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Indication and Usage, Procedural Sedation ( 1.2 ) 12/2022 Dosage and Administration, Recommended Dosage ( 2.2 ) 12/2022 Dosage and Administration, Preparation of Solution ( 2.4 ) 08/2022 Warnings and Precautions, Withdrawal ( 5.5 ) 12/2022 Warnings and Precautions, Hyperthermia or Pyrexia ( 5.7 ) 08/2022
<table styleCode="Noautorules" width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td valign="top"><paragraph>Indication and Usage, Procedural Sedation (<linkHtml href="#ID_a11d225b-b7e0-441a-a1c2-dde9b1c6484f">1.2</linkHtml>)</paragraph></td><td align="center" valign="top"><paragraph>12/2022</paragraph></td></tr><tr><td valign="top"><paragraph>Dosage and Administration, Recommended Dosage (<linkHtml href="#ID_8be24d35-77bd-487e-83d0-7d04dd1ad70b">2.2</linkHtml>)</paragraph></td><td align="center" valign="top"><paragraph>12/2022</paragraph></td></tr><tr><td valign="top"><paragraph>Dosage and Administration, Preparation of Solution (<linkHtml href="#ID_6eb1ee8f-8ea8-4d29-a092-d19ea6306472">2.4</linkHtml>)</paragraph></td><td align="center" valign="top"><paragraph>08/2022</paragraph></td></tr><tr><td valign="top"><paragraph>Warnings and Precautions, Withdrawal (<linkHtml href="#ID_b047b720-2925-4e4e-b30c-b8e1f3879bfd">5.5</linkHtml>)</paragraph></td><td align="center" valign="top"><paragraph>12/2022</paragraph></td></tr><tr><td valign="top"><paragraph>Warnings and Precautions, Hyperthermia or Pyrexia (<linkHtml href="#ID_c7adf5bb-3c6b-4a24-aa28-27fc6d5b16d7">5.7</linkHtml>)</paragraph></td><td align="center" valign="top"><paragraph>08/2022</paragraph></td></tr></tbody></table>
1 INDICATIONS AND USAGE PRECEDEX 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 PRECEDEX 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 PRECEDEX is indicated for sedation of initially intubated and mechanically ventilated adult patients during treatment in an intensive care setting. PRECEDEX should be administered by continuous infusion not to exceed 24 hours. PRECEDEX has been continuously infused in mechanically ventilated adult patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue PRECEDEX prior to extubation. 1.2 Procedural Sedation PRECEDEX is indicated for sedation of non-intubated adult patients prior to and/or during surgical and other procedures. PRECEDEX is indicated for sedation of non-intubated pediatric patients aged 1 month to less than 18 years prior to and during non-invasive procedures.
2 DOSAGE AND ADMINISTRATION • Individualize and titrate PRECEDEX dosing to desired clinical effect. ( 2.1 ) • Administer PRECEDEX using a controlled infusion device. ( 2.1 ) • The 200 mcg/50 mL, and 400 mcg/100 mL single-dose bottles 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 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 ) • 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 to 1.5 mcg/kg/ hour ; patients 2 to less than 18 years old initiate at 2.0 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 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 • PRECEDEX dosing should be individualized and titrated to desired clinical response. • PRECEDEX is not indicated for infusions lasting longer than 24 hours. • PRECEDEX 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 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 .
: 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 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 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 PRECEDEX 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 PRECEDEX. 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. PRECEDEX in 0.9% Sodium Chloride Injection, 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL) PRECEDEX in 0.9% Sodium Chloride Injection is supplied in glass containers containing a premixed, ready to use dexmedetomidine hydrochloride solution in 0.9% sodium chloride in water. No further dilution of this preparation is necessary. 2.5 Administration with Other Fluids PRECEDEX infusion should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established. PRECEDEX has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam. PRECEDEX 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 PRECEDEX to some types of natural rubber. Although PRECEDEX is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.
3 DOSAGE FORMS AND STRENGTHS PRECEDEX (dexmedetomidine hydrochloride) in 0.9% sodium chloride injection is a clear and colorless solution, ready to use. It is available as: • PRECEDEX 200 mcg/50 mL (4 mcg/mL) single-dose glass bottle. • PRECEDEX 400 mcg/100 mL (4 mcg/mL) single-dose glass bottle. PRECEDEX in 0.9% Sodium Chloride Injection, 200 mcg/50 mL and 400 mcg/100 mL (4 mcg/mL) in a single-dose glass bottle. Ready to use. ( 3 )
5 WARNINGS AND PRECAUTIONS • Monitoring : Continuously monitor patients while receiving PRECEDEX. ( 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. ( 5.6 ) 5.1 Drug Administration PRECEDEX 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 PRECEDEX, patients should be continuously monitored while receiving PRECEDEX. 5.2 Hypotension, Bradycardia, and Sinus Arrest Clinically significant episodes of bradycardia and sinus arrest have been reported with PRECEDEX 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 PRECEDEX infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of PRECEDEX, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because PRECEDEX 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 PRECEDEX-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required. Caution should be exercised when administering PRECEDEX to patients with advanced heart block and/or severe ventricular dysfunction. Because PRECEDEX 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 PRECEDEX an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with PRECEDEX. 5.3 Transient Hypertension Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of PRECEDEX.
armacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with PRECEDEX. 5.3 Transient Hypertension Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of PRECEDEX. 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 PRECEDEX 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%) PRECEDEX adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) PRECEDEX 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 PRECEDEX (<6 hours). In pediatric patients, mild transient withdrawal symptoms of emergence delirium or agitation were seen after discontinuation of short‑term infusions of PRECEDEX (<2 hours) [see Adverse Reactions (6.1) ]. 5.6 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) ] . 5.7 Hyperthermia or Pyrexia PRECEDEX may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue PRECEDEX if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes. 5.8 Hepatic Impairment Since PRECEDEX clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration (2.2 , 2.3 )] .
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 Hospira, Inc. at 1-800-441-4100, 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 PRECEDEX for sedation in the Intensive Care Unit setting in which 1,007 adult patients received PRECEDEX. 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 PRECEDEX group and 10 subjects in the randomized PRECEDEX group had exposure for greater than 24 hours. Adverse Event All PRECEDEX (N = 1007) (%) Randomized PRECEDEX (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 PRECEDEX for sedation in the surgical intensive care unit setting in which 387 adult patients received PRECEDEX for less than 24 hours.
ular 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 PRECEDEX for sedation in the surgical intensive care unit setting in which 387 adult patients received PRECEDEX 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, PRECEDEX 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 PRECEDEX 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 Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value. 42% 19% Bradycardia Requiring Intervention 5% 1% Systolic Hypertension Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value. 28% 42% Tachycardia Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value. 25% 44% Tachycardia Requiring Intervention 10% 10% Diastolic Hypertension 12% 15% Hypertension 11% 15% Hypertension Requiring Intervention Includes any type of hypertension 19% 30% Hypokalemia 9% 13% Pyrexia 7% 2% Agitation 7% 6% Hyperglycemia 7% 2% Constipation 6% 6% Hypoglycemia 5% 6% Respiratory Failure 5% 3% Renal Failure Acute 2% 1% Acute Respiratory Distress Syndrome 2% 1% Generalized Edema 2% 6% Hypomagnesemia 1% 7% The following adverse events occurred between 2 and 5% for PRECEDEX 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 PRECEDEX Group PRECEDEX (mcg/kg/hr) Adverse Event ≤0.7 Average maintenance dose over the entire study drug administration.
.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 PRECEDEX Group PRECEDEX (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 PRECEDEX. 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 PRECEDEX and comparator groups in both studies. Table 7: Adverse Reactions with an Incidence >2%— Adult Procedural Sedation Population Adverse Event PRECEDEX (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 PRECEDEX. In pediatric patients 1 month to less than 2 years old, the median total dose for the PRECEDEX 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 PRECEDEX 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.
d 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 PRECEDEX 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 PRECEDEX dose. Mild transient withdrawal symptoms of emergence delirium or agitation occurred in 3 of 122 patients after discontinuation of PRECEDEX 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 N = Number of pediatric patients evaluable for adverse events. PRECEDEX Low Dose (N = 42) PRECEDEX Middle Dose (N = 42) PRECEDEX High Dose (N = 38) Total (N = 122) Number (%) of Pediatric Patients n (%) n (%) n (%) n (%) Adverse Event Bradypnea Bradypnea was defined as respiratory rate <1 st centile of the age adjusted normal range. 33 (79) 27 (64) 22 (58) 82 (67) Bradycardia Bradycardia was defined as a decrease in HR of 30% from baseline or absolute HR ≤1 st 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 ≥95 th 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 PRECEDEX. 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 PRECEDEX during post-approval use of the drug.
s 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 PRECEDEX during post-approval use of the drug. Table 9: Adverse Reactions Experienced During Post-Approval Use of PRECEDEX 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
<table ID="_RefTable3" width="97.8%"><caption>Table 3: Adverse Reactions with an Incidence >2%-Adult Intensive Care Unit Sedation Population <24 hours<footnote ID="_Ref114750343">26 subjects in the all PRECEDEX group and 10 subjects in the randomized PRECEDEX group had exposure for greater than 24 hours.</footnote></caption><col width="28%"/><col width="18%"/><col width="18%"/><col width="18%"/><col width="17%"/><tbody><tr><td styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">All PRECEDEX</content></paragraph><paragraph><content styleCode="bold">(N = 1007)</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Randomized PRECEDEX</content></paragraph><paragraph><content styleCode="bold">(N = 798)</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N = 400)</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Propofol</content></paragraph><paragraph><content styleCode="bold">(N = 188)</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypotension</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>24%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>11%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Bradycardia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center"
/td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Bradycardia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Atrial Fibrillation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Pyrexia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Dry Mouth</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypovolemia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Atelectasis</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Pleural Effusion</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode=
styleCode="Rrule Botrule " valign="top"><paragraph>Pleural Effusion</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode= "Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Agitation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Tachycardia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hyperthermia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Chills</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hyperglycemia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypoxia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule
otrule " valign="top"><paragraph>Hypoxia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Post-procedural Hemorrhage</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Pulmonary Edema</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypocalcemia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Acidosis</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Urine Output Decreased</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Sinus Tachycardia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Ventricular Tachycardia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styl
eCode="Rrule Botrule " valign="top"><paragraph>Ventricular Tachycardia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styl eCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Wheezing</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Edema Peripheral</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><1%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>2%</paragraph></td></tr></tbody></table>
align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>2%</paragraph></td></tr></tbody></table> <table ID="_RefTable4" width="97.8%"><caption>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 </caption><col width="33%"/><col width="34%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Randomized Dexmedetomidine</content></paragraph><paragraph><content styleCode="bold">(N = 387)</content></paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N = 379)</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypotension</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypertension</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Bradycardia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Fever</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Atrial Fibrillation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypoxia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Tachycardia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>5%</p
align="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Tachycardia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>5%</p aragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hemorrhage</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Anemia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Dry Mouth</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Rigors</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Agitation </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hyperpyrexia </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Pain</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hyperglycemia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Acidosis</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Pleural Effusion</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Oliguria</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph><1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Thirst</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><1%</para
aragraph><1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Thirst</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><1%</para graph></td></tr></tbody></table>
aragraph><1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Thirst</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><1%</para graph></td></tr></tbody></table> <table ID="_RefTable5" width="99.02%"><caption>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</caption><col width="42%"/><col width="29%"/><col width="29%"/><tbody><tr><td styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Dexmedetomidine</content></paragraph><paragraph><content styleCode="bold">(N = 244)</content></paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Midazolam</content></paragraph><paragraph><content styleCode="bold">(N = 122)</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypotension<footnote ID="_Ref183551747">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.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>56%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>56%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypotension Requiring Intervention</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>27%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Bradycardia<footnote ID="_Ref183551355">Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>42%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Bradycardia Requiring Intervention</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Systolic Hypertension<footnote ID="_Ref183551391">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.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>42%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Tachycardia<footnote ID="_Ref183551476">Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Lrule Toprule Bot
476">Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode="Lrule Toprule Bot rule " valign="top"><paragraph>44%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Tachycardia Requiring Intervention</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>10%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Diastolic Hypertension<footnoteRef IDREF="_Ref183551391"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>15%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypertension<footnoteRef IDREF="_Ref183551391"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>15%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypertension Requiring Intervention<footnote ID="_Ref183551728">Includes any type of hypertension</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypokalemia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Pyrexia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Agitation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hyperglycemia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypoglycemia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Respiratory Failure</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td style
d></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Respiratory Failure</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td style Code="Rrule Botrule " valign="top"><paragraph>Renal Failure Acute</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Acute Respiratory Distress Syndrome</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Generalized Edema</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Hypomagnesemia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>7%</paragraph></td></tr></tbody></table>
><tr><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Hypomagnesemia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1%</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>7%</paragraph></td></tr></tbody></table> <table ID="_RefTable6" width="97.8%"><caption>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 PRECEDEX Group</caption><col width="44%"/><col width="21%"/><col width="19%"/><col width="16%"/><tbody><tr><td align="center" colspan="4" styleCode="Botrule Toprule " valign="top"><paragraph><content styleCode="bold">PRECEDEX (mcg/kg/hr)</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">≤0.7</content><footnote ID="_Ref114750898">Average maintenance dose over the entire study drug administration.</footnote></paragraph><paragraph><content styleCode="bold">(N = 95)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">>0.7 to ≤1.1</content><footnoteRef IDREF="_Ref114750898"/></paragraph><paragraph><content styleCode="bold">(N = 78)</content></paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">>1.1</content><footnoteRef IDREF="_Ref114750898"/></paragraph><paragraph><content styleCode="bold">(N = 71)</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Agitation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>8%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>14%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Anxiety</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Edema Peripheral</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>5%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>7%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Atrial Fibrillation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>4%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="
e Toprule Botrule " valign="middle"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>4%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign=" top"><paragraph>Respiratory Failure</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>6%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>10%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Acute Respiratory Distress Syndrome</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>3%</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="middle"><paragraph>9%</paragraph></td></tr></tbody></table>
nter" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>1%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>3%</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="middle"><paragraph>9%</paragraph></td></tr></tbody></table> <table ID="_RefTable7" width="98%"><caption>Table 7: Adverse Reactions with an Incidence >2%— Adult Procedural Sedation Population</caption><col width="37%"/><col width="29%"/><col width="34%"/><thead><tr><th align="left" styleCode="Rrule Botrule Toprule " valign="bottom"><content styleCode="bold">Adverse Event</content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">PRECEDEX</content> <content styleCode="bold">(N = 318)</content> <content styleCode="bold">(%)</content></th><th align="center" styleCode="Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N = 113)</content> <content styleCode="bold">(%)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Hypotension<footnote ID="_Ref126601594">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.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>54%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>30%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Respiratory Depression<footnote ID="_Ref126601771">Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or >25% decrease from baseline.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>37%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>32%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Bradycardia<footnote ID="_Ref126601784">Bradycardia was defined in absolute and relative terms as <40 beats per minute or ≤30% lower than pre-study drug infusion value.
tyleCode="Lrule Toprule Botrule " valign="top"><paragraph>32%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Bradycardia<footnote ID="_Ref126601784">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 <content styleCode="italics">[see <linkHtml href="#ID_141e5ed6-497d-4a32-81d1-caccfe8ecb04">Clinical Studies (14.2)</linkHtml>]</content>.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypertension<footnote ID="_Ref126601818">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.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>24%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Tachycardia<footnote ID="_Ref126601829">Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Dry Mouth</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hypoxia<footnote ID="_Ref126601849">Hypoxia was defined in absolute and relative terms as SpO<sub>2</sub> <90% or 10% decrease from baseline.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Bradypnea</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table>
></tr><tr><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Bradypnea</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>4%</paragraph></td></tr></tbody></table> <table ID="_RefTable8" width="97.8%"><caption>Table 8: Treatment-Emergent Adverse Events with Incidence >5%—Pediatric Patients During Non-invasive Procedure</caption><col width="39%"/><col width="17%"/><col width="17%"/><col width="17%"/><col width="11%"/><tfoot><tr><td align="left" colspan="5" valign="top">N = Number of pediatric patients evaluable for adverse events.</td></tr></tfoot><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">PRECEDEX</content></paragraph><paragraph><content styleCode="bold">Low Dose</content></paragraph><paragraph><content styleCode="bold">(N = 42)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">PRECEDEX</content></paragraph><paragraph><content styleCode="bold">Middle Dose</content></paragraph><paragraph><content styleCode="bold">(N = 42)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">PRECEDEX</content></paragraph><paragraph><content styleCode="bold">High Dose</content></paragraph><paragraph><content styleCode="bold">(N = 38)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Total</content></paragraph><paragraph><content styleCode="bold">(N = 122)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Number (%) of Pediatric Patients</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">n (%)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Adverse Event</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Bradypnea<footnote ID="_Ref126601964">Bradypnea was defined as respiratory rate <1<sup>st</sup> centile of the age adjusted normal range.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>33 (79)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>27 (64)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>22 (58)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>82 (67)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Bradycardia<footnote ID="_Ref126602075">Bradycardia was defined as a decrease in HR of 30% from baseline or absolute HR ≤1<sup>st</sup> ce
align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>82 (67)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Bradycardia<footnote ID="_Ref126602075">Bradycardia was defined as a decrease in HR of 30% from baseline or absolute HR ≤1<sup>st</sup> ce ntile of the age adjusted normal range.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>24 (57)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>24 (57)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>27 (71)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>75 (62)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypertension<footnote ID="_Ref126602095">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.
paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypertension<footnote ID="_Ref126602095">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<sup>th</sup> percentile for gender, age, and height.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11 (26)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17 (41)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>18 (47)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>46 (38)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypotension<footnote ID="_Ref126602113">Hypotension was defined as a decrease in systolic blood pressure ≥30% from baseline.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13 (31)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11 (26)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6 (16)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>30 (25)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypoxia<footnote ID="_Ref183552000">Hypoxia was defined as oxygen saturation <90% for any duration.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6 (14)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3 (7)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1 (3)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10 (8)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diastolic Hypertension<footnoteRef IDREF="_Ref126602095"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3 (7)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3 (7)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4 (11)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10 (8)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Systolic Hypertension<footnoteRef IDREF="_Ref126602095"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1 (2)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5 (12)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3 (8)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9 (7)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Tachycardia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3 (7)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1 (2)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><par
ph>Tachycardia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3 (7)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1 (2)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><par agraph>1 (3)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>5 (4)</paragraph></td></tr></tbody></table>
ph>Tachycardia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3 (7)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1 (2)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><par agraph>1 (3)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>5 (4)</paragraph></td></tr></tbody></table> <table ID="_RefID0EFOAI" width="100%"><caption>Table 9: Adverse Reactions Experienced During Post-Approval Use of PRECEDEX</caption><col width="38%"/><col width="62%"/><tbody><tr><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">System Organ Class</content></paragraph></td><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Preferred Term</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Blood and Lymphatic System Disorders</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Anemia</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Cardiac Disorders</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Eye Disorders</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Photopsia, visual impairment</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Gastrointestinal Disorders</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Abdominal pain, diarrhea, nausea, vomiting</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>General Disorders and Administration Site Conditions</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Chills, hyperpyrexia, pain, pyrexia, thirst</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Hepatobiliary Disorders</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Hepatic function abnormal, hyperbilirubinemia</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Investigations</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Metabolism and Nutrition Disorders</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Nervous System Disorders</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Psychiatric Disorders</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Agitation, confusional state, delirium, hallucination, illusion</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Renal and Urinary Disorders</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Oliguria, polyuria</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Respiratory, Thoracic and Mediastinal Disorders</paragraph></td><td styleCode="Lrule Topr
valign="top"><paragraph>Renal and Urinary Disorders</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Oliguria, polyuria</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Respiratory, Thoracic and Mediastinal Disorders</paragraph></td><td styleCode="Lrule Topr ule Botrule " valign="top"><paragraph>Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Skin and Subcutaneous Tissue Disorders</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Hyperhidrosis, pruritus, rash, urticaria</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Surgical and Medical Procedures</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Light anesthesia</paragraph></td></tr><tr><td styleCode="Rrule Botrule Toprule " valign="top"><paragraph>Vascular Disorders</paragraph></td><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph>Blood pressure fluctuation, hemorrhage, hypertension, hypotension</paragraph></td></tr></tbody></table>
7 DRUG INTERACTIONS Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of PRECEDEX or the concomitant medication may be required. ( 7.1 ) 7.1 Anesthetics, Sedatives, Hypnotics, Opioids Co-administration of PRECEDEX 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 PRECEDEX and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with PRECEDEX, a reduction in dosage of PRECEDEX 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 PRECEDEX 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.
