Dexmedetomidine

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.

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.

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, 5.6)] . • 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 a dose reduction [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: Consider a dose reduction [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)] . Maintenance of Procedural Sedation For adult patients: the maintenance infusion is generally 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 . Adjust the rate of the maintenance infusion to achieve the targeted level of sedatio

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 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 4. 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 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) Hypotension 1 56% 56% Hypotension Requiring Intervention 28% 27% Bradycardia 2 42% 19% Bradycardia Requiring Intervention 5% 1% Systolic Hypertension 3 28% 42% Tachycardi

7 DRUG INTERACTIONS Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine or the concomitant medication may be required. (7.1) 7.1 Anesthetics, Sedatives, Hypnotics, Opioids Co-administration of dexmedetomidine with anesthetics, sedatives, hypnotics, and opioids is likely to lead to an enhancement of effects. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between dexmedetomidine and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with dexmedetomidine, a reduction in dosage of dexmedetomidine or the concomitant anesthetic, sedative, hypnotic or opioid may be required. 7.2 Neuromuscular Blockers In one study of 10 healthy adult volunteers, administration of dexmedetomidine for 45 minutes at a plasma concentration of one ng/mL resulted in no clinically meaningful increases in the magnitude of neuromuscular blockade associated with rocuronium administration.