DEXMEDETOMIDINE HYDROCHLORIDE IN 0.9% SODIUM CHLORIDE

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a sterile, nonpyrogenic ready to use solution suitable for intravenous infusion. Dexmedetomidine hydrochloride is a central alpha2-adrenergic agonist. Dexmedetomidine hydrochloride is the S‑enantiomer of medetomidine. Dexmedetomidine hydrochloride chemical name is 1H-Imidazole, 4-[1-(2,3dimethylphenyl)ethyl]-, monohydrochloride, (S). Dexmedetomidine hydrochloride has a molecular weight of 236.7 and the empirical formula is C 13 H 16 N 2 •HCl and the structural formula is: Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is supplied as a clear, colorless, isotonic solution with a pH between 4.5 to 5.5. Each mL contains 4.72 mcg of dexmedetomidine hydrochloride equivalent to 4 mcg (0.004 mg) of dexmedetomidine and 9 mg of sodium chloride in water and is ready to be used. The solution is preservative-free and contains no additives or chemical stabilizers. Dexmedetomidine Hydrochloride Structural Formula

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is an 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 hydrochloride in 0.9% sodium chloride 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) • Sedation of non-intubated pediatric patients aged 1 month to less than 18 years prior to and during non-invasive procedures. ( 1.2 ) 1.1 Intensive Care Unit Sedation Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is indicated for sedation of initially intubated and mechanically ventilated adult patients during treatment in an intensive care setting. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be administered by continuous infusion not to exceed 24 hours. Dexmedetomidine hydrochloride in 0.9% sodium chloride 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 hydrochloride in 0.9% sodium chloride injection prior to extubation. 1.2 Procedural Sedation Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is indicated for sedation of non-intubated adult patients prior to and/or during surgical and other procedures. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is indicated for sedation of non-intubated pediatric patients aged 1 month to less than 18 years prior to and during non-invasive procedures.

• Individualize and titrate dexmedetomidine hydrochloride in 0.9% sodium chloride injection dosing to desired clinical effect. (2.1) • Administer dexmedetomidine hydrochloride in 0.9% sodium chloride injection using a controlled infusion device. (2.1) • The 200 mcg/50mL and 400 mcg/100 mL single-dose Galaxy containers do not require further dilution prior to administration. (2.4) • For Adult Intensive Care Unit Sedation : Initiate at one mcg/kg over 10 minutes , followed by a maintenance infusion of 0.2 mcg/kg/ hour 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 mcg/kg/ hour to 1 mcg/kg/ hour . (2.2) • For Sedation of Pediatric Patients During Non-invasive Procedures: Patients 1 month to less than 2 years old initiate at 1.5 mcg/kg over 10 minutes followed by a maintenance infusion of 1.5 mcg/kg/ hour and titrated to achieve desired clinical effect with dosage ranging from 0.5 mcg/kg/ hour to 1.5 mcg/kg/ hour ; patients 2 to less than 18 years old initiate at 2 mcg/kg over 10 minutes followed by a maintenance infusion of 1.5 mcg/kg/ hour and titrated to achieve desired clinical effect with dosage ranging from 0.5 mcg/kg/ hour to 1.5 mcg/kg/ hour . ( 2.2 ) • Alternative Doses : Recommended for patients over 65 years of age and awake fiberoptic intubation patients. (2.2) 2.1 Administration Instructions • Dexmedetomidine hydrochloride in 0.9% sodium chloride injection dosing should be individualized and titrated to desired clinical response. • Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is not indicated for infusions lasting longer than 24 hours. • Dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be administered using a controlled infusion device. 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 mcg/kg/ hour 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 mcg/kg/ hour to 1 mcg/kg/ hour . Adjust the rate of the maintenance infusion to achieve the targeted level of sedation. For awake fiberoptic intubation in adult patients : a maintenance infusion of 0.7 mcg/kg/ hour is recommended until the endotracheal tube is secured. 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) ]. Table 2: Recommended Dosage in Pediatric Patients INDICATION DOSAGE AND ADMINISTRATION Initiation of Sedation During Non-invasive Procedures For pediatric patients: • 1 month to less than 2 years: a loading infusion of 1.5 mcg/kg over 10 minutes . • 2 to less than 18 years: a loading infusion of 2 mcg/kg over 10 minutes . Consider a reduction in dosage if clinically indicated. Maintenance of Sedation During Non-invasive Procedures For pediatric patients: • 1 month to less than 18 years: the maintenance infusion is generally initiated at 1.5 mcg/kg/ hour and titrated to achieve desired clinical effect with dosage ranging from 0.5 mcg/kg/ hour to 1.5 mcg/kg/ hour . As clinically warranted, titrate the maintenance dose to individual patient clinical response. 2.3 Dosage Adjustment Due to possible pharmacodynamic interactions, a reduction in dosage of dexmedetomidine hydrochloride in 0.9% sodium chloride injection or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered [ see Drug Interactions (7.1) ]. Dosage reductions may need to be considered for adult patients with hepatic impairment, and geriatric patients [ see Warnings and Precautions (5.8) , Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. 2.4 Preparation of Solution Strict aseptic technique must always be maintained during handling of dexmedetomidine hydrochloride in 0.9% sodium chloride injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if product is discolored or if precipitate matter is present. Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection is supplied in Galaxy containers: • 200 mcg/50 mL (4 mcg/mL) • 400 mcg/100 mL (4 mcg/mL) These presentations contain a premixed, ready to use dexmedetomidine hydrochloride solution in 0.9% sodium chloride in water. No further dilution of these preparations is necessary. Instructions for Use for Galaxy Containers: 1. Check the container for minute leaks by squeezing it firmly. If leaks are found, or if the seal is not intact, discard the solution as the sterility may be compromised. 2. Do not use if the solution is cloudy or a precipitate is present. 3. Use aseptic technique. Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete. Preparation for Administration: 1. Suspend container from support. 2. Remove protector from outlet port at bottom of Galaxy container. 3. Attach Intravenous administration set to outlet port. Refer to the manufacturer’s instructions accompanying the administration set for complete directions. 2.5 Administration with Other Fluids Dexmedetomidine hydrochloride in 0.9% sodium chloride injection infusion should not be co‑administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been shown to be compatible when administered with the following intravenous fluids: • 0.9% sodium chloride in water • 5% dextrose in water • 20% mannitol • Lactated Ringer’s solution • 100 mg/mL magnesium sulfate solution • 0.3% potassium chloride solution 2.6 Compatibility with Natural Rubber Compatibility studies have demonstrated the potential for absorption of dexmedetomidine hydrochloride in 0.9% sodium chloride injection to some types of natural rubber. Although dexmedetomidine hydrochloride in 0.9% sodium chloride injection is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.