8 USE IN SPECIFIC POPULATIONS • Geriatric Patients: Dose reduction should be considered. ( 2.2 , 2.3 , 5.2 , 8.5 ) • Hepatic Impairment: Dose reduction should be considered. ( 2.2 , 2.3 , 5.8 , 8.6 ) 8.1 Pregnancy Risk Summary Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of caesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta. In animal reproduction studies, fetal toxicity that lower fetal viability and reduced live fetuses occurred with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 1.8 times the maximum recommended human dose (MRHD) of 17.8 mcg/kg/day. Developmental toxicity (low pup weights and adult offspring weights, decreased F1 grip strength, increased early implantation loss and decreased viability of second-generation offspring) occurred when pregnant rats were subcutaneously administered dexmedetomidine at doses less than the clinical dose from late pregnancy through lactation and weaning (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Increased post-implantation losses and reduced live fetuses in the presence of maternal toxicity (i.e. decreased body weight) were noted in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine 200 mcg/kg/day (equivalent to 1.8 times the intravenous MRHD of 17.8 mcg/kg/day based on body surface area [BSA]) during the period of organogenesis (Gestation Day [GD] 6 to 15). No malformations were reported. No malformations or embryo-fetal toxicity were noted in a rabbit embryo-fetal development study in which pregnant does were administered dexmedetomidine intravenously at doses of up to 96 mcg/kg/day (approximately half the human exposure at the MRHD based on AUC) during the period of organogenesis (GD 6 to 18). Reduced pup and adult offspring birth weights, and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at doses of 8 mcg/kg/day (0.07 times the MRHD based on BSA) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21).
delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21). In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously. 8.2 Lactation Risk Summary Available published literature reports the presence of dexmedetomidine in human milk following intravenous administration (see Data ) . There is no information regarding the effects of dexmedetomidine on the breastfed infant or the effects on milk production. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for PRECEDEX and any potential adverse effects on the breastfed infant from PRECEDEX or from the underlying condition. Data In two published clinical studies, a total of 14 women were given intravenous dexmedetomidine 6 mcg/kg/hour for 10 minutes after delivery followed by continuous infusion of 0.2–0.7 mcg/kg/hour. Breast milk and maternal blood samples were collected at 0, 6, 12, and 24 hours after discontinuation of dexmedetomidine. Plasma and milk dexmedetomidine concentrations were detectable up to 6 hours in most subjects, up to 12 hours in one subject and undetectable in all at 24 hours. The milk-to-plasma ratio from single paired maternal milk and plasma concentrations at each time point ranged from 0.53 to 0.95. The relative infant dose was estimated to range from 0.02 to 0.098%. 8.4 Pediatric Use Sedation for Non-Invasive Procedures The safety and efficacy of PRECEDEX have been established in pediatric patients 1 month to less than 18 years of age for sedation during non-invasive procedures. Use in this age group is based on one randomized double-blind, dose-ranging safety and efficacy trial in non-intubated pediatric patients 1 month to less than 17 years of age who required sedation prior to undergoing MRI scans [see Clinical Studies (14.2) ] . An increase in frequency of bradypnea, bradycardia, hypertension and hypotension was observed in pediatric patients treated with PRECEDEX [see Adverse Reactions (6.1) ]. The overall safety profile of PRECEDEX in pediatric patients was consistent with the known safety profile in adults [see Adverse Reactions (6.1) ] . The safety and effectiveness of PRECEDEX have not been established in pediatric patients less than 1 month of age. ICU Sedation The safety and efficacy of PRECEDEX have not been established in pediatric patients for ICU sedation. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of PRECEDEX for these patient populations. 8.5 Geriatric Use Intensive Care Unit Sedation A total of 729 patients in the clinical studies were 65 years of age and over. A total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of PRECEDEX [see Warnings and Precautions (5.2) ] . Therefore, a dose reduction may be considered in patients over 65 years of age [see Dosage and Administration (2.2 , 2.3 ), Clinical Pharmacology (12.3) ] . Procedural Sedation A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over.
(5.2) ] . Therefore, a dose reduction may be considered in patients over 65 years of age [see Dosage and Administration (2.2 , 2.3 ), Clinical Pharmacology (12.3) ] . Procedural Sedation A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in PRECEDEX-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age. 8.6 Hepatic Impairment Since PRECEDEX clearance decreases with increasing severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration (2.2 , 2.3) , Clinical Pharmacology (12.3) ] .
8.1 Pregnancy Risk Summary Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of caesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta. In animal reproduction studies, fetal toxicity that lower fetal viability and reduced live fetuses occurred with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 1.8 times the maximum recommended human dose (MRHD) of 17.8 mcg/kg/day. Developmental toxicity (low pup weights and adult offspring weights, decreased F1 grip strength, increased early implantation loss and decreased viability of second-generation offspring) occurred when pregnant rats were subcutaneously administered dexmedetomidine at doses less than the clinical dose from late pregnancy through lactation and weaning (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Increased post-implantation losses and reduced live fetuses in the presence of maternal toxicity (i.e. decreased body weight) were noted in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine 200 mcg/kg/day (equivalent to 1.8 times the intravenous MRHD of 17.8 mcg/kg/day based on body surface area [BSA]) during the period of organogenesis (Gestation Day [GD] 6 to 15). No malformations were reported. No malformations or embryo-fetal toxicity were noted in a rabbit embryo-fetal development study in which pregnant does were administered dexmedetomidine intravenously at doses of up to 96 mcg/kg/day (approximately half the human exposure at the MRHD based on AUC) during the period of organogenesis (GD 6 to 18). Reduced pup and adult offspring birth weights, and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at doses of 8 mcg/kg/day (0.07 times the MRHD based on BSA) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21). In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously.
8.4 Pediatric Use Sedation for Non-Invasive Procedures The safety and efficacy of PRECEDEX have been established in pediatric patients 1 month to less than 18 years of age for sedation during non-invasive procedures. Use in this age group is based on one randomized double-blind, dose-ranging safety and efficacy trial in non-intubated pediatric patients 1 month to less than 17 years of age who required sedation prior to undergoing MRI scans [see Clinical Studies (14.2) ] . An increase in frequency of bradypnea, bradycardia, hypertension and hypotension was observed in pediatric patients treated with PRECEDEX [see Adverse Reactions (6.1) ]. The overall safety profile of PRECEDEX in pediatric patients was consistent with the known safety profile in adults [see Adverse Reactions (6.1) ] . The safety and effectiveness of PRECEDEX have not been established in pediatric patients less than 1 month of age. ICU Sedation The safety and efficacy of PRECEDEX have not been established in pediatric patients for ICU sedation. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of PRECEDEX for these patient populations.
8.5 Geriatric Use Intensive Care Unit Sedation A total of 729 patients in the clinical studies were 65 years of age and over. A total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of PRECEDEX [see Warnings and Precautions (5.2) ] . Therefore, a dose reduction may be considered in patients over 65 years of age [see Dosage and Administration (2.2 , 2.3 ), Clinical Pharmacology (12.3) ] . Procedural Sedation A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in PRECEDEX-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance PRECEDEX (dexmedetomidine hydrochloride) is not a controlled substance. 9.3 Dependence The dependence potential of PRECEDEX has not been studied in humans. However, since studies in rodents and primates have demonstrated that PRECEDEX exhibits pharmacologic actions similar to those of clonidine, it is possible that PRECEDEX may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [see Warnings and Precautions (5.5) ] .
9.3 Dependence The dependence potential of PRECEDEX has not been studied in humans. However, since studies in rodents and primates have demonstrated that PRECEDEX exhibits pharmacologic actions similar to those of clonidine, it is possible that PRECEDEX may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [see Warnings and Precautions (5.5) ] .
10 OVERDOSAGE The tolerability of PRECEDEX 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 PRECEDEX 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 PRECEDEX (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.
11 DESCRIPTION PRECEDEX (dexmedetomidine hydrochloride) in 0.9% Sodium Chloride Injection (4 mcg/mL) is a sterile, nonpyrogenic ready to use solution suitable for intravenous infusion. PRECEDEX contains dexmedetomidine hydrochloride as the active pharmaceutical ingredient. Dexmedetomidine hydrochloride is a central alpha 2 -adrenergic agonist. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine. Dexmedetomidine hydrochloride chemical name is 1H-Imidazole, 4-[1-(2,3-dimethylphenyl)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: PRECEDEX in 0.9% Sodium Chloride Injection is ready to be used. It is supplied as a clear, colorless, isotonic solution with a pH between 4.5 to 8.0. Each mL contains 4.72 mcg of dexmedetomidine hydrochloride (equivalent to 4 mcg or 0.004 mg of dexmedetomidine) and 9 mg sodium chloride in water for injection. The solution is preservative-free and contains no additives or chemical stabilizers. Chemical structure
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action PRECEDEX is a relatively selective centrally acting alpha 2 -adrenergic agonist with sedative properties. Alpha 2 selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha 1 and alpha 2 activity is observed following slow intravenous infusion of high doses (≥1,000 mcg/kg) or with rapid intravenous administration. 12.2 Pharmacodynamics In a study in healthy adult volunteers (N = 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when PRECEDEX was administered by intravenous infusion at doses within the recommended dose range (0.2–0.7 mcg/kg/hr). 12.3 Pharmacokinetics Following intravenous administration to adults, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t 1/2 ) of approximately 6 minutes; a terminal elimination half-life (t 1/2 ) of approximately 2 hours; and steady-state volume of distribution (V ss ) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg. Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered to adults by intravenous infusion for up to 24 hours. Table 10 shows the main pharmacokinetic parameters when PRECEDEX was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours. Table 10: Mean ± SD Pharmacokinetic Parameters in Adults Abbreviations: t 1/2 = half-life, CL = clearance, V ss = steady-state volume of distribution. Parameter Loading Infusion (min)/Total Infusion Duration (hrs) 10 min/12 hrs 10 min/24 hrs 10 min/24 hrs 35 min/24 hrs Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr) 0.3/0.17 0.3/0.17 0.6/0.33 1.25/0.70 t 1/2 Presented as harmonic mean and pseudo standard deviation. , hour 1.78 ± 0.30 2.22 ± 0.59 2.23 ± 0.21 2.50 ± 0.61 CL, liter/hour 46.3 ± 8.3 43.1 ± 6.5 35.3 ± 6.8 36.5 ± 7.5 V ss , liter 88.7 ± 22.9 102.4 ± 20.3 93.6 ± 17.0 99.6 ± 17.8 Avg C ss Mean C ss = Average steady-state concentration of dexmedetomidine. The mean C ss was calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions. , ng/mL 0.27 ± 0.05 0.27 ± 0.05 0.67 ± 0.10 1.37 ± 0.20 The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively. Dexmedetomidine pharmacokinetic parameters in adults after PRECEDEX maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetic (PK) parameters after PRECEDEX maintenance dosing for <24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t 1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively. Distribution The steady-state volume of distribution (V ss ) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested.
ly. Distribution The steady-state volume of distribution (V ss ) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of PRECEDEX that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects. The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro , and negligible changes in the plasma protein binding of PRECEDEX were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by PRECEDEX was explored in vitro and none of these compounds appeared to be significantly displaced by PRECEDEX. Elimination Metabolism Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide. Excretion The terminal elimination half-life (t 1/2 ) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified. Specific Populations Male and Female Patients There was no observed difference in PRECEDEX pharmacokinetics due to sex. Geriatric Patients The pharmacokinetic profile of PRECEDEX was not altered by age. There were no differences in the pharmacokinetics of PRECEDEX in young (18–40 years), middle age (41–65 years), and elderly (>65 years) subjects. Pediatric Patients A population PK analysis was conducted with data collected from mechanically ventilated pediatric patients less than 17 years of age from 4 clinical studies. A linear 2-compartment model was found to best characterize the pooled dexmedetomidine concentration data. Mean PK parameters for each age group are summarized in Table 11 .
n PK analysis was conducted with data collected from mechanically ventilated pediatric patients less than 17 years of age from 4 clinical studies. A linear 2-compartment model was found to best characterize the pooled dexmedetomidine concentration data. Mean PK parameters for each age group are summarized in Table 11 . Table 11: Geometric Mean Point Estimates and 95% Confidence Intervals of PK Parameters by Pediatric Age Group Abbreviations: CL = plasma clearance, Vc = volume of the central compartment. Age Group N CL (L/h) Vc (L) 1 to less than 6 months 14 6.94 (5.46, 8.81) 4.34 (3.25, 5.81) 6 to less than 12 months 15 8.15 (7.01, 9.47) 7.29 (5.57, 9.53) 12 to less than 24 months 13 10.76 (9.09, 12.74) 7.35 (5.59, 9.67) 2 to less than 6 years 26 15.89 (14.00, 18.04) 13.78 (10.66, 17.83) 6 to less than 17 years 28 24.45 (19.34, 30.92) 24.47 (17.06, 35.10) Patients with Hepatic Impairment In adult subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for PRECEDEX were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy adult subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy adult subjects, respectively. Although PRECEDEX is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see Dosage and Administration (2.2) , Warnings and Precautions (5.8) ] . Patients with Renal Impairment Dexmedetomidine pharmacokinetics (C max , T max , AUC, t 1/2 , CL, and V ss ) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects. Drug Interaction Studies In vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.
12.1 Mechanism of Action PRECEDEX is a relatively selective centrally acting alpha 2 -adrenergic agonist with sedative properties. Alpha 2 selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha 1 and alpha 2 activity is observed following slow intravenous infusion of high doses (≥1,000 mcg/kg) or with rapid intravenous administration.
12.2 Pharmacodynamics In a study in healthy adult volunteers (N = 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when PRECEDEX was administered by intravenous infusion at doses within the recommended dose range (0.2–0.7 mcg/kg/hr).
