acting alpha 2 -adrenergic agonist with sedative properties. Alpha 2 selectivity was observed in animals following slow intravenous infusion of low and medium doses (10 mcg/kg to 300 mcg/kg). Both alpha 1 and alpha 2 activity is observed following slow intravenous infusion of high doses (greater than or equal to 1000 mcg/kg) or with rapid intravenous administration.

2 DOSAGE AND ADMINISTRATION • Individualize and titrate dosing to desired clinical effect. (2.1) • Administration duration should not exceed 24 hours. (2.1) • Administer intravenously using a controlled infusion device. (2.1) • Dexmedetomidine Injection must be diluted prior to administration. (2.1) • Dexmedetomidine Injection in 5% Dextrose 200 mcg/50 mL and 400 mcg/100 mL single-dose bags, do not require dilution prior to administration. (2.1) • To be administered only by health care providers skilled in management of patients in the intensive care or operating room setting. (2.1) • Continuously monitor blood pressure, heart rate, and oxygen levels during administration and as clinically appropriate after discontinuation. (2.1) • It is not necessary to discontinue Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection prior to extubation. • For Adult Intensive Care Unit Sedation : • Initiate at one mcg/kg over 10 minutes , followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/ hour . (2.2) • For Adult Procedural Sedation : Initiate at one mcg/kg over 10 minutes , followed by a maintenance infusion 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 . (2.2) • Alternative Doses : Recommended for patients over 65 years of age and awake fiberoptic intubation patients. (2.2) • See full prescribing information for recommended dosage, reconstitution, dilution, and administration instructions. (2.2, 2.3, 2.4 ,2.5, 2.6, 2.7) 2.1 Administration Instructions • Individualize and titrate dosing to desired clinical response. • Administer by continuous intravenous infusion using a controlled infusion device. • Administration duration should not exceed 24 hours [see Warnings and Precautions (5.5, 5.7)] . • Dexmedetomidine Injection must be diluted prior to administration [see Dosage and Administration (2.4)] . • Dexmedetomidine in 5% Dextrose Injection 200 mcg/50 mL and 400mcg/100mL single-dose bags do not require further dilution prior to administration. • Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection should be administered only by health care providers skilled in the management of patients in the intensive care or operating room setting . • Continuously monitor blood pressure, heart rate and oxygen levels during the use of Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection and as clinically appropriate after discontinuation. • Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection has been continuously infused in mechanically ventilated adult patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection prior to extubation. • Use administration components made with synthetic or coated natural rubber gaskets. Dexmedetomidine Injection and Dexmedetomidine in 5% Dextrose Injection has the potential for absorption into some types of natural rubber. 2.2 Recommended Dosage Table 1: Recommended Dosage in Adult Patients 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: Consider a dose reduction [see Use in Specific Populations (8.5)] . For adult patients with impaired hepatic function: Consider a dose reduction [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: Consider a dose reduction [see Use in Specific Populations (8.5)]. For adult patients with impaired hepatic function: Consider

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) • 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 WG Critical Care at 1-866-562-4708 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 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 (N = 1007) (%) 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 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 c

5 WARNINGS AND PRECAUTIONS • Monitoring: Continuously monitor patients while receiving dexmedetomidine. (5.1) • 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 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) • Co-administration with Other Vasodilators or Negative Chronotropic Agents: Use with caution due to additive pharmacodynamic effects. (5.2) • Transient Hypertension: Observed primarily during the loading dose. Consider reduction in loading infusion rate. (5.3) • Arousability: Patients can become aroused/alert with stimulation; this alone should not be considered as lack of efficacy. (5.4) • 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. (5.7) 5.1 Drug Administration Dexmedetomidine 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. 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, 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 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 an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine. 5.3 Transient Hypertension Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of dexmedetomidine. 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 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, regardl

4 CONTRAINDICATIONS None. None. ( 4 )

10 OVERDOSAGE The tolerability of dexmedetomidine was studied in one study in which healthy adult subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hr. The maximum blood concentration achieved in this study was approximately 13 times the upper boundary of the therapeutic range. The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second-degree heart block. No hemodynamic compromise was noted with the atrioventricular block and the heart block resolved spontaneously within one minute. Five adult patients received an overdose of dexmedetomidine in the intensive care unit sedation studies. Two of these patients had no symptoms reported; one patient received a 2 mcg/kg loading dose over 10 minutes (twice the recommended loading dose) and one patient received a maintenance infusion of 0.8 mcg/kg/hr. Two other patients who received a 2 mcg/kg loading dose over 10 minutes, experienced bradycardia and/or hypotension. One patient who received a loading bolus dose of undiluted dexmedetomidine (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.