None. None. (4)

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 Baxter Healthcare at 1-866-888-2472, 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 hydrochloride in 0.9% sodium chloride injection for sedation in the Intensive Care Unit setting in which 1,007 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 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 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 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% 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 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 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 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 hydrochloride in 0.9% sodium chloride injection 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 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 42% 19% Bradycardia Requiring Intervention 5% 1% Systolic Hypertension Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower 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 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 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 Hydrochloride in 0.9% Sodium Chloride Group Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride (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% 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 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 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 hydrochloride in 0.9% sodium chloride injection and comparator groups in both studies. Table 7: Adverse Reactions with an Incidence > 2%-Adult Procedural Sedation Population Adverse Event Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection (N = 318) (%) Placebo (N = 113) (%) Hypotension 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. 54% 30% Respiratory Depression Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or >25% decrease from baseline. 37% 32% Bradycardia 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) ]. 14% 4% Hypertension 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. 13% 24% Tachycardia Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value. 5% 17% Nausea 3% 2% Dry Mouth 3% 1% Hypoxia Hypoxia was defined in absolute and relative terms as SpO 2 <90% or 10% decrease from baseline. 2% 3% Bradypnea 2% 4% 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 hydrochloride in 0.9% sodium chloride injection. In pediatric patients 1 month to less than 2 years old, the median total dose for the dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 hydrochloride in 0.9% sodium chloride injection 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 hydrochloride in 0.9% sodium chloride injection dose. Mild transient withdrawal symptoms of emergence delirium or agitation occurred in 3 of 122 patients after discontinuation of dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 Hydrochloride in 0.9% Sodium Chloride Injection Low Dose (N = 42) Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection Middle Dose (N = 42) Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection High Dose (N = 38) Total (N = 122) Number (%) of Pediatric Patients n (%) n (%) n (%) n (%) Adverse Event Bradypnea N = Number of pediatric patients evaluable for adverse events. 33 (79) 27 (64) 22 (58) 82 (67) Bradycardia Bradycardia was defined as a decrease in HR of 30% from baseline or absolute HR ≤1st centile of the age adjusted normal range. 24 (57) 24 (57) 27 (71) 75 (62) Hypertension 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 ≥95th percentile for gender, age, and height. 11 (26) 17 (41) 18 (47) 46 (38) Hypotension Hypotension was defined as a decrease in systolic blood pressure ≥30% from baseline. 13 (31) 11 (26) 6 (16) 30 (25) Hypoxia Hypoxia was defined as oxygen saturation <90% for any duration. 6 (14) 3 (7) 1 (3) 10 (8) Diastolic Hypertension 3 (7) 3 (7) 4 (11) 10 (8) Systolic Hypertension 1 (2) 5 (12) 3 (8) 9 (7) Tachycardia 3 (7) 1 (2) 1 (3) 5 (4) 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of dexmedetomidine hydrochloride in 0.9% sodium chloride injection. 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 hydrochloride in 0.9% sodium chloride injection during post-approval use of the drug. Table 9: Adverse Reactions Experienced During Post-Approval Use of Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection 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 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

Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine hydrochloride in 0.9% sodium chloride injection or the concomitant medication may be required. (7.1) 7.1 Anesthetics, Sedatives, Hypnotics, Opioids Co-administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 hydrochloride in 0.9% sodium chloride injection and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with dexmedetomidine hydrochloride in 0.9% sodium chloride injection, a reduction in dosage of dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 hydrochloride in 0.9% sodium chloride injection 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.