12.3 Pharmacokinetics Following intravenous administration to adults, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t 1/2 ) of approximately 6 minutes; a terminal elimination half-life (t 1/2 ) of approximately 2 hours; and steady-state volume of distribution (V ss ) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg. Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered to adults by intravenous infusion for up to 24 hours. Table 10 shows the main pharmacokinetic parameters when PRECEDEX was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours. Table 10: Mean ± SD Pharmacokinetic Parameters in Adults Abbreviations: t 1/2 = half-life, CL = clearance, V ss = steady-state volume of distribution. Parameter Loading Infusion (min)/Total Infusion Duration (hrs) 10 min/12 hrs 10 min/24 hrs 10 min/24 hrs 35 min/24 hrs Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr) 0.3/0.17 0.3/0.17 0.6/0.33 1.25/0.70 t 1/2 Presented as harmonic mean and pseudo standard deviation. , hour 1.78 ± 0.30 2.22 ± 0.59 2.23 ± 0.21 2.50 ± 0.61 CL, liter/hour 46.3 ± 8.3 43.1 ± 6.5 35.3 ± 6.8 36.5 ± 7.5 V ss , liter 88.7 ± 22.9 102.4 ± 20.3 93.6 ± 17.0 99.6 ± 17.8 Avg C ss Mean C ss = Average steady-state concentration of dexmedetomidine. The mean C ss was calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions. , ng/mL 0.27 ± 0.05 0.27 ± 0.05 0.67 ± 0.10 1.37 ± 0.20 The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively. Dexmedetomidine pharmacokinetic parameters in adults after PRECEDEX maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetic (PK) parameters after PRECEDEX maintenance dosing for <24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t 1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively. Distribution The steady-state volume of distribution (V ss ) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of PRECEDEX that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects. The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro , and negligible changes in the plasma protein binding of PRECEDEX were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by PRECEDEX was explored in vitro and none of these compounds appeared to be significantly displaced by PRECEDEX.
itro , and negligible changes in the plasma protein binding of PRECEDEX were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by PRECEDEX was explored in vitro and none of these compounds appeared to be significantly displaced by PRECEDEX. Elimination Metabolism Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide. Excretion The terminal elimination half-life (t 1/2 ) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified. Specific Populations Male and Female Patients There was no observed difference in PRECEDEX pharmacokinetics due to sex. Geriatric Patients The pharmacokinetic profile of PRECEDEX was not altered by age. There were no differences in the pharmacokinetics of PRECEDEX in young (18–40 years), middle age (41–65 years), and elderly (>65 years) subjects. Pediatric Patients A population PK analysis was conducted with data collected from mechanically ventilated pediatric patients less than 17 years of age from 4 clinical studies. A linear 2-compartment model was found to best characterize the pooled dexmedetomidine concentration data. Mean PK parameters for each age group are summarized in Table 11 . Table 11: Geometric Mean Point Estimates and 95% Confidence Intervals of PK Parameters by Pediatric Age Group Abbreviations: CL = plasma clearance, Vc = volume of the central compartment.
best characterize the pooled dexmedetomidine concentration data. Mean PK parameters for each age group are summarized in Table 11 . Table 11: Geometric Mean Point Estimates and 95% Confidence Intervals of PK Parameters by Pediatric Age Group Abbreviations: CL = plasma clearance, Vc = volume of the central compartment. Age Group N CL (L/h) Vc (L) 1 to less than 6 months 14 6.94 (5.46, 8.81) 4.34 (3.25, 5.81) 6 to less than 12 months 15 8.15 (7.01, 9.47) 7.29 (5.57, 9.53) 12 to less than 24 months 13 10.76 (9.09, 12.74) 7.35 (5.59, 9.67) 2 to less than 6 years 26 15.89 (14.00, 18.04) 13.78 (10.66, 17.83) 6 to less than 17 years 28 24.45 (19.34, 30.92) 24.47 (17.06, 35.10) Patients with Hepatic Impairment In adult subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for PRECEDEX were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy adult subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy adult subjects, respectively. Although PRECEDEX is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see Dosage and Administration (2.2) , Warnings and Precautions (5.8) ] . Patients with Renal Impairment Dexmedetomidine pharmacokinetics (C max , T max , AUC, t 1/2 , CL, and V ss ) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects. Drug Interaction Studies In vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.
<table ID="_RefTable10" width="97.8%"><caption>Table 10: Mean ± SD Pharmacokinetic Parameters in Adults</caption><col width="20%"/><col width="21%"/><col width="20%"/><col width="19%"/><col width="19%"/><tfoot><tr><td align="left" colspan="5" valign="top">Abbreviations: t<sub>1/2</sub> = half-life, CL = clearance, V<sub>ss</sub> = steady-state volume of distribution.</td></tr></tfoot><tbody><tr><td rowspan="4" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Parameter</content></paragraph></td><td align="center" colspan="4" styleCode="Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Loading Infusion (min)/Total Infusion Duration (hrs)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">10 min/12 hrs</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">10 min/24 hrs</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">10 min/24 hrs</content></paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">35 min/24 hrs</content></paragraph></td></tr><tr><td align="center" colspan="4" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">0.3/0.17</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">0.3/0.17</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">0.6/0.33</content></paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">1.25/0.70</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">t<sub>1/2</sub></content><footnote ID="_Ref114752686">Presented as harmonic mean and pseudo standard deviation.</footnote><content styleCode="bold">, hour</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1.78 ± 0.30</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2.22 ± 0.59</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>2.23 ± 0.21</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>2.50 ± 0.61</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">CL, liter/hour</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>46.3 ± 8.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>43.1 ± 6.5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>35.3 ± 6.8</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>3
<td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>43.1 ± 6.5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>35.3 ± 6.8</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>3 6.5 ± 7.5</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="bottom"><paragraph><content styleCode="bold">V<sub>ss</sub>, liter </content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>88.7 ± 22.9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>102.4 ± 20.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>93.6 ± 17.0</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>99.6 ± 17.8</paragraph></td></tr><tr><td styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Avg C<sub>ss</sub></content><footnote ID="_Ref114752712">Mean C<sub>ss</sub> = Average steady-state concentration of dexmedetomidine. The mean C<sub>ss</sub> was calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions.</footnote><content styleCode="bold">, ng/mL</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>0.27 ± 0.05</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>0.27 ± 0.05</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>0.67 ± 0.10</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="middle"><paragraph>1.37 ± 0.20</paragraph></td></tr></tbody></table>
le " valign="middle"><paragraph>0.27 ± 0.05</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph>0.67 ± 0.10</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="middle"><paragraph>1.37 ± 0.20</paragraph></td></tr></tbody></table> <table ID="_RefTable11" width="99.02%"><caption>Table 11: Geometric Mean Point Estimates and 95% Confidence Intervals of PK Parameters by Pediatric Age Group</caption><col width="26%"/><col width="23%"/><col width="25%"/><col width="25%"/><tfoot><tr><td align="left" colspan="4" valign="top">Abbreviations: CL = plasma clearance, Vc = volume of the central compartment.</td></tr></tfoot><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Age Group</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">CL (L/h)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Vc (L)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 to less than 6 months</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.94 (5.46, 8.81)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.34 (3.25, 5.81)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>6 to less than 12 months</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8.15 (7.01, 9.47)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7.29 (5.57, 9.53)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>12 to less than 24 months</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10.76 (9.09, 12.74)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7.35 (5.59, 9.67)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 to less than 6 years</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15.89 (14.00, 18.04)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13.78 (10.66, 17.83)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>6 to less than 17 years</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>24.45 (19.34, 30.92)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>24.47 (17.06, 35.10)</paragraph></td></tr></tbody></table>
13.2 Animal Toxicology and/or Pharmacology There were no differences in the adrenocorticotropic hormone (ACTH)-stimulated cortisol response in dogs following a single dose of dexmedetomidine compared to saline control. However, after continuous subcutaneous infusions of dexmedetomidine at 3 mcg/kg/hr and 10 mcg/kg/hr for one week in dogs (exposures estimated to be within the clinical range), the ACTH-stimulated cortisol response was diminished by approximately 27% and 40%, respectively, compared to saline-treated control animals indicating a dose-dependent adrenal suppression.
14 CLINICAL STUDIES The safety and efficacy of PRECEDEX has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1,185 adult patients. 14.1 Intensive Care Unit Sedation Two randomized, double-blind, parallel-group, placebo-controlled multicenter clinical trials included 754 adult patients being treated in a surgical intensive care unit. All patients were initially intubated and received mechanical ventilation. These trials evaluated the sedative properties of PRECEDEX by comparing the amount of rescue medication (midazolam in one trial and propofol in the second) required to achieve a specified level of sedation (using the standardized Ramsay Sedation Scale) between PRECEDEX and placebo from onset of treatment to extubation or to a total treatment duration of 24 hours. The Ramsay Level of Sedation Scale is displayed in Table 12 . Table 12: Ramsay Level of Sedation Scale Clinical Score Level of Sedation Achieved 6 Asleep, no response 5 Asleep, sluggish response to light glabellar tap or loud auditory stimulus 4 Asleep, but with brisk response to light glabellar tap or loud auditory stimulus 3 Patient responds to commands 2 Patient cooperative, oriented, and tranquil 1 Patient anxious, agitated, or restless In the first study, 175 adult patients were randomized to receive placebo and 178 to receive PRECEDEX by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion rate was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive “rescue” midazolam as needed to augment the study drug infusion. In addition, morphine sulfate was administered for pain as needed. The primary outcome measure for this study was the total amount of rescue medication (midazolam) needed to maintain sedation as specified while intubated. Patients randomized to placebo received significantly more midazolam than patients randomized to PRECEDEX (see Table 13 ). A second prospective primary analysis assessed the sedative effects of PRECEDEX by comparing the percentage of adult patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of adult patients in the PRECEDEX group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 13 ). Table 13: Midazolam Use as Rescue Medication During Intubation (ITT) Study One ITT (intent-to-treat) population includes all randomized patients. Placebo (N = 175) PRECEDEX (N = 178) p-value Mean Total Dose (mg) of Midazolam 19 mg 5 mg 0.0011 ANOVA model with treatment center. Standard deviation 53 mg 19 mg Categorized Midazolam Use 0 mg 43 (25%) 108 (61%) <0.001 Chi-square. 0–4 mg 34 (19%) 36 (20%) >4 mg 98 (56%) 34 (19%) A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the PRECEDEX and placebo groups. On average, PRECEDEX-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h). In addition, 44% (79 of 178 patients) of PRECEDEX patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group.
in the PRECEDEX and placebo groups. On average, PRECEDEX-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h). In addition, 44% (79 of 178 patients) of PRECEDEX patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group. In a second study, 198 adult patients were randomized to receive placebo and 203 to receive PRECEDEX by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive “rescue” propofol as needed to augment the study drug infusion. In addition, morphine sulfate was administered as needed for pain. The primary outcome measure for this study was the total amount of rescue medication (propofol) needed to maintain sedation as specified while intubated. Adult patients randomized to placebo received significantly more propofol than adult patients randomized to PRECEDEX (see Table 14 ). A significantly greater percentage of adult patients in the PRECEDEX group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see Table 14 ). Table 14: Propofol Use as Rescue Medication During Intubation (ITT) Study Two Placebo (N = 198) PRECEDEX (N = 203) p-value Mean Total Dose (mg) of Propofol 513 mg 72 mg <0.0001 ANOVA model with treatment center. Standard deviation 782 mg 249 mg Categorized Propofol Use 0 mg 47 (24%) 122 (60%) <0.001 Chi-square. 0–50 mg 30 (15%) 43 (21%) >50 mg 121 (61%) 38 (19%) A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the PRECEDEX and placebo groups. On average, PRECEDEX-treated patients received less morphine sulfate for pain than placebo-treated patients (0.43 versus 0.89 mg/h). In addition, 41% (83 of 203 patients) of PRECEDEX patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group. In a controlled clinical trial, PRECEDEX was compared to midazolam for ICU sedation exceeding 24 hours duration. PRECEDEX was not shown to be superior to midazolam for the primary efficacy endpoint, the percent of time patients were adequately sedated (81% versus 81%). In addition, administration of PRECEDEX for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [see Adverse Reactions (6.1) ] . 14.2 Procedural Sedation Adult Patients The safety and efficacy of PRECEDEX for sedation of non-intubated adult patients prior to and/or during surgical and other procedures was evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials. Study 1 evaluated the sedative properties of PRECEDEX in adult patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated PRECEDEX in adult patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure. In Study 1, the sedative properties of PRECEDEX were evaluated by comparing the percent of adult patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer’s Assessment of Alertness/Sedation Scale (see Table 15 ).
ubation prior to a surgical or diagnostic procedure. In Study 1, the sedative properties of PRECEDEX were evaluated by comparing the percent of adult patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer’s Assessment of Alertness/Sedation Scale (see Table 15 ). Table 15: Observer’s Assessment of Alertness/Sedation Assessment Categories Responsiveness Speech Facial Expression Eyes Composite Score Responds readily to name spoken in normal tone Normal Normal Clear, no ptosis 5 (alert) Lethargic response to name spoken in normal tone Mild slowing or thickening Mild relaxation Glazed or mild ptosis (less than half the eye) 4 Responds only after name is called loudly and/or repeatedly Slurring or prominent slowing Marked relaxation (slack jaw) Glazed and marked ptosis (half the eye or more) 3 Responds only after mild prodding or shaking Few recognizable words – – 2 Does not respond to mild prodding or shaking – – – 1 (deep sleep) Adult patients were randomized to receive a loading infusion of either PRECEDEX 1 mcg/kg, PRECEDEX 0.5 mcg/kg, or placebo (normal saline) given over 10 minutes and followed by a maintenance infusion started at 0.6 mcg/kg/hr. The maintenance infusion of study drug could be titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr to achieve the targeted sedation score (Observer’s Assessment of Alertness/Sedation Scale ≤4). Adult patients were allowed to receive rescue midazolam as needed to achieve and/or maintain an Observer’s Assessment of Alertness/Sedation Scale ≤4. After achieving the desired level of sedation, a local or regional anesthetic block was performed. Demographic characteristics were similar between the PRECEDEX and comparator groups. Efficacy results showed that PRECEDEX was more effective than the comparator group when used to sedate non-intubated patients requiring monitored anesthesia care during surgical and other procedures (see Table 15 ). In Study 2, the sedative properties of PRECEDEX were evaluated by comparing the percent of adult patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see Table 12 ). Adult patients were randomized to receive a loading infusion of PRECEDEX 1 mcg/kg or placebo (normal saline) given over 10 minutes and followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired level of sedation, topicalization of the airway occurred. Adult patients were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay Sedation Scale ≥2. Demographic characteristics were similar between the PRECEDEX and comparator groups. For efficacy results see Table 16 . Table 16: Key Efficacy Results of Adult Procedural Sedation Studies Study Loading Infusion Treatment Arm Number of Patients Enrolled Based on ITT population defined as all randomized and treated patients. % Not Requiring Midazolam Rescue Confidence Normal approximation to the binomial with continuity correction. Interval on the Difference vs. Placebo Mean (SD) Total Dose (mg) of Rescue Midazolam Required Confidence Intervals of the Mean Rescue Dose Study 1 Dexmedetomidine 0.5 mcg/kg 134 40 37 (27, 48) 1.4 (1.7) -2.7 (-3.4, -2.0) Dexmedetomidine 1 mcg/kg 129 54 51 (40, 62) 0.9 (1.5) -3.1 (-3.8, -2.5) Placebo 63 3 – 4.1 (3.0) – Study 2 Dexmedetomidine 1 mcg/kg 55 53 39 (20, 57) 1.1 (1.5) -1.8 (-2.7, -0.9) Placebo 50 14 – 2.9 (3.0) – Pediatric Patients The safety and efficacy of PRECEDEX for sedation of non-intubated pediatric patients aged 1 month to less than 17 years undergoing MRI scans was evaluated in one randomized, double-blind, dose-ranging, dose‑controlled multicenter clinical trial utilizing 3 different PRECEDEX dosages.
14 – 2.9 (3.0) – Pediatric Patients The safety and efficacy of PRECEDEX for sedation of non-intubated pediatric patients aged 1 month to less than 17 years undergoing MRI scans was evaluated in one randomized, double-blind, dose-ranging, dose‑controlled multicenter clinical trial utilizing 3 different PRECEDEX dosages. The sedative properties of PRECEDEX were evaluated by age group and by the percent of pediatric patients at the high dose level versus the low dose level who did not require concomitant propofol to complete the MRI scan. A total of 122 pediatric patients were randomized to the PRECEDEX low dose group (42 of 122), the middle dose group (42 of 122) or the high dose treatment group (38 of 122). All patients received a PRECEDEX loading dose infusion over 10 minutes followed by a maintenance infusion for the duration of the MRI scan ( Table 17 ). If an adequate level of sedation was not achieved within 5 minutes after the start of the PRECEDEX maintenance infusion, patients could receive concomitant propofol as needed based on clinical judgment to achieve and/or maintain adequate sedation. Table 17: PRECEDEX Loading and Maintenance Doses High Dose Middle Dose Low Dose Age Loading Dose (10 min) Maintenance Dose Loading Dose (10 min) Maintenance Dose Loading Dose (10 min) Maintenance Dose 1 month to less than 2 years 1.5 mcg/kg 1.5 mcg/kg/h 1 mcg/kg 1 mcg/kg/h 0.5 mcg/kg 0.5 mcg/kg/h 2 to less than 17 years 2 mcg/kg 1.5 mcg/kg/h 1.2 mcg /kg 1 mcg/kg/h 0.5 mcg/kg 0.5 mcg kg/h The primary efficacy results from this pediatric procedural sedation study are summarized in Table 18 . In the combined age group, the percent of pediatric patients not requiring concomitant propofol was 14.3% (6/42) in the low dose group and 63.2% (24/38) in the high dose group. The percentage of patients at the PRECEDEX high dose who completed the MRI without concomitant propofol was statistically greater than the percentage in the PRECEDEX low dose group (p<0.001). Table 18: Percent of Pediatric Patients not Requiring Concomitant Propofol by Age Group and Overall Age Group High Dose Middle Dose Low Dose High Dose vs Low Dose n (%) 95% CI Exact 95% CI of proportion of subjects not requiring propofol in each dose level. n (%) 95% CI n (%) 95% CI Odds Ratio 95% CI p-values; CI is confidence interval of odds ratio. p-value 1 month to less than 2 years N=59 9/18 (50.0%) (0.26, 0.74) 2/21 (9.5%) (0.01, 0.30) 2/20 (15.0%) (0.03, 0.38) 0.18 (0.04, 0.82) 0.022 2 to less than 17 years N=63 15/20 (75.0%) (0.51, 0.91) 13/21 (61.9%) (0.38, 0.82) 3/22 (13.6%) (0.03, 0.35) 0.05 (0.01, 0.26) <0.001 Overall N=122 24/38 (63.2%) (0.46, 0.78) 15/42 (35.7%) (0.22, 0.52) 6/42 (14.3%) (0.05, 0.29) 0.10 (0.03, 0.29) <0.001 Secondarily, the sedative properties were also evaluated by examining the percent of time at a target sedation score using the Pediatric Sedation State Scale (PSSS). The PSSS is a validated 6-point scale specifically designed for evaluating pediatric patients undergoing sedation for diagnostic and therapeutic procedures. The PSSS measures the effectiveness and quality of procedural sedation in children. The target sedation level was indicated by a PSSS score of 2 (i.e., patient is quiet [asleep or awake], not moving during procedure, has no frown [or brow furrow] indicating pain or anxiety and no verbalization of any complaint). In the PRECEDEX high dose group, pediatric patients in both the combined and individual age group were at the target sedation rating scale score (PSSS of 2) for a mean >87% of the time during the PRECEDEX maintenance infusion. In both the combined and individual age group, an increase in the percentage of time at the target sedation rating scale score (PSSS of 2) was observed with increasing PRECEDEX dosage.
<table ID="_RefTable12" width="98%"><caption>Table 12: Ramsay Level of Sedation Scale</caption><col width="24%"/><col width="76%"/><thead><tr><th align="left" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Clinical Score</content></th><th align="left" styleCode="Botrule Lrule Toprule " valign="top"><content styleCode="bold">Level of Sedation Achieved</content></th></tr></thead><tbody><tr><td align="center" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph>6</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>Asleep, no response</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>5</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>Asleep, sluggish response to light glabellar tap or loud auditory stimulus</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>4</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>Asleep, but with brisk response to light glabellar tap or loud auditory stimulus</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>3</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>Patient responds to commands</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>2</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>Patient cooperative, oriented, and tranquil</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph>1</paragraph></td><td styleCode="Botrule Lrule Toprule " valign="middle"><paragraph>Patient anxious, agitated, or restless</paragraph></td></tr></tbody></table>
paragraph>Patient cooperative, oriented, and tranquil</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Toprule " valign="middle"><paragraph>1</paragraph></td><td styleCode="Botrule Lrule Toprule " valign="middle"><paragraph>Patient anxious, agitated, or restless</paragraph></td></tr></tbody></table> <table width="98%"><caption>Table 13: Midazolam Use as Rescue Medication During Intubation (ITT) Study One</caption><col width="40%"/><col width="22%"/><col width="20%"/><col width="18%"/><tfoot><tr><td align="left" colspan="4" valign="top">ITT (intent-to-treat) population includes all randomized patients.</td></tr></tfoot><tbody><tr><td styleCode="Rrule Botrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N = 175)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">PRECEDEX</content></paragraph><paragraph><content styleCode="bold">(N = 178)</content></paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">p-value</content></paragraph></td></tr><tr><td styleCode="Rrule " valign="top"><paragraph><content styleCode="bold">Mean Total Dose (mg) of Midazolam</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>19 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>5 mg</paragraph></td><td align="center" styleCode="Lrule Toprule " valign="top"><paragraph>0.0011<footnote ID="_Ref114842623">ANOVA model with treatment center.</footnote></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Standard deviation</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>53 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>19 mg</paragraph></td><td styleCode="Lrule Botrule " valign="top"/></tr><tr><td colspan="4" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Categorized Midazolam Use</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>43 (25%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>108 (61%)</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph><0.001<footnote ID="_Ref114842645">Chi-square.</footnote></paragraph></td></tr><tr><td align="center" styleCode="Rrule " valign="top"><paragraph>0–4 mg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>34 (19%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule " valign="top"><paragraph>36 (20%)</paragraph></td><td styleCode="Lrule Toprule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph>>4 mg</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>98 (56%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>34 (19%)</paragraph></td><td styleCode="Botrule Lrule Toprule " valign="top"/></tr></tbody></table>
ph>>4 mg</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>98 (56%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>34 (19%)</paragraph></td><td styleCode="Botrule Lrule Toprule " valign="top"/></tr></tbody></table> <table ID="_Ref115198292" width="98%"><caption>Table 14: Propofol Use as Rescue Medication During Intubation (ITT) Study Two</caption><col width="36%"/><col width="21%"/><col width="23%"/><col width="21%"/><thead><tr><th align="left" styleCode="Rrule Botrule Toprule " valign="top"/><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold"> (N = 198)</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">PRECEDEX</content> <content styleCode="bold"> (N = 203)</content></th><th align="center" styleCode="Botrule Toprule " valign="bottom"><content styleCode="bold">p-value</content></th></tr></thead><tbody><tr><td styleCode="Rrule Toprule " valign="top"><paragraph><content styleCode="bold">Mean Total Dose (mg) of Propofol</content></paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>513 mg</paragraph></td><td align="center" styleCode="Rrule Toprule " valign="top"><paragraph>72 mg</paragraph></td><td align="center" styleCode="Toprule " valign="top"><paragraph><0.0001<footnote ID="_Ref114842679">ANOVA model with treatment center.</footnote></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Standard deviation</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>782 mg</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>249 mg</paragraph></td><td styleCode="Botrule " valign="top"/></tr><tr><td colspan="4" styleCode="Botrule " valign="top"><paragraph><content styleCode="bold">Categorized Propofol Use</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0 mg</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>47 (24%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>122 (60%)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph><0.001<footnote ID="_Ref114842699">Chi-square.</footnote></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0–50 mg</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>30 (15%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>43 (21%)</paragraph></td><td styleCode="Botrule " valign="top"/></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>>50 mg</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>121 (61%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>38 (19%)</paragraph></td><td styleCode="Botrule " valign="top"/></tr></tbody></table>
e="Rrule Botrule " valign="top"><paragraph>>50 mg</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>121 (61%)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>38 (19%)</paragraph></td><td styleCode="Botrule " valign="top"/></tr></tbody></table> <table ID="_RefTable15" width="98%"><caption>Table 15: Observer’s Assessment of Alertness/Sedation</caption><col width="26%"/><col width="19%"/><col width="19%"/><col width="18%"/><col width="18%"/><thead><tr><th align="center" colspan="5" styleCode="Botrule Toprule " valign="top"><content styleCode="bold">Assessment Categories</content></th></tr><tr><th align="left" styleCode="Rrule Botrule " valign="bottom"><content styleCode="bold">Responsiveness</content></th><th align="center" styleCode="Rrule Botrule " valign="bottom"><content styleCode="bold">Speech</content></th><th align="center" styleCode="Rrule Botrule " valign="bottom"><content styleCode="bold">Facial Expression</content></th><th align="center" styleCode="Rrule Botrule " valign="bottom"><content styleCode="bold">Eyes</content></th><th align="center" styleCode="Botrule " valign="bottom"><content styleCode="bold">Composite Score</content></th></tr></thead><tbody><tr><td styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Responds readily to name spoken in normal tone</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Normal</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Normal</paragraph></td><td align="center" styleCode="Rrule Toprule Botrule " valign="top"><paragraph>Clear, no ptosis</paragraph></td><td align="center" styleCode="Toprule Botrule " valign="top"><paragraph>5 (alert)</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Lethargic response to name spoken in normal tone</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Mild slowing or thickening</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Mild relaxation</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Glazed or mild ptosis (less than half the eye)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Responds only after name is called loudly and/or repeatedly</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Slurring or prominent slowing</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Marked relaxation (slack jaw)</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Glazed and marked ptosis (half the eye or more)</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Responds only after mild prodding or shaking</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>Few recognizable words</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>–</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>–</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Botrule " valign="top"><paragraph>Does not respond to mild prodding or shaking</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>–</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>–</paragraph></td><td align="center" styleCode="Rrule
" valign="top"><paragraph>Does not respond to mild prodding or shaking</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>–</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>–</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="middle"><paragraph>–</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>1 (deep sleep)</paragraph></td></tr></tbody></table> <table ID="_RefTable16" width="99.02%"><caption>Table 16: Key Efficacy Results of Adult Procedural Sedation Studies</caption><col width="9%"/><col width="18%"/><col width="17%"/><col width="13%"/><col width="14%"/><col width="14%"/><col width="14%"/><tbody><tr><td styleCode="Rrule Botrule Toprule " valign="middle"><paragraph><content styleCode="bold">Study</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Loading Infusion Treatment Arm</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Number of Patients Enrolled</content><footnote ID="_Ref114842952">Based on ITT population defined as all randomized and treated patients.</footnote></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">% Not Requiring Midazolam Rescue</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Confidence</content><footnote ID="_Ref114842784">Normal approximation to the binomial with continuity correction.</footnote><content styleCode="bold"> Interval on the Difference vs.
/content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Confidence</content><footnote ID="_Ref114842784">Normal approximation to the binomial with continuity correction.</footnote><content styleCode="bold"> Interval on the Difference vs. Placebo</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Mean (SD) Total Dose (mg) of Rescue Midazolam Required</content></paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Confidence</content><footnoteRef IDREF="_Ref114842784"/><content styleCode="bold"> Intervals of the Mean Rescue Dose</content></paragraph></td></tr><tr><td rowspan="3" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Study 1</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Dexmedetomidine 0.5 mcg/kg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>134</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>40</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>37 (27, 48)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="middle"><paragraph>1.4 (1.7)</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="middle"><paragraph>-2.7</paragraph><paragraph>(-3.4, -2.0)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Dexmedetomidine 1 mcg/kg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>129</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>54</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>51 (40, 62)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.9 (1.5)</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>-3.1</paragraph><paragraph>(-3.8, -2.5)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Placebo</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>63</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>–</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.1 (3.0)</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>–</paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Toprule Botrule " valign="middle"><paragraph><content styleCode="bold">Study 2</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Dexmedetomidine 1 mcg/kg</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>55</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>53</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>39 (20, 57)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.1 (1.5)</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>-1.8</paragraph><paragraph>(-2.7, -0.9)</paragraph></t
e Lrule Toprule Botrule " valign="top"><paragraph>39 (20, 57)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.1 (1.5)</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>-1.8</paragraph><paragraph>(-2.7, -0.9)</paragraph></t d></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Placebo</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>50</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>–</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2.9 (3.0)</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>–</paragraph></td></tr></tbody></table>
eCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>–</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2.9 (3.0)</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>–</paragraph></td></tr></tbody></table> <table ID="_RefTable17" width="97.8%"><caption>Table 17: PRECEDEX Loading and Maintenance Doses</caption><col width="15%"/><col width="13%"/><col width="16%"/><col width="13%"/><col width="15%"/><col width="13%"/><col width="15%"/><tbody><tr><td styleCode="Rrule Lrule Toprule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">High Dose</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Middle Dose</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Low Dose</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Age </content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Loading Dose </content></paragraph><paragraph><content styleCode="bold">(10 min)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Maintenance Dose</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Loading Dose </content></paragraph><paragraph><content styleCode="bold">(10 min)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Maintenance Dose</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Loading Dose </content></paragraph><paragraph><content styleCode="bold">(10 min)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Maintenance Dose</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 month to less than 2 years</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.5 mcg/kg</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1.5 mcg/kg/h</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 mcg/kg</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 mcg/kg/h</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5 mcg/kg</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>0.5 mcg/kg/h</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2 to less than 17 years</paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph>2 mcg/kg</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.5 mcg/kg/h</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.2 mcg /kg</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1 mcg/kg/h</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.5 mcg/kg</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.5 mcg kg/h</
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1 mcg/kg/h</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.5 mcg/kg</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.5 mcg kg/h</ paragraph></td></tr></tbody></table>
<td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1 mcg/kg/h</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.5 mcg/kg</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.5 mcg kg/h</ paragraph></td></tr></tbody></table> <table ID="_RefTable18" width="97.8%"><caption>Table 18: Percent of Pediatric Patients not Requiring Concomitant Propofol by Age Group and Overall</caption><col width="16%"/><col width="11%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="17%"/><col width="15%"/><tbody><tr styleCode="Toprule"><td styleCode="Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Age Group</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">High Dose</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Middle Dose</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Low Dose</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">High Dose vs Low Dose</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"/><td valign="top"/><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">n (%)</content></paragraph><paragraph><content styleCode="bold">95% CI</content><footnote ID="_Ref126342116">Exact 95% CI of proportion of subjects not requiring propofol in each dose level.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">n (%)</content></paragraph><paragraph><content styleCode="bold">95% CI</content><footnoteRef IDREF="_Ref126342116"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">n (%)</content></paragraph><paragraph><content styleCode="bold">95% CI</content><footnoteRef IDREF="_Ref126342116"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Odds Ratio</content></paragraph><paragraph><content styleCode="bold">95% CI</content><footnote ID="_Ref126342179">p-values; CI is confidence interval of odds ratio.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">p-value</content><footnoteRef IDREF="_Ref126342179"/></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1 month to less than 2 years</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>N=59</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9/18 (50.0%)</paragraph><paragraph>(0.26, 0.74)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2/21 (9.5%)</paragraph><paragraph>(0.01, 0.30)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2/20 (15.0%)</paragraph><paragraph>(0.03, 0.38)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.18 (0.04, 0.82)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.022</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 to less than 17 years</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule B
n="top"><paragraph>0.18 (0.04, 0.82)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.022</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2 to less than 17 years</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule B otrule " valign="top"><paragraph>N=63</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15/20 (75.0%)</paragraph><paragraph>(0.51, 0.91)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13/21 (61.9%)</paragraph><paragraph>(0.38, 0.82)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3/22 (13.6%)</paragraph><paragraph>(0.03, 0.35)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.05 (0.01, 0.26)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><0.001</paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Overall</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>N=122</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>24/38 (63.2%)</paragraph><paragraph>(0.46, 0.78)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>15/42 (35.7%)</paragraph><paragraph>(0.22, 0.52)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>6/42 (14.3%)</paragraph><paragraph>(0.05, 0.29)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.10 (0.03, 0.29)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><0.001</paragraph></td></tr></tbody></table>
16 HOW SUPPLIED/STORAGE AND HANDLING Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.] Do not use if product is discolored or if precipitate matter is present. PRECEDEX (dexmedetomidine hydrochloride in 0.9% Sodium Chloride) injection (4 mcg/mL) is clear and colorless. The strength is based on the dexmedetomidine base. Discard unused portion. Unit of Sale Concentration NDC 0409-4596-20 Tray of 20 single‑dose clear glass bottles 200 mcg/50 mL (4 mcg/mL) NDC 0409-0155-02 Tray of 10 single‑dose clear glass bottles 400 mcg/100 mL (4 mcg/mL)
<table width="98%"><col width="49%"/><col width="51%"/><tbody><tr styleCode="Toprule"><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Unit of Sale</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Concentration</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">NDC 0409-4596-20</content></paragraph><paragraph>Tray of 20 single‑dose clear glass bottles</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>200 mcg/50 mL</paragraph><paragraph>(4 mcg/mL)</paragraph></td></tr><tr styleCode="Botrule"><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">NDC 0409-0155-02</content></paragraph><paragraph>Tray of 10 single‑dose clear glass bottles</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>400 mcg/100 mL</paragraph><paragraph>(4 mcg/mL)</paragraph></td></tr></tbody></table>
17 PATIENT COUNSELING INFORMATION PRECEDEX is indicated for short-term intravenous sedation. Dosage must be individualized and titrated to the desired clinical effect. Blood pressure, heart rate and oxygen levels will be monitored both continuously during the infusion of PRECEDEX and as clinically appropriate after discontinuation. • When PRECEDEX is infused for more than 6 hours, patients should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours. • Additionally, patients should be informed to report symptoms that may occur within 48 hours after the administration of PRECEDEX such as: weakness, confusion, excessive sweating, weight loss, abdominal pain, salt cravings, diarrhea, constipation, dizziness or light-headedness. • Advise breastfeeding mothers who were exposed to PRECEDEX to monitor breastfed neonates for irritability [see Use in Specific Populations (8.2) ] . Distributed by Hospira, Inc. Lake Forest, IL 60045 PREMIERProRx ® is a registered trademark of Premier Healthcare Alliance, L.P., used under license. LAB-1531-2.0 PremierProRx logo
1 INDICATIONS AND USAGE Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride 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 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 ) 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. Pediatric use information is approved for Hospira Inc.'s PRECEDEX TM (dexmedetomidine hydrochloride) in sodium chloride injection. However, due to Hospira Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
2 DOSAGE AND ADMINISTRATION 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 400 mcg per 100 mL single-dose bags 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 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 ) 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 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 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.
d 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 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 )]. Pediatric use information is approved for Hospira Inc.'s PRECEDEX TM (dexmedetomidine hydrochloride) in sodium chloride injection. However, due to Hospira Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 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, 400 mcg per 100 mL (4 mcg per mL) Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection is supplied in flexible containers containing a premixed, ready to use dexmedetomidine hydrochloride solution in 0.9% sodium chloride in water. No further dilution of these preparations is necessary. 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.
3 DOSAGE FORMS AND STRENGTHS Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection is a clear and colorless solution, ready to use. It is available as: Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection, 400 mcg per 100 mL (4 mcg per mL) infusion bag container. Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection, 400 mcg per 100 mL (4 mcg per mL) in flexible bag containers. Ready to use. ( 3 )
5 WARNINGS AND PRECAUTIONS Monitoring : Continuously monitor patients while receiving dexmedetomidine hydrochloride in 0.9% sodium chloride injection. ( 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. ( 5.6 ) 5.1 Drug Administration Dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 hydrochloride in 0.9% sodium chloride injection. 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 hydrochloride in 0.9% sodium chloride injection, 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 hydrochloride in 0.9% sodium chloride injection 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.
ction 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 hydrochloride in 0.9% sodium chloride injection an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine hydrochloride in 0.9% sodium chloride injection. 5.3 Transient Hypertension Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of dexmedetomidine hydrochloride in 0.9% sodium chloride injection. 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 hydrochloride in 0.9% sodium chloride injection 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 hydrochloride in 0.9% sodium chloride injection adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) dexmedetomidine hydrochloride in 0.9% sodium chloride injection adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events were nausea, vomiting, and agitation [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 hydrochloride in 0.9% sodium chloride injection (<6 hours). In pediatric patients, mild transient withdrawal symptoms of emergence delirium or agitation were seen after discontinuation of short-term infusions of dexmedetomidine hydrochloride in 0.9% sodium chloride injection (<2 hours). Pediatric use information is approved for Hospira Inc.'s PRECEDEX TM (dexmedetomidine hydrochloride) in sodium chloride injection. However, due to Hospira Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 5.6 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 )]. 5.7 Hyperthermia or Pyrexia Dexmedetomidine may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue dexmedetomidine hydrochloride in 0.9% sodium chloride injection if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes. 5.8 Hepatic Impairment Since dexmedetomidine clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration ( 2.2 , 2.3 )] .
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 Sagent Pharmaceuticals at 1-866-625-1618 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 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* Adverse Event All Dexmedetomidine (N = 1007) (%) Randomized Dexmedetomidine (N = 798) (%) Placebo (N = 400) (%) Propofol (N = 188) (%) * 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. 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.
as 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) † 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. 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% 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%).
% 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 Injection Group Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection (mcg/kg/hr) Adverse Event ≤0.7* (N = 95) >0.7 to ≤1.1* (N = 78) >1.1* (N = 71) * Average maintenance dose over the entire study drug administration. 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 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. Adverse Event Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection (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% Pediatric use information is approved for Hospira Inc.'s PRECEDEX TM (dexmedetomidine hydrochloride) in sodium chloride injection. However, due to Hospira Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of dexmedetomidine hydrochloride in 0.9% sodium chloride injection.
n sodium chloride injection. However, due to Hospira Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 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
<table ID="t3" width="100%"><caption>Table 3: Adverse Reactions with an Incidence >2%-Adult Intensive Care Unit Sedation Population <24 hours* </caption><col width="27.560%" align="left"/><col width="21.860%" align="left"/><col width="21.860%" align="left"/><col width="13.740%" align="left"/><col width="14.980%" align="left"/><thead><tr><th align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Event</content></th><th align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">All</content> <content styleCode="bold">Dexmedetomidine</content> <content styleCode="bold">(N = 1007)</content> <content styleCode="bold">(%)</content></th><th align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Randomized</content> <content styleCode="bold">Dexmedetomidine</content> <content styleCode="bold">(N = 798)</content> <content styleCode="bold">(%)</content></th><th align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N = 400)</content> <content styleCode="bold">(%)</content></th><th align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Propofol</content> <content styleCode="bold">(N = 188)</content> <content styleCode="bold">(%)</content></th></tr></thead><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">* 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.
oot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">* 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. </paragraph></td></tr></tfoot><tbody><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypotension </td><td align="center" valign="top" styleCode="Botrule Rrule">25% </td><td align="center" valign="top" styleCode="Botrule Rrule">24% </td><td align="center" valign="top" styleCode="Botrule Rrule">12% </td><td align="center" valign="top" styleCode="Botrule Rrule">13% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypertension </td><td align="center" valign="top" styleCode="Botrule Rrule">12% </td><td align="center" valign="top" styleCode="Botrule Rrule">13% </td><td align="center" valign="top" styleCode="Botrule Rrule">19% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Nausea </td><td align="center" valign="top" styleCode="Botrule Rrule">9% </td><td align="center" valign="top" styleCode="Botrule Rrule">9% </td><td align="center" valign="top" styleCode="Botrule Rrule">9% </td><td align="center" valign="top" styleCode="Botrule Rrule">11% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Bradycardia </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Atrial Fibrillation </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">7% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Pyrexia </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Dry Mouth </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Vomiting </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypovolemia </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Atelectasis </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botru
" valign="top" styleCode="Botrule Rrule">5% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Atelectasis </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botru le Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">6% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Pleural Effusion </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="middle" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">6% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Agitation </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="middle" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Tachycardia </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="middle" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Anemia </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="middle" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hyperthermia </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="middle" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Chills </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="middle" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hyperglycemia </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="middle" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypoxia </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="middle" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Post-procedural Hemorrhage </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="middle" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Pulmonary Edema </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="
<td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Pulmonary Edema </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign=" top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypocalcemia </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Acidosis </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Urine Output Decreased </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Sinus Tachycardia </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Ventricular Tachycardia </td><td align="center" valign="top" styleCode="Botrule Rrule"><1% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Wheezing </td><td align="center" valign="top" styleCode="Botrule Rrule"><1% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Edema Peripheral </td><td align="center" valign="top" styleCode="Botrule Rrule"><1% </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr></tbody></table>
le Rrule">Edema Peripheral </td><td align="center" valign="top" styleCode="Botrule Rrule"><1% </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr></tbody></table> <table ID="t4" width="100%"><caption>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 </caption><col width="27.258%" align="left"/><col width="39.420%" align="left"/><col width="33.322%" align="left"/><thead><tr><th align="center" valign="middle" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Event</content> </th><th align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Randomized Dexmedetomidine</content> <content styleCode="bold">(N = 387)</content></th><th align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N = 379)</content></th></tr></thead><tbody><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypotension </td><td align="center" valign="top" styleCode="Botrule Rrule">28% </td><td align="center" valign="top" styleCode="Botrule Rrule">13% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypertension </td><td align="center" valign="top" styleCode="Botrule Rrule">16% </td><td align="center" valign="top" styleCode="Botrule Rrule">18% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Nausea </td><td align="center" valign="top" styleCode="Botrule Rrule">11% </td><td align="center" valign="top" styleCode="Botrule Rrule">9% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Bradycardia </td><td align="center" valign="top" styleCode="Botrule Rrule">7% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Fever </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Vomiting </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td><td align="center" valign="top" styleCode="Botrule Rrule">6% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Atrial Fibrillation </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypoxia </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Tachycardia </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hemorrhage </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Anemia </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Dry Mouth </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrul
ign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Dry Mouth </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrul e">1% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Rigors </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Agitation </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hyperpyrexia </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Pain </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hyperglycemia </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Acidosis </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Pleural Effusion </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Oliguria </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule"><1% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Thirst </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule"><1% </td></tr></tbody></table>
% </td><td align="center" valign="top" styleCode="Botrule Rrule"><1% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Thirst </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule"><1% </td></tr></tbody></table> <table ID="t5" width="100%"><caption>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 </caption><col width="43.767%" align="left"/><col width="30.200%" align="left"/><col width="26.033%" align="left"/><thead><tr><th align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Event</content></th><th align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Dexmedetomidine</content> <content styleCode="bold">(N = 244)</content></th><th align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Midazolam</content> <content styleCode="bold">(N = 122)</content></th></tr></thead><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>†</sup> Includes any type of hypertension. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>1</sup> 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. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>2</sup> Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>3</sup> 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. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>4</sup> Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.
lative terms as ≥30% higher than pre-study drug infusion value. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>4</sup> Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value. </paragraph></td></tr></tfoot><tbody><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypotension<sup>1</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">56% </td><td align="center" valign="top" styleCode="Botrule Rrule">56% </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Hypotension Requiring Intervention </td><td align="center" valign="top" styleCode="Botrule Rrule">28% </td><td align="center" valign="top" styleCode="Botrule Rrule">27% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Bradycardia<sup>2</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">42% </td><td align="center" valign="top" styleCode="Botrule Rrule">19% </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Bradycardia Requiring Intervention </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Systolic Hypertension<sup>3</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">28% </td><td align="center" valign="top" styleCode="Botrule Rrule">42% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Tachycardia<sup>4</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">25% </td><td align="center" valign="top" styleCode="Botrule Rrule">44% </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Tachycardia Requiring Intervention </td><td align="center" valign="top" styleCode="Botrule Rrule">10% </td><td align="center" valign="top" styleCode="Botrule Rrule">10% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Diastolic Hypertension<sup>3</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">12% </td><td align="center" valign="top" styleCode="Botrule Rrule">15% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypertension<sup>3</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">11% </td><td align="center" valign="top" styleCode="Botrule Rrule">15% </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Hypertension Requiring Intervention<sup>†</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">19% </td><td align="center" valign="top" styleCode="Botrule Rrule">30% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypokalemia </td><td align="center" valign="top" styleCode="Botrule Rrule">9% </td><td align="center" valign="top" styleCode="Botrule Rrule">13% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Pyrexia </td><td align="center" valign="top" styleCode="Botrule Rrule">7% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Agitation </td><td align="center" valign="top" styleCode="Botrule Rrule">7% </td><td align="center" valign="top" styleCode="Botrule Rrule">6% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hyperglycemia </td><td align="center" valign="top" styleCode="Botrule Rrule">7% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Constipation </td><td align="center" valign="top" styleCode="Botrule R
de="Botrule Lrule Rrule">Hyperglycemia </td><td align="center" valign="top" styleCode="Botrule Rrule">7% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Constipation </td><td align="center" valign="top" styleCode="Botrule R rule">6% </td><td align="center" valign="top" styleCode="Botrule Rrule">6% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypoglycemia </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">6% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Respiratory Failure </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Renal Failure Acute </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Acute Respiratory Distress Syndrome </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Generalized Edema </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">6% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypomagnesemia </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">7% </td></tr></tbody></table>
% </td><td align="center" valign="top" styleCode="Botrule Rrule">6% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypomagnesemia </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">7% </td></tr></tbody></table> <table ID="t6" width="100%"><caption>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 Injection Group </caption><col width="42.400%" align="left"/><col width="24.100%" align="left"/><col width="18.325%" align="left"/><col width="15.175%" align="left"/><thead><tr><th colspan="4" align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection (mcg/kg/hr)</content></th></tr><tr><th align="center" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Adverse Event</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">≤0.7*</content> <content styleCode="bold">(N = 95)</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">>0.7 to ≤1.1*</content> <content styleCode="bold">(N = 78)</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">>1.1*</content> <content styleCode="bold">(N = 71)</content></th></tr></thead><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">* Average maintenance dose over the entire study drug administration.
><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">>1.1*</content> <content styleCode="bold">(N = 71)</content></th></tr></thead><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">* Average maintenance dose over the entire study drug administration. </paragraph></td></tr></tfoot><tbody><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Constipation </td><td align="center" valign="top" styleCode="Botrule Rrule">6% </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">14% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Agitation </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">8% </td><td align="center" valign="top" styleCode="Botrule Rrule">14% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Anxiety </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">9% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Edema Peripheral </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">7% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Atrial Fibrillation </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td><td align="center" valign="top" styleCode="Botrule Rrule">9% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Respiratory Failure </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">6% </td><td align="center" valign="top" styleCode="Botrule Rrule">10% </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Acute Respiratory Distress Syndrome </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">9% </td></tr></tbody></table>
d align="left" valign="top" styleCode="Botrule Lrule Rrule">Acute Respiratory Distress Syndrome </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">9% </td></tr></tbody></table> <table ID="t7" width="100%"><caption>Table 7: Adverse Reactions with an Incidence >2% - Adult Procedural Sedation Population </caption><col width="28.033%" align="left"/><col width="48.400%" align="left"/><col width="23.567%" align="left"/><tfoot><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>1</sup> 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. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>2</sup> Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or >25% decrease from baseline. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>3</sup> 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 <content styleCode="italics">[see Clinical Studies (<linkHtml href="#s76">14.2</linkHtml>)]</content>. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>4</sup> 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. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>5</sup> Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>6</sup> Hypoxia was defined in absolute and relative terms as SpO<sub>2</sub> <90% or 10% decrease from baseline.
ative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value. </paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote"><sup>6</sup> Hypoxia was defined in absolute and relative terms as SpO<sub>2</sub> <90% or 10% decrease from baseline. </paragraph></td></tr></tfoot><tbody><tr><td align="center" valign="middle" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Event</content></td><td align="center" valign="middle" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection</content> <content styleCode="bold">(N = 318)</content> <content styleCode="bold">(%)</content></td><td align="center" valign="middle" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N = 113)</content> <content styleCode="bold">(%)</content></td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypotension<sup>1</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">54% </td><td align="center" valign="top" styleCode="Botrule Rrule">30% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Respiratory Depression<sup>2</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">37% </td><td align="center" valign="top" styleCode="Botrule Rrule">32% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Bradycardia<sup>3</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">14% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypertension<sup>4</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">13% </td><td align="center" valign="top" styleCode="Botrule Rrule">24% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Tachycardia<sup>5</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">5% </td><td align="center" valign="top" styleCode="Botrule Rrule">17% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Nausea </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Dry Mouth </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td><td align="center" valign="top" styleCode="Botrule Rrule">1% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Hypoxia<sup>6</sup></td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Bradypnea </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td></tr></tbody></table>
le">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">3% </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule">Bradypnea </td><td align="center" valign="top" styleCode="Botrule Rrule">2% </td><td align="center" valign="top" styleCode="Botrule Rrule">4% </td></tr></tbody></table> <table ID="t9" width="100%"><caption>Table 9: Adverse Reactions Experienced During Post-Approval Use of Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection </caption><col width="38.900%" align="left"/><col width="61.100%" align="left"/><thead><tr><th align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">System Organ Class</content></th><th align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Preferred Term</content></th></tr></thead><tbody><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Blood and Lymphatic System Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Anemia </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Cardiac Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Eye Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Photopsia, visual impairment </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Gastrointestinal Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Abdominal pain, diarrhea, nausea, vomiting </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">General Disorders and Administration Site Conditions </td><td align="left" valign="top" styleCode="Botrule Rrule">Chills, hyperpyrexia, pain, pyrexia, thirst </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Hepatobiliary Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Hepatic function abnormal, hyperbilirubinemia </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Investigations </td><td align="left" valign="top" styleCode="Botrule Rrule">Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Metabolism and Nutrition Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Nervous System Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Psychiatric Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Agitation, confusional state, delirium, hallucination, illusion </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Renal and Urinary Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Oliguria, polyuria </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Respiratory, Thoracic and Mediastinal Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis </td></tr><tr><td al
ia </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Respiratory, Thoracic and Mediastinal Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis </td></tr><tr><td al ign="left" valign="top" styleCode="Botrule Lrule Rrule">Skin and Subcutaneous Tissue Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Hyperhidrosis, pruritus, rash, urticaria </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Surgical and Medical Procedures </td><td align="left" valign="top" styleCode="Botrule Rrule">Light anesthesia </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Vascular Disorders </td><td align="left" valign="top" styleCode="Botrule Rrule">Blood pressure fluctuation, hemorrhage, hypertension, hypotension </td></tr></tbody></table>
7 DRUG INTERACTIONS 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 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 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.
8 USE IN SPECIFIC POPULATIONS Geriatric Patients: Dose reduction should be considered. ( 2.2 , 2.3 , 5.2 , 8.5 ) Hepatic Impairment: Dose reduction should be considered. ( 2.2 , 2.3 , 5.8 , 8.6 ) Pediatric use information is approved for Hospira Inc.'s PRECEDEX TM (dexmedetomidine hydrochloride) in sodium chloride injection. However, due to Hospira Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. 8.1 Pregnancy Risk Summary Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of caesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta. In animal reproduction studies, fetal toxicity that lower fetal viability and reduced live fetuses occurred with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 1.8 times the maximum recommended human dose (MRHD) of 17.8 mcg/kg/day. Developmental toxicity (low pup weights and adult offspring weights, decreased F1 grip strength, increased early implantation loss and decreased viability of second-generation offspring) occurred when pregnant rats were subcutaneously administered dexmedetomidine at doses less than the clinical dose from late pregnancy through lactation and weaning (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Increased post-implantation losses and reduced live fetuses in the presence of maternal toxicity (i.e. decreased body weight) were noted in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine 200 mcg/kg/day (equivalent to 1.8 times the intravenous MRHD of 17.8 mcg/kg/day based on body surface area [BSA]) during the period of organogenesis (Gestation Day [GD] 6 to 15). No malformations were reported. No malformations or embryo-fetal toxicity were noted in a rabbit embryo-fetal development study in which pregnant does were administered dexmedetomidine intravenously at doses of up to 96 mcg/kg/day (approximately half the human exposure at the MRHD based on AUC) during the period of organogenesis (GD 6 to 18). Reduced pup and adult offspring birth weights, and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at doses of 8 mcg/kg/day (0.07 times the MRHD based on BSA) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25).
t offspring birth weights, and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at doses of 8 mcg/kg/day (0.07 times the MRHD based on BSA) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21). In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously. 8.2 Lactation Risk Summary Available published literature reports the presence of dexmedetomidine in human milk following intravenous administration (see Data) . There is no information regarding the effects of dexmedetomidine on the breastfed infant or the effects on milk production. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for dexmedetomidine and any potential adverse effects on the breastfed infant from dexmedetomidine or from the underlying condition. Data In two published clinical studies, a total of 14 women were given intravenous dexmedetomidine 6 mcg/kg/hour for 10 minutes after delivery followed by continuous infusion of 0.2 to 0.7 mcg/kg/hour. Breast milk and maternal blood samples were collected at 0, 6, 12, and 24 hours after discontinuation of dexmedetomidine. Plasma and milk dexmedetomidine concentrations were detectable up to 6 hours in most subjects, up to 12 hours in one subject and undetectable in all at 24 hours. The milk-to-plasma ratio from single paired maternal milk and plasma concentrations at each time point ranged from 0.53 to 0.95. The relative infant dose was estimated to range from 0.02 to 0.098%. 8.4 Pediatric Use Sedation for Non-Invasive Procedures The safety and effectiveness of dexmedetomidine hydrochloride in 0.9% sodium chloride injection have not been established in pediatric patients less than 1 month of age. Pediatric use information is approved for Hospira Inc.'s PRECEDEX TM (dexmedetomidine hydrochloride) in sodium chloride injection. However, due to Hospira Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. ICU Sedation The safety and efficacy of dexmedetomidine hydrochloride in 0.9% sodium chloride injection have not been established in pediatric patients for ICU sedation. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for these patient populations. 8.5 Geriatric Use Intensive Care Unit Sedation A total of 729 patients in the clinical studies were 65 years of age and over. A total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection [see Warnings and Precautions ( 5.2 )]. Therefore, a dose reduction may be considered in patients over 65 years of age [see Dosage and Administration ( 2.2 , 2.3 ), Clinical Pharmacology ( 12.3 )].
a and hypotension was observed following administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection [see Warnings and Precautions ( 5.2 )]. Therefore, a dose reduction may be considered in patients over 65 years of age [see Dosage and Administration ( 2.2 , 2.3 ), Clinical Pharmacology ( 12.3 )]. Procedural Sedation A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in dexmedetomidine-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age. 8.6 Hepatic Impairment Since dexmedetomidine clearance decreases with increasing severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration ( 2.2 , 2.3 ), Clinical Pharmacology ( 12.3 )].
8.1 Pregnancy Risk Summary Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of caesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta. In animal reproduction studies, fetal toxicity that lower fetal viability and reduced live fetuses occurred with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 1.8 times the maximum recommended human dose (MRHD) of 17.8 mcg/kg/day. Developmental toxicity (low pup weights and adult offspring weights, decreased F1 grip strength, increased early implantation loss and decreased viability of second-generation offspring) occurred when pregnant rats were subcutaneously administered dexmedetomidine at doses less than the clinical dose from late pregnancy through lactation and weaning (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Increased post-implantation losses and reduced live fetuses in the presence of maternal toxicity (i.e. decreased body weight) were noted in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine 200 mcg/kg/day (equivalent to 1.8 times the intravenous MRHD of 17.8 mcg/kg/day based on body surface area [BSA]) during the period of organogenesis (Gestation Day [GD] 6 to 15). No malformations were reported. No malformations or embryo-fetal toxicity were noted in a rabbit embryo-fetal development study in which pregnant does were administered dexmedetomidine intravenously at doses of up to 96 mcg/kg/day (approximately half the human exposure at the MRHD based on AUC) during the period of organogenesis (GD 6 to 18). Reduced pup and adult offspring birth weights, and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at doses of 8 mcg/kg/day (0.07 times the MRHD based on BSA) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21). In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously.
8.4 Pediatric Use Sedation for Non-Invasive Procedures The safety and effectiveness of dexmedetomidine hydrochloride in 0.9% sodium chloride injection have not been established in pediatric patients less than 1 month of age. Pediatric use information is approved for Hospira Inc.'s PRECEDEX TM (dexmedetomidine hydrochloride) in sodium chloride injection. However, due to Hospira Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. ICU Sedation The safety and efficacy of dexmedetomidine hydrochloride in 0.9% sodium chloride injection have not been established in pediatric patients for ICU sedation. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for these patient populations.
8.5 Geriatric Use Intensive Care Unit Sedation A total of 729 patients in the clinical studies were 65 years of age and over. A total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection [see Warnings and Precautions ( 5.2 )]. Therefore, a dose reduction may be considered in patients over 65 years of age [see Dosage and Administration ( 2.2 , 2.3 ), Clinical Pharmacology ( 12.3 )]. Procedural Sedation A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in dexmedetomidine-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Dexmedetomidine hydrochloride is not a controlled substance. 9.3 Dependence The dependence potential of dexmedetomidine hydrochloride in 0.9% sodium chloride injection has not been studied in humans. However, since studies in rodents and primates have demonstrated that dexmedetomidine exhibits pharmacologic actions similar to those of clonidine, it is possible that dexmedetomidine hydrochloride in 0.9% sodium chloride injection may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [see Warnings and Precautions ( 5.5 )].
9.3 Dependence The dependence potential of dexmedetomidine hydrochloride in 0.9% sodium chloride injection has not been studied in humans. However, since studies in rodents and primates have demonstrated that dexmedetomidine exhibits pharmacologic actions similar to those of clonidine, it is possible that dexmedetomidine hydrochloride in 0.9% sodium chloride injection may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [see Warnings and Precautions ( 5.5 )].
10 OVERDOSAGE The tolerability of dexmedetomidine hydrochloride in 0.9% sodium chloride injection 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 hydrochloride in 0.9% sodium chloride injection 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.
11 DESCRIPTION Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection (4 mcg per mL) is a sterile, nonpyrogenic ready to use solution suitable for intravenous infusion. Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection contains dexmedetomidine hydrochloride as the active pharmaceutical ingredient. Dexmedetomidine hydrochloride is a central alpha 2 -adrenergic agonist. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine. Dexmedetomidine hydrochloride chemical name is 1H-Imidazole, 4-[1-(2,3-dimethylphenyl)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, USP 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 7.0. Each mL contains 4.72 mcg of dexmedetomidine hydrochloride, USP (equivalent to 4 mcg or 0.004 mg of dexmedetomidine) and 9 mg sodium chloride in water for injection and is ready to be used. The solution is preservative-free and contains no additives or chemical stabilizers. Structural Formula
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a relatively selective centrally acting alpha 2 -adrenergic agonist with sedative properties. Alpha 2 selectivity is observed in animals following slow intravenous infusion of low and medium doses (10 to 300 mcg/kg). Both alpha 1 and alpha 2 activity is observed following slow intravenous infusion of high doses (≥1,000 mcg/kg) or with rapid intravenous administration. 12.2 Pharmacodynamics In a study in healthy adult volunteers (N = 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when dexmedetomidine hydrochloride in 0.9% sodium chloride injection was administered by intravenous infusion at doses within the recommended dose range (0.2 to 0.7 mcg/kg/hr). 12.3 Pharmacokinetics Following intravenous administration to adults, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t 1/2 ) of approximately 6 minutes; a terminal elimination half-life (t 1/2 ) of approximately 2 hours; and steady-state volume of distribution (V ss ) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg. Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered to adults by intravenous infusion for up to 24 hours. Table 10 shows the main pharmacokinetic parameters when dexmedetomidine hydrochloride in 0.9% sodium chloride injection was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours. Table 10: Mean ± SD Pharmacokinetic Parameters in Adults Parameter Loading Infusion (min)/Total Infusion Duration (hrs) 10 min/12 hrs 10 min/24 hrs 10 min/24 hrs 35 min/24 hrs Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr) 0.3/0.17 0.3/0.17 0.6/0.33 1.25/0.70 Abbreviations: t 1/2 = half-life, CL = clearance, V ss = steady-state volume of distribution. * Presented as harmonic mean and pseudo standard deviation. # Mean C ss = Average steady-state concentration of dexmedetomidine. The mean C ss was calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions. t 1/2 * , hour 1.78 ± 0.30 2.22 ± 0.59 2.23 ± 0.21 2.50 ± 0.61 CL, liter/hour 46.3 ± 8.3 43.1 ± 6.5 35.3 ± 6.8 36.5 ± 7.5 V ss , liter 88.7 ± 22.9 102.4 ± 20.3 93.6 ± 17.0 99.6 ± 17.8 Avg C ss # , ng/mL 0.27 ± 0.05 0.27 ± 0.05 0.67 ± 0.10 1.37 ± 0.20 The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively. Dexmedetomidine pharmacokinetic parameters in adults after dexmedetomidine hydrochloride in 0.9% sodium chloride injection maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetic (PK) parameters after dexmedetomidine hydrochloride in 0.9% sodium chloride injection maintenance dosing for <24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t 1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively.
4 mcg/kg/hr for >24 hours were similar to the pharmacokinetic (PK) parameters after dexmedetomidine hydrochloride in 0.9% sodium chloride injection maintenance dosing for <24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t 1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively. Distribution The steady-state volume of distribution (V ss ) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of dexmedetomidine that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects. The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro , and negligible changes in the plasma protein binding of dexmedetomidine were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine was explored in vitro and none of these compounds appeared to be significantly displaced by dexmedetomidine hydrochloride in 0.9% sodium chloride injection. Elimination Metabolism Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide. Excretion The terminal elimination half-life (t 1/2 ) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified. Specific Populations Male and Female Patients There was no observed difference in dexmedetomidine pharmacokinetics due to sex. Geriatric Patients The pharmacokinetic profile of dexmedetomidine was not altered by age.
ent and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified. Specific Populations Male and Female Patients There was no observed difference in dexmedetomidine pharmacokinetics due to sex. Geriatric Patients The pharmacokinetic profile of dexmedetomidine was not altered by age. There were no differences in the pharmacokinetics of dexmedetomidine in young (18 to 40 years), middle age (41 to 65 years), and elderly (>65 years) subjects. Pediatric Patients Pediatric use information is approved for Hospira Inc.'s PRECEDEX TM (dexmedetomidine hydrochloride) in sodium chloride injection. However, due to Hospira Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. Patients with Hepatic Impairment In adult subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for dexmedetomidine were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy adult subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy adult subjects, respectively. Although dexmedetomidine hydrochloride in 0.9% sodium chloride injection is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.8 )]. Patients with Renal Impairment Dexmedetomidine pharmacokinetics (C max , T max , AUC, t 1/2 , CL, and V ss ) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects. Drug Interaction Studies In vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.
12.1 Mechanism of Action Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a relatively selective centrally acting alpha 2 -adrenergic agonist with sedative properties. Alpha 2 selectivity is observed in animals following slow intravenous infusion of low and medium doses (10 to 300 mcg/kg). Both alpha 1 and alpha 2 activity is observed following slow intravenous infusion of high doses (≥1,000 mcg/kg) or with rapid intravenous administration.
12.2 Pharmacodynamics In a study in healthy adult volunteers (N = 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when dexmedetomidine hydrochloride in 0.9% sodium chloride injection was administered by intravenous infusion at doses within the recommended dose range (0.2 to 0.7 mcg/kg/hr).
12.3 Pharmacokinetics Following intravenous administration to adults, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t 1/2 ) of approximately 6 minutes; a terminal elimination half-life (t 1/2 ) of approximately 2 hours; and steady-state volume of distribution (V ss ) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg. Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered to adults by intravenous infusion for up to 24 hours. Table 10 shows the main pharmacokinetic parameters when dexmedetomidine hydrochloride in 0.9% sodium chloride injection was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours. Table 10: Mean ± SD Pharmacokinetic Parameters in Adults Parameter Loading Infusion (min)/Total Infusion Duration (hrs) 10 min/12 hrs 10 min/24 hrs 10 min/24 hrs 35 min/24 hrs Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr) 0.3/0.17 0.3/0.17 0.6/0.33 1.25/0.70 Abbreviations: t 1/2 = half-life, CL = clearance, V ss = steady-state volume of distribution. * Presented as harmonic mean and pseudo standard deviation. # Mean C ss = Average steady-state concentration of dexmedetomidine. The mean C ss was calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions. t 1/2 * , hour 1.78 ± 0.30 2.22 ± 0.59 2.23 ± 0.21 2.50 ± 0.61 CL, liter/hour 46.3 ± 8.3 43.1 ± 6.5 35.3 ± 6.8 36.5 ± 7.5 V ss , liter 88.7 ± 22.9 102.4 ± 20.3 93.6 ± 17.0 99.6 ± 17.8 Avg C ss # , ng/mL 0.27 ± 0.05 0.27 ± 0.05 0.67 ± 0.10 1.37 ± 0.20 The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively. Dexmedetomidine pharmacokinetic parameters in adults after dexmedetomidine hydrochloride in 0.9% sodium chloride injection maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetic (PK) parameters after dexmedetomidine hydrochloride in 0.9% sodium chloride injection maintenance dosing for <24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t 1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively. Distribution The steady-state volume of distribution (V ss ) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of dexmedetomidine that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects. The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro , and negligible changes in the plasma protein binding of dexmedetomidine were observed.
icantly decreased in subjects with hepatic impairment compared to healthy subjects. The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro , and negligible changes in the plasma protein binding of dexmedetomidine were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine was explored in vitro and none of these compounds appeared to be significantly displaced by dexmedetomidine hydrochloride in 0.9% sodium chloride injection. Elimination Metabolism Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide. Excretion The terminal elimination half-life (t 1/2 ) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified. Specific Populations Male and Female Patients There was no observed difference in dexmedetomidine pharmacokinetics due to sex. Geriatric Patients The pharmacokinetic profile of dexmedetomidine was not altered by age. There were no differences in the pharmacokinetics of dexmedetomidine in young (18 to 40 years), middle age (41 to 65 years), and elderly (>65 years) subjects. Pediatric Patients Pediatric use information is approved for Hospira Inc.'s PRECEDEX TM (dexmedetomidine hydrochloride) in sodium chloride injection. However, due to Hospira Inc.'s marketing exclusivity rights, this drug product is not labeled with that information. Patients with Hepatic Impairment In adult subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for dexmedetomidine were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy adult subjects, respectively.
ing degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for dexmedetomidine were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy adult subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy adult subjects, respectively. Although dexmedetomidine hydrochloride in 0.9% sodium chloride injection is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.8 )]. Patients with Renal Impairment Dexmedetomidine pharmacokinetics (C max , T max , AUC, t 1/2 , CL, and V ss ) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects. Drug Interaction Studies In vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.
<table ID="t10" width="100%"><caption>Table 10: Mean ± SD Pharmacokinetic Parameters in Adults </caption><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><thead><tr><th rowspan="4" align="justify" valign="top" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Parameter</content></th><th colspan="4" align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Loading Infusion (min)/Total Infusion Duration (hrs)</content></th></tr><tr><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">10 min/12 hrs</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">10 min/24 hrs</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">10 min/24 hrs</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">35 min/24 hrs</content></th></tr><tr><th colspan="4" align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr)</content></th></tr><tr><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">0.3/0.17</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">0.3/0.17</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">0.6/0.33</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">1.25/0.70</content></th></tr></thead><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">Abbreviations: t<sub>1/2</sub> = half-life, CL = clearance, V<sub>ss</sub> = steady-state volume of distribution. </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote"><sup>*</sup> Presented as harmonic mean and pseudo standard deviation. </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote"><sup>#</sup> Mean C<sub>ss</sub> = Average steady-state concentration of dexmedetomidine. The mean C<sub>ss</sub> was calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions.
t" valign="top"><paragraph styleCode="footnote"><sup>#</sup> Mean C<sub>ss</sub> = Average steady-state concentration of dexmedetomidine. The mean C<sub>ss</sub> was calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions. </paragraph></td></tr></tfoot><tbody><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">t</content><content styleCode="bold"><sub>1/2</sub></content><content styleCode="bold"><sup>*</sup></content><content styleCode="bold">, hour</content></td><td align="center" valign="top" styleCode="Botrule Rrule">1.78 ± 0.30 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.22 ± 0.59 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.23 ± 0.21 </td><td align="center" valign="top" styleCode="Botrule Rrule">2.50 ± 0.61 </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">CL, liter/hour</content></td><td align="center" valign="top" styleCode="Botrule Rrule">46.3 ± 8.3 </td><td align="center" valign="top" styleCode="Botrule Rrule">43.1 ± 6.5 </td><td align="center" valign="top" styleCode="Botrule Rrule">35.3 ± 6.8 </td><td align="center" valign="top" styleCode="Botrule Rrule">36.5 ± 7.5 </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">V</content><content styleCode="bold"><sub>ss</sub></content><content styleCode="bold">, liter</content></td><td align="center" valign="top" styleCode="Botrule Rrule">88.7 ± 22.9 </td><td align="center" valign="top" styleCode="Botrule Rrule">102.4 ± 20.3 </td><td align="center" valign="top" styleCode="Botrule Rrule">93.6 ± 17.0 </td><td align="center" valign="top" styleCode="Botrule Rrule">99.6 ± 17.8 </td></tr><tr><td align="justify" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Avg C</content><content styleCode="bold"><sub>ss </sub></content><content styleCode="bold"><sup>#</sup></content><content styleCode="bold">, ng/mL</content></td><td align="center" valign="top" styleCode="Botrule Rrule">0.27 ± 0.05 </td><td align="center" valign="top" styleCode="Botrule Rrule">0.27 ± 0.05 </td><td align="center" valign="top" styleCode="Botrule Rrule">0.67 ± 0.10 </td><td align="center" valign="top" styleCode="Botrule Rrule">1.37 ± 0.20 </td></tr></tbody></table>
14 CLINICAL STUDIES The safety and efficacy of dexmedetomidine hydrochloride in 0.9% sodium chloride injection has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1,185 adult patients. 14.1 Intensive Care Unit Sedation Two randomized, double-blind, parallel-group, placebo-controlled multicenter clinical trials included 754 adult patients being treated in a surgical intensive care unit. All patients were initially intubated and received mechanical ventilation. These trials evaluated the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection by comparing the amount of rescue medication (midazolam in one trial and propofol in the second) required to achieve a specified level of sedation (using the standardized Ramsay Sedation Scale) between dexmedetomidine hydrochloride in 0.9% sodium chloride injection and placebo from onset of treatment to extubation or to a total treatment duration of 24 hours. The Ramsay Level of Sedation Scale is displayed in Table 12 . Table 12: Ramsay Level of Sedation Scale Clinical Score Level of Sedation Achieved 6 Asleep, no response 5 Asleep, sluggish response to light glabellar tap or loud auditory stimulus 4 Asleep, but with brisk response to light glabellar tap or loud auditory stimulus 3 Patient responds to commands 2 Patient cooperative, oriented, and tranquil 1 Patient anxious, agitated, or restless In the first study, 175 adult patients were randomized to receive placebo and 178 to receive dexmedetomidine hydrochloride in 0.9% sodium chloride injection by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion rate was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive “rescue” midazolam as needed to augment the study drug infusion. In addition, morphine sulfate was administered for pain as needed. The primary outcome measure for this study was the total amount of rescue medication (midazolam) needed to maintain sedation as specified while intubated. Patients randomized to placebo received significantly more midazolam than patients randomized to dexmedetomidine hydrochloride in 0.9% sodium chloride injection (see Table 13 ). A second prospective primary analysis assessed the sedative effects of dexmedetomidine hydrochloride in 0.9% sodium chloride injection by comparing the percentage of adult patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of adult patients in the dexmedetomidine hydrochloride group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 13 ). Table 13: Midazolam Use as Rescue Medication During Intubation (ITT) Study One ITT (intent-to-treat) population includes all randomized patients. * ANOVA model with treatment center. ** Chi-square.
tained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 13 ). Table 13: Midazolam Use as Rescue Medication During Intubation (ITT) Study One ITT (intent-to-treat) population includes all randomized patients. * ANOVA model with treatment center. ** Chi-square. Placebo (N = 175) Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection (N = 178) p-value Mean Total Dose (mg) of Midazolam Standard deviation 19 mg 53 mg 5 mg 19 mg 0.0011* Categorized Midazolam Use 0 mg 43 (25%) 108 (61%) <0.001** 0–4 mg 34 (19%) 36 (20%) >4 mg 98 (56%) 34 (19%) A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and placebo groups. On average, dexmedetomidine hydrochloride in 0.9% sodium chloride injection-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h). In addition, 44% (79 of 178 patients) of dexmedetomidine hydrochloride in 0.9% sodium chloride injection patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group. In a second study, 198 adult patients were randomized to receive placebo and 203 to receive dexmedetomidine hydrochloride in 0.9% sodium chloride injection by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive “rescue” propofol as needed to augment the study drug infusion. In addition, morphine sulfate was administered as needed for pain. The primary outcome measure for this study was the total amount of rescue medication (propofol) needed to maintain sedation as specified while intubated. Adult patients randomized to placebo received significantly more propofol than adult patients randomized to dexmedetomidine hydrochloride in 0.9% sodium chloride injection (see Table 14 ). A significantly greater percentage of adult patients in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see Table 14 ). Table 14: Propofol Use as Rescue Medication During Intubation (ITT) Study Two * ANOVA model with treatment center. ** Chi-square. Placebo (N = 198) Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection (N = 203) p-value Mean Total Dose (mg) of Propofol Standard deviation 513 mg 782 mg 72 mg 249 mg <0.0001* Categorized Propofol Use 0 mg 47 (24%) 122 (60%) <0.001** 0–50 mg 30 (15%) 43 (21%) >50 mg 121 (61%) 38 (19%) A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and placebo groups. On average, dexmedetomidine hydrochloride in 0.9% sodium chloride injection-treated patients received less morphine sulfate for pain than placebo-treated patients (0.43 versus 0.89 mg/h). In addition, 41% (83 of 203 patients) of dexmedetomidine hydrochloride in 0.9% sodium chloride injection patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group. In a controlled clinical trial, dexmedetomidine hydrochloride in 0.9% sodium chloride injection was compared to midazolam for ICU sedation exceeding 24 hours duration. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection was not shown to be superior to midazolam for the primary efficacy endpoint, the percent of time patients were adequately sedated (81% versus 81%).
de in 0.9% sodium chloride injection was compared to midazolam for ICU sedation exceeding 24 hours duration. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection was not shown to be superior to midazolam for the primary efficacy endpoint, the percent of time patients were adequately sedated (81% versus 81%). In addition, administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [see Adverse Reactions ( 6.1 )]. 14.2 Procedural Sedation Adult Patients The safety and efficacy of dexmedetomidine hydrochloride in 0.9% sodium chloride injection for sedation of non-intubated adult patients prior to and/or during surgical and other procedures was evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials. Study 1 evaluated the sedative properties of dexmedetomidine in adult patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated dexmedetomidine hydrochloride in 0.9% sodium chloride injection in adult patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure. In Study 1, the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection were evaluated by comparing the percent of adult patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer's Assessment of Alertness/Sedation Scale (see Table 15 ). Table 15: Observer's Assessment of Alertness/Sedation Assessment Categories Responsiveness Speech Facial Expression Eyes Composite Score Responds readily to name spoken in normal tone Normal Normal Clear, no ptosis 5 (alert) Lethargic response to name spoken in normal tone Mild slowing or thickening Mild relaxation Glazed or mild ptosis (less than half the eye) 4 Responds only after name is called loudly and/or repeatedly Slurring or prominent slowing Marked relaxation (slack jaw) Glazed and marked ptosis (half the eye or more) 3 Responds only after mild prodding or shaking Few recognizable words – – 2 Does not respond to mild prodding or shaking – – – 1 (deep sleep) Adult patients were randomized to receive a loading infusion of either dexmedetomidine hydrochloride in 0.9% sodium chloride injection 1 mcg/kg, dexmedetomidine hydrochloride in 0.9% sodium chloride injection 0.5 mcg/kg, or placebo (normal saline) given over 10 minutes and followed by a maintenance infusion started at 0.6 mcg/kg/hr. The maintenance infusion of study drug could be titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr to achieve the targeted sedation score (Observer's Assessment of Alertness/Sedation Scale ≤4). Adult patients were allowed to receive rescue midazolam as needed to achieve and/or maintain an Observer's Assessment of Alertness/Sedation Scale ≤4. After achieving the desired level of sedation, a local or regional anesthetic block was performed. Demographic characteristics were similar between the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and comparator groups. Efficacy results showed that dexmedetomidine hydrochloride in 0.9% sodium chloride injection was more effective than the comparator group when used to sedate non-intubated patients requiring monitored anesthesia care during surgical and other procedures (see Table 15 ). In Study 2, the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection were evaluated by comparing the percent of adult patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see Table 12 ).
ures (see Table 15 ). In Study 2, the sedative properties of dexmedetomidine hydrochloride in 0.9% sodium chloride injection were evaluated by comparing the percent of adult patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see Table 12 ). Adult patients were randomized to receive a loading infusion of dexmedetomidine hydrochloride in 0.9% sodium chloride injection 1 mcg/kg or placebo (normal saline) given over 10 minutes and followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired level of sedation, topicalization of the airway occurred. Adult patients were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay Sedation Scale ≥2. Demographic characteristics were similar between the dexmedetomidine hydrochloride in 0.9% sodium chloride injection and comparator groups. For efficacy results see Table 16 . Table 16: Key Efficacy Results of Adult Procedural Sedation Studies a Based on ITT population defined as all randomized and treated patients. b Normal approximation to the binomial with continuity correction. Study Loading Infusion Treatment Arm Number of Patients Enrolled a % Not Requiring Midazolam Rescue Confidence b Interval on the Difference vs. Placebo Mean (SD) Total Dose (mg) of Rescue Midazolam Required Confidence b Intervals of the Mean Rescue Dose Study 1 Dexmedetomidine 0.5 mcg/kg 134 40 37 (27, 48) 1.4 (1.7) -2.7 (-3.4, -2.0) Dexmedetomidine 1 mcg/kg 129 54 51 (40, 62) 0.9 (1.5) -3.1 (-3.8, -2.5) Placebo 63 3 – 4.1 (3.0) – Study 2 Dexmedetomidine 1 mcg/kg 55 53 39 (20, 57) 1.1 (1.5) -1.8 (-2.7, -0.9) Placebo 50 14 – 2.9 (3.0) – Pediatric use information is approved for Hospira Inc.'s PRECEDEX TM (dexmedetomidine hydrochloride) in sodium chloride injection. However, due to Hospira Inc.'s marketing exclusivity rights, this drug product is not labeled with that information.
<table ID="t12" width="100%"><caption>Table 12: Ramsay Level of Sedation Scale </caption><col width="28.800%" align="left"/><col width="71.200%" align="left"/><tbody><tr><td align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Clinical Score</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Level of Sedation Achieved</content></td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">6 </td><td align="left" valign="top" styleCode="Botrule Rrule">Asleep, no response </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">5 </td><td align="left" valign="top" styleCode="Botrule Rrule">Asleep, sluggish response to light glabellar tap or loud auditory stimulus </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">4 </td><td align="left" valign="top" styleCode="Botrule Rrule">Asleep, but with brisk response to light glabellar tap or loud auditory stimulus </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">3 </td><td align="left" valign="top" styleCode="Botrule Rrule">Patient responds to commands </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">2 </td><td align="left" valign="top" styleCode="Botrule Rrule">Patient cooperative, oriented, and tranquil </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">1 </td><td align="left" valign="top" styleCode="Botrule Rrule">Patient anxious, agitated, or restless </td></tr></tbody></table>
Rrule">2 </td><td align="left" valign="top" styleCode="Botrule Rrule">Patient cooperative, oriented, and tranquil </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">1 </td><td align="left" valign="top" styleCode="Botrule Rrule">Patient anxious, agitated, or restless </td></tr></tbody></table> <table ID="t13" width="100%"><caption>Table 13: Midazolam Use as Rescue Medication During Intubation (ITT) Study One </caption><col width="24.975%" align="left"/><col width="18.850%" align="left"/><col width="43.700%" align="left"/><col width="12.475%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">ITT (intent-to-treat) population includes all randomized patients. </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">* ANOVA model with treatment center. </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">** Chi-square. </paragraph></td></tr></tfoot><tbody><tr><td align="justify" valign="top" styleCode="Toprule Botrule Lrule Rrule"/><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N = 175)</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection</content> <content styleCode="bold">(N = 178)</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">p-value</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Mean Total Dose (mg) of Midazolam</content> Standard deviation </td><td align="center" valign="top" styleCode="Botrule Rrule">19 mg 53 mg </td><td align="center" valign="top" styleCode="Botrule Rrule">5 mg 19 mg </td><td align="center" valign="top" styleCode="Botrule Rrule">0.0011* </td></tr><tr><td colspan="4" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Categorized Midazolam Use</content></td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">0 mg </td><td align="center" valign="top" styleCode="Botrule Rrule">43 (25%) </td><td align="center" valign="top" styleCode="Botrule Rrule">108 (61%) </td><td align="center" valign="top" styleCode="Botrule Rrule"><0.001** </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">0–4 mg </td><td align="center" valign="top" styleCode="Botrule Rrule">34 (19%) </td><td align="center" valign="top" styleCode="Botrule Rrule">36 (20%) </td><td align="center" valign="top" styleCode="Botrule Rrule"/></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">>4 mg </td><td align="center" valign="top" styleCode="Botrule Rrule">98 (56%) </td><td align="center" valign="top" styleCode="Botrule Rrule">34 (19%) </td><td align="center" valign="top" styleCode="Botrule Rrule"/></tr></tbody></table>
Rrule"/></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">>4 mg </td><td align="center" valign="top" styleCode="Botrule Rrule">98 (56%) </td><td align="center" valign="top" styleCode="Botrule Rrule">34 (19%) </td><td align="center" valign="top" styleCode="Botrule Rrule"/></tr></tbody></table> <table ID="t14" width="100%"><caption>Table 14: Propofol Use as Rescue Medication During Intubation (ITT) Study Two </caption><col width="31.025%" align="left"/><col width="15.625%" align="left"/><col width="39.075%" align="left"/><col width="14.275%" align="left"/><tfoot><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">* ANOVA model with treatment center. </paragraph></td></tr><tr><td colspan="4" align="left" valign="top"><paragraph styleCode="footnote">** Chi-square. </paragraph></td></tr></tfoot><tbody><tr><td align="justify" valign="top" styleCode="Toprule Botrule Lrule Rrule"/><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Placebo</content> <content styleCode="bold">(N = 198)</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection</content> <content styleCode="bold">(N = 203)</content></td><td align="center" valign="bottom" styleCode="Toprule Botrule Rrule"><content styleCode="bold">p-value</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Mean Total Dose (mg) of Propofol</content> Standard deviation </td><td align="center" valign="top" styleCode="Botrule Rrule">513 mg 782 mg </td><td align="center" valign="top" styleCode="Botrule Rrule">72 mg 249 mg </td><td align="center" valign="top" styleCode="Botrule Rrule"><0.0001* </td></tr><tr><td colspan="4" align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Categorized Propofol Use</content></td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">0 mg </td><td align="center" valign="top" styleCode="Botrule Rrule">47 (24%) </td><td align="center" valign="top" styleCode="Botrule Rrule">122 (60%) </td><td align="center" valign="bottom" styleCode="Botrule Rrule"><0.001** </td></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">0–50 mg </td><td align="center" valign="top" styleCode="Botrule Rrule">30 (15%) </td><td align="center" valign="top" styleCode="Botrule Rrule">43 (21%) </td><td align="center" valign="bottom" styleCode="Botrule Rrule"/></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">>50 mg </td><td align="center" valign="top" styleCode="Botrule Rrule">121 (61%) </td><td align="center" valign="top" styleCode="Botrule Rrule">38 (19%) </td><td align="center" valign="bottom" styleCode="Botrule Rrule"/></tr></tbody></table>
e"/></tr><tr><td align="center" valign="top" styleCode="Botrule Lrule Rrule">>50 mg </td><td align="center" valign="top" styleCode="Botrule Rrule">121 (61%) </td><td align="center" valign="top" styleCode="Botrule Rrule">38 (19%) </td><td align="center" valign="bottom" styleCode="Botrule Rrule"/></tr></tbody></table> <table ID="t15" width="100%"><caption>Table 15: Observer's Assessment of Alertness/Sedation </caption><col width="27.215%" align="left"/><col width="16.637%" align="left"/><col width="23.295%" align="left"/><col width="17.516%" align="left"/><col width="15.337%" align="left"/><thead><tr><th colspan="5" align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Assessment Categories</content></th></tr><tr><th align="center" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Responsiveness</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">Speech</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">Facial Expression</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">Eyes</content></th><th align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">Composite Score</content></th></tr></thead><tbody><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Responds readily to name spoken in normal tone </td><td align="center" valign="top" styleCode="Botrule Rrule"> Normal </td><td align="center" valign="top" styleCode="Botrule Rrule"> Normal </td><td align="center" valign="top" styleCode="Botrule Rrule"> Clear, no ptosis </td><td align="center" valign="top" styleCode="Botrule Rrule"> 5 (alert) </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Lethargic response to name spoken in normal tone </td><td align="center" valign="top" styleCode="Botrule Rrule">Mild slowing or thickening </td><td align="center" valign="top" styleCode="Botrule Rrule">Mild relaxation </td><td align="center" valign="top" styleCode="Botrule Rrule">Glazed or mild ptosis (less than half the eye) </td><td align="center" valign="top" styleCode="Botrule Rrule"> 4 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Responds only after name is called loudly and/or repeatedly </td><td align="center" valign="top" styleCode="Botrule Rrule">Slurring or prominent slowing </td><td align="center" valign="top" styleCode="Botrule Rrule">Marked relaxation (slack jaw) </td><td align="center" valign="top" styleCode="Botrule Rrule">Glazed and marked ptosis (half the eye or more) </td><td align="center" valign="top" styleCode="Botrule Rrule"> 3 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Responds only after mild prodding or shaking </td><td align="center" valign="top" styleCode="Botrule Rrule">Few recognizable words </td><td align="center" valign="top" styleCode="Botrule Rrule"> – </td><td align="center" valign="top" styleCode="Botrule Rrule"> – </td><td align="center" valign="top" styleCode="Botrule Rrule"> 2 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule">Does not respond to mild prodding or shaking </td><td align="center" valign="top" styleCode="Botrule Rrule"> – </td><td align="center" valign="top" styleCode="Botrule Rrule"> – </td><td align="center" valign="top" styleCode="Botrule Rrule"> – </td><td align="center" valign="top" styleCode="Botrule Rrule"> 1 (deep sleep) </td></tr></tbody></table>
><td align="center" valign="top" styleCode="Botrule Rrule"> – </td><td align="center" valign="top" styleCode="Botrule Rrule"> – </td><td align="center" valign="top" styleCode="Botrule Rrule"> – </td><td align="center" valign="top" styleCode="Botrule Rrule"> 1 (deep sleep) </td></tr></tbody></table> <table ID="t16" width="100%"><caption>Table 16: Key Efficacy Results of Adult Procedural Sedation Studies </caption><col width="10.199%" align="left"/><col width="18.969%" align="left"/><col width="13.127%" align="left"/><col width="13.669%" align="left"/><col width="14.369%" align="left"/><col width="13.669%" align="left"/><col width="15.998%" align="left"/><tfoot><tr><td colspan="7" align="left" valign="top"><paragraph styleCode="footnote"><sup>a</sup> Based on ITT population defined as all randomized and treated patients. </paragraph></td></tr><tr><td colspan="7" align="left" valign="top"><paragraph styleCode="footnote"><sup>b</sup> Normal approximation to the binomial with continuity correction. </paragraph></td></tr></tfoot><tbody><tr><td align="center" valign="top" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Study</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Loading Infusion Treatment Arm</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Number of Patients Enrolled</content><content styleCode="bold"><sup>a</sup></content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">% Not Requiring Midazolam Rescue</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Confidence</content><content styleCode="bold"><sup>b </sup></content><content styleCode="bold">Interval on the Difference vs.
eCode="Toprule Botrule Rrule"><content styleCode="bold">% Not Requiring Midazolam Rescue</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Confidence</content><content styleCode="bold"><sup>b </sup></content><content styleCode="bold">Interval on the Difference vs. Placebo</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Mean (SD) Total Dose (mg) of Rescue Midazolam Required</content></td><td align="center" valign="top" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Confidence</content><content styleCode="bold"><sup>b </sup></content><content styleCode="bold">Intervals of the Mean Rescue Dose</content></td></tr><tr><td rowspan="3" align="center" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Study 1</content></td><td align="center" valign="top" styleCode="Botrule Rrule">Dexmedetomidine 0.5 mcg/kg </td><td align="center" valign="middle" styleCode="Botrule Rrule">134 </td><td align="center" valign="middle" styleCode="Botrule Rrule">40 </td><td align="center" valign="middle" styleCode="Botrule Rrule">37 (27, 48) </td><td align="center" valign="middle" styleCode="Botrule Rrule">1.4 (1.7) </td><td align="center" valign="middle" styleCode="Botrule Rrule">-2.7 (-3.4, -2.0) </td></tr><tr><td align="center" valign="top" styleCode="Botrule Rrule">Dexmedetomidine 1 mcg/kg </td><td align="center" valign="middle" styleCode="Botrule Rrule">129 </td><td align="center" valign="middle" styleCode="Botrule Rrule">54 </td><td align="center" valign="middle" styleCode="Botrule Rrule">51 (40, 62) </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.9 (1.5) </td><td align="center" valign="middle" styleCode="Botrule Rrule">-3.1 (-3.8, -2.5) </td></tr><tr><td align="center" valign="top" styleCode="Botrule Rrule">Placebo </td><td align="center" valign="top" styleCode="Botrule Rrule">63 </td><td align="center" valign="top" styleCode="Botrule Rrule">3 </td><td align="center" valign="top" styleCode="Botrule Rrule">– </td><td align="center" valign="top" styleCode="Botrule Rrule">4.1 (3.0) </td><td align="center" valign="top" styleCode="Botrule Rrule">– </td></tr><tr><td rowspan="2" align="center" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Study 2</content></td><td align="center" valign="top" styleCode="Botrule Rrule">Dexmedetomidine 1 mcg/kg </td><td align="center" valign="top" styleCode="Botrule Rrule">55 </td><td align="center" valign="top" styleCode="Botrule Rrule">53 </td><td align="center" valign="top" styleCode="Botrule Rrule">39 (20, 57) </td><td align="center" valign="top" styleCode="Botrule Rrule">1.1 (1.5) </td><td align="center" valign="top" styleCode="Botrule Rrule">-1.8 (-2.7, -0.9) </td></tr><tr><td align="center" valign="top" styleCode="Botrule Rrule">Placebo </td><td align="center" valign="top" styleCode="Botrule Rrule">50 </td><td align="center" valign="top" styleCode="Botrule Rrule">14 </td><td align="center" valign="top" styleCode="Botrule Rrule">– </td><td align="center" valign="top" styleCode="Botrule Rrule">2.9 (3.0) </td><td align="center" valign="top" styleCode="Botrule Rrule">– </td></tr></tbody></table>
16 HOW SUPPLIED/STORAGE AND HANDLING Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection (4 mcg per mL) is clear and colorless. The strength is based on the dexmedetomidine base. NDC Dexmedetomidine Hydrochloride in 0.9% Sodium Package Factor Chloride Injection (4 mcg per mL) 25021-617-82 400 mcg per 100 mL Single-Dose Bag 20 bags per carton Storage Conditions Store at 20º to 25ºC (68º to 77ºF); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Do not use if product is discolored or if precipitate matter is present. Do not freeze. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free, PVC-free, DEHP-free. The container closure is not made with natural rubber latex.
<table width="100%" styleCode="Noautorules"><col width="23.041%" align="left"/><col width="52.951%" align="left"/><col width="24.008%" align="left"/><tbody><tr><td align="justify" valign="top"><content styleCode="bold">NDC</content></td><td align="justify" valign="top"><content styleCode="bold">Dexmedetomidine Hydrochloride in 0.9% Sodium</content></td><td align="justify" valign="top"><content styleCode="bold">Package Factor</content></td></tr><tr><td align="justify" valign="top"/><td align="justify" valign="top"><content styleCode="bold">Chloride Injection (4 mcg per mL)</content></td><td align="justify" valign="top"/></tr><tr><td align="justify" valign="top">25021-617-82 </td><td align="justify" valign="top">400 mcg per 100 mL Single-Dose Bag </td><td align="justify" valign="top">20 bags per carton </td></tr></tbody></table>
Storage Conditions Store at 20º to 25ºC (68º to 77ºF); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Do not use if product is discolored or if precipitate matter is present. Do not freeze. Discard unused portion. Sterile, Nonpyrogenic, Preservative-free, PVC-free, DEHP-free. The container closure is not made with natural rubber latex.
17 PATIENT COUNSELING INFORMATION Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is indicated for short-term intravenous sedation. Dosage must be individualized and titrated to the desired clinical effect. Blood pressure, heart rate and oxygen levels will be monitored both continuously during the infusion of dexmedetomidine hydrochloride in 0.9% sodium chloride injection and as clinically appropriate after discontinuation. When dexmedetomidine hydrochloride in 0.9% sodium chloride injection is infused for more than 6 hours, patients should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours. Additionally, patients should be informed to report symptoms that may occur within 48 hours after the administration of dexmedetomidine hydrochloride in 0.9% sodium chloride injection such as: weakness, confusion, excessive sweating, weight loss, abdominal pain, salt cravings, diarrhea, constipation, dizziness or light-headedness. Advise breastfeeding mothers who were exposed to dexmedetomidine hydrochloride in 0.9% sodium chloride injection to monitor breastfed neonates for irritability [see Use in Specific Populations ( 8.2 )] . sagent ® Mfd. for SAGENT Pharmaceuticals Schaumburg, IL 60173 (USA) Made in India ©2024 Sagent Pharmaceuticals November 2024
1 INDICATIONS AND USAGE Dexmedetomidine 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 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 is indicated for sedation of initially intubated and mechanically ventilated adult patients during treatment in an intensive care setting. Dexmedetomidine injection should be administered by continuous infusion not to exceed 24 hours. 1.2 Procedural Sedation Dexmedetomidine 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) 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 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 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 as clinically appropriate after discontinuation. Dexmedetomidine 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. Use administration components made with synthetic or coated natural rubber gaskets. Dexmedetomidine 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)].
)] . 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 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)] . 2.3 Dosage Adjustment Due to possible pharmacodynamic interactions, a reduction in dosage of dexmedetomidine 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 Injection and Dexmedetomidine in 5% Dextrose 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 Injection, 400 mcg/4 mL (100 mcg/mL) and 1000 mcg/10 mL (100 mcg/mL) Dexmedetomidine Injection must be diluted with 0.9% sodium chloride injection to achieve required concentration (4 mcg/mL) prior to administration. Preparation of solutions is the same, whether for the loading dose or maintenance infusion. To prepare the solution, do one of the following : Withdraw 2 mL of Dexmedetomidine Injection, and add to 48 mL of 0.9% Sodium Chloride Injection to a total volume of 50 mL or Withdraw 4 mL of Dexmedetomidine Injection, and add to 96 mL of 0.9% Sodium Chloride Injection to a total of volume of 100 mL Gently shake and mix well. Prior to use, may store the diluted dexmedetomidine solution for up to 4 hours at room temperature or up to 24 hours at 2 o to 8 o C. Discard unused portion. 2.5 Administration with Other Fluids Dexmedetomidine Injection should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established. Dexmedetomidine Injection has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam.
with Other Fluids Dexmedetomidine Injection should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established. Dexmedetomidine Injection has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam. Dexmedetomidine Injection is compatible with and may be co- administered with: 0.9% Sodium Chloride Injection 5% Dextrose Injection in water 20% Mannitol Injection Lactated Ringer's Injection 100 mg/mL Magnesium Sulfate Injection 0.3% potassium chloride solution 2.6 Compatibility with Natural Rubber Compatibility studies have demonstrated the potential for absorption of dexmedetomidine to some types of natural rubber. Although dexmedetomidine is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.
3 DOSAGE FORMS AND STRENGTHS Dexmedetomidine Injection, USP is clear, colorless, sterile, and nonpyrogenic solution suitable for intravenous infusion following dilution and is available in 100 mcg/mL vial, strength as follows: 400 mcg/4 mL (100 mcg/mL) in a multiple-dose vial 1000 mcg in 10 mL in a multiple-dose vial Injection: 400 mcg/4 mL (100 mcg/mL) in a multiple-dose vial. (3) 1000 mcg/10 mL (100 mcg/mL) in a multiple-dose vial. (3)
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. (5.6) 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.
ronic 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, regardless of dose, 12 (5%) dexmedetomidine injection adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) dexmedetomidine injection adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events were nausea, vomiting, and agitation [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). 5.6 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)] . 5.7 Hyperthermia or Pyrexia Dexmedetomidine may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue dexmedetomidine if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes. 5.8 Hepatic Impairment Since dexmedetomidine clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration (2.2, 2.3)] .
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 Somerset Therapeutics, LLC at +1 800-417-9175 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 injection for sedation in the Intensive Care Unit setting in which 1,007 adult patients received dexmedetomidine injection. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% ≥65 years of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 2. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [see Warnings and Precautions (5.2)] . Table 2: Adverse Reactions with an Incidence >2%— Adult Intensive Care Unit Sedation Population <24 hours * Adverse Event All Dexmedetomidine Injection (N = 1007) (%) Randomized Dexmedetomidine Injection (N = 798) (%) Placebo (N = 400) (%) Propofol (N = 188) (%) Hypotension 25% 24% 12% 13% Hypertension 12% 13% 19% 4% Nausea 9% 9% 9% 11% Bradycardia 5% 5% 3% 0 Atrial Fibrillation 4% 5% 3% 7% Pyrexia 4% 4% 4% 4% Dry Mouth 4% 3% 1% 1% Vomiting 3% 3% 5% 3% Hypovolemia 3% 3% 2% 5% Atelectasis 3% 3% 3% 6% Pleural Effusion 2% 2% 1% 6% Agitation 2% 2% 3% 1% Tachycardia 2% 2% 4% 1% Anemia 2% 2% 2% 2% Hyperthermia 2% 2% 3% 0 Chills 2% 2% 3% 2% Hyperglycemia 2% 2% 2% 3% Hypoxia 2% 2% 2% 3% Post-procedural Hemorrhage 2% 2% 3% 4% Pulmonary Edema 1% 1% 1% 3% Hypocalcemia 1% 1% 0 2% Acidosis 1% 1% 1% 2% Urine Output Decreased 1% 1% 0 2% Sinus Tachycardia 1% 1% 1% 2% Ventricular Tachycardia <1% 1% 1% 5% Wheezing <1% 1% 0 2% Edema Peripheral <1% 0 1% 2% * 26 subjects in the all dexmedetomidine injection group and 10 subjects in the randomized dexmedetomidine injection group had exposure for greater than 24 hours. Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of dexmedetomidine injection for sedation in the surgical intensive care unit setting in which 387 adult patients received dexmedetomidine injection for less than 24 hours. The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 3).
ation in the surgical intensive care unit setting in which 387 adult patients received dexmedetomidine injection for less than 24 hours. The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 3). Table 3: Treatment-Emergent Adverse Events Occurring in >1% of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion <24 Hours ICU Sedation 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 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 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 injection group is provided in Table 5. Table 4: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation 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 injection and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%). Table 5.
pm or in relative terms as ≥30% greater than pre-study drug infusion value. The following adverse events occurred between 2 and 5% for dexmedetomidine injection and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%). Table 5. Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Dexmedetomidine Injection Group Dexmedetomidine Injection 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 6. 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 injection and comparator groups in both studies. Table 6: Adverse Reactions that Occurred with an Incidence of Greater than 2% and Greater in the Placebo Group in Clinical Trials of Dexmedetomidine Injection for Adult Procedural Adverse Event Dexmedetomidine Injection (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 SpO2 <90% or 10% decrease from baseline. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of dexmedetomidine 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 injection during post approval use of the drug.
luntarily 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 injection during post approval use of the drug. Table 7: Adverse Reactions Experienced During Post-Approval Use of Dexmedetomidine hydrochloride 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
<table ID="ID65" width="589" styleCode="Noautorules"><caption/><col width="110"/><col width="157"/><col width="142"/><col width="76"/><col width="104"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"> <content styleCode="bold"> Adverse Event</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> All Dexmedetomidine</content> <content styleCode="bold"> Injection</content> <content styleCode="bold"> (N = 1007) (%)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Randomized Dexmedetomidine</content> <content styleCode="bold"> Injection</content> <content styleCode="bold"> (N = 798) (%)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo</content> <content styleCode="bold"> (N = 400) (%)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Propofol</content> <content styleCode="bold"> (N = 188) </content> <content styleCode="bold"> (%)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypotension </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 25% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 24% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 12% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypertension </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 12% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Bradycardia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Atrial Fibrillation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Pyrexia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dry Mouth </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" a
styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dry Mouth </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" a lign="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Vomiting </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypovolemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Atelectasis </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Pleural Effusion </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Agitation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Tachycardia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Anemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hyperthermia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Chills </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hyperglycemia </td><td valign=
ter"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hyperglycemia </td><td valign= "top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypoxia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Post-procedural Hemorrhage </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Pulmonary Edema </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypocalcemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Acidosis </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Urine Output Decreased </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Sinus Tachycardia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Ventricular Tachycardia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> <1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Wheezing </td><td valign="top" styleCode=" Botrule Rrule" align="center"> <1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="to
er"> 5% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Wheezing </td><td valign="top" styleCode=" Botrule Rrule" align="center"> <1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="to p" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Edema Peripheral </td><td valign="top" styleCode=" Botrule Rrule" align="center"> <1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td colspan="5" valign="top" styleCode="Lrule Botrule Rrule" align="left"><sup>*</sup>26 subjects in the all dexmedetomidine injection group and 10 subjects in the randomized dexmedetomidine injection group had exposure for greater than 24 hours. </td></tr></tbody></table>
p" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Edema Peripheral </td><td valign="top" styleCode=" Botrule Rrule" align="center"> <1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td colspan="5" valign="top" styleCode="Lrule Botrule Rrule" align="left"><sup>*</sup>26 subjects in the all dexmedetomidine injection group and 10 subjects in the randomized dexmedetomidine injection group had exposure for greater than 24 hours. </td></tr></tbody></table> <table ID="ID67" width="436" styleCode="Noautorules"><caption/><col width="155"/><col width="151"/><col width="130"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"> <content styleCode="bold"> Adverse Event</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Randomized Dexmedetomidine (N = 387)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (N = 379)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypotension </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypertension </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 16% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 18% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Bradycardia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Fever </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Vomiting </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Atrial Fibrillation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypoxia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Tachycardia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hemorrhage </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Anemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dry Mouth </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Rigors </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top"
</td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Rigors </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Agitation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hyperpyrexia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Pain </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hyperglycemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Acidosis </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Pleural Effusion </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Oliguria </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> <1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Thirst </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> <1% </td></tr></tbody></table>
td><td valign="top" styleCode=" Botrule Rrule" align="center"> <1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Thirst </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> <1% </td></tr></tbody></table> <table ID="ID69" width="639" styleCode="Noautorules"><caption/><col width="213"/><col width="213"/><col width="213"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> Adverse Event</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Dexmedetomidine</content> <content styleCode="bold"> (N = 244)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Midazolam</content> <content styleCode="bold"> (N = 122)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypotension<sup>1</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 56% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 56% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypotension Requiring Intervention </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 27% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Bradycardia<sup>2</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 42% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Bradycardia Requiring Intervention </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Systolic Hypertension<sup>3</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 28% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 42% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Tachycardia<sup>4</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 25% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 44% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Tachycardia Requiring Intervention </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Diastolic Hypertension<sup>3</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 12% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 15% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypertension<sup>3</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 11% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 15% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypertension Requiring Intervention† </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 30% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypokalemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Pyrexia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </t
Rrule" align="center"> 9% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Pyrexia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </t d></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Agitation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hyperglycemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Constipation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypoglycemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Respiratory Failure </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Renal Failure Acute </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Acute Respiratory Distress Syndrome </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Generalized Edema </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypomagnesemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td></tr><tr><td colspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left"><sup>†</sup> Includes any type of hypertension.
trule Rrule" align="left"> Hypomagnesemia </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td></tr><tr><td colspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left"><sup>†</sup> Includes any type of hypertension. <sup>1</sup> 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. <sup>2</sup> Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value. <sup>3</sup> 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. <sup>4</sup> Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value. </td></tr></tbody></table>
ressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value. <sup>4</sup> Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value. </td></tr></tbody></table> <table ID="ID71" width="522" styleCode="Noautorules"><caption/><col width="227"/><col width="76"/><col width="115"/><col width="104"/><tbody><tr><td colspan="4" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Dexmedetomidine Injection mcg/kg/hr</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> <content styleCode="bold"> Adverse Event</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> ≤0.7*</content> <content styleCode="bold"> (N = 95)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> >0.7 to ≤1.1*</content> <content styleCode="bold"> (N = 78)</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> >1.1*</content> <content styleCode="bold"> (N = 71)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Constipation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Agitation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 8% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Anxiety </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Edema Peripheral </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 7% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Atrial Fibrillation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Respiratory Failure </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 6% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 10% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Acute Respiratory Distress Syndrome </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"> *Average maintenance dose over the entire study drug administration </td></tr></tbody></table>
</td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 9% </td></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"> *Average maintenance dose over the entire study drug administration </td></tr></tbody></table> <table ID="ID73" width="540" styleCode="Noautorules"><caption/><col width="216"/><col width="145"/><col width="180"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"> <content styleCode="bold"> Adverse Event</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Dexmedetomidine Injection</content> <content styleCode="bold"> (N = 318) </content> <content styleCode="bold"> (%)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (N = 113) (%)</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypotension<sup>1</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 54% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 30% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Respiratory Depression<sup>2</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 37% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 32% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Bradycardia<sup>3</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypertension<sup>4</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 13% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 24% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Tachycardia<sup>5</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 17% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nausea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Dry Mouth </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hypoxia<sup>6</sup> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3% </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Bradypnea </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2% </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4% </td></tr><tr><td colspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left"><sup>1</sup>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. <sup>2</sup> Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or >25% decrease from baseline. <sup>3</sup> Bradycardia was defined in absolute and relative terms as <40 beats per minute or ≤30% lower than pre-study drug infusion value.
mmHg. <sup>2</sup> Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or >25% decrease from baseline. <sup>3</sup> 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 <content styleCode="italics">[see Clinical Studies (14.2)]</content> . <sup>4</sup> 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. <sup>5</sup> Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value. <sup>6</sup> Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline. </td></tr></tbody></table>
d pressure of >100 mmHg. <sup>5</sup> Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value. <sup>6</sup> Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline. </td></tr></tbody></table> <table ID="ID76" width="559" styleCode="Noautorules"><caption/><col width="238"/><col width="321"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> System Organ Class</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Preferred Term</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Blood and Lymphatic System Disorders </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Anemia </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Cardiac Disorders </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Eye Disorders </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Photopsia, visual impairment </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Gastrointestinal Disorders </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Abdominal pain, diarrhea, nausea, vomiting </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> General Disorders and Administration Site Conditions </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Chills, hyperpyrexia, pain, pyrexia, thirst </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Hepatobiliary Disorders </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Hepatic function abnormal, hyperbilirubinemia </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Investigations </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Metabolism and Nutrition Disorders </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Nervous System Disorders </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Psychiatric Disorders </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Agitation, confusional state, delirium, hallucination, illusion </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Renal and Urinary Disorders </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Oliguria, polyuria </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Respiratory, Thoracic and Mediastinal Disorders </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Skin and Subcutaneous Tissue Disorders </td><td valign="top" style
s </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Skin and Subcutaneous Tissue Disorders </td><td valign="top" style Code=" Botrule Rrule" align="left"> Hyperhidrosis, pruritus, rash, urticaria </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Surgical and Medical Procedures </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Light anesthesia </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Vascular Disorders </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Blood pressure fluctuation, hemorrhage, hypertension, hypotension </td></tr></tbody></table>
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 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.
8 USE IN SPECIFIC POPULATIONS Geriatric Patients: Dose reduction should be considered. (2.2, 2.3, 5.2, 8.5) Hepatic Impairment: Dose reduction should be considered. (2.2, 2.3, 5.8, 8.6) 8.1 Pregnancy Risk Summary Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of caesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta. In animal reproduction studies, fetal toxicity that lower fetal viability and reduced live fetuses occurred with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 1.8 times the maximum recommended human dose (MRHD) of 17.8 mcg/kg/day. Developmental toxicity (low pup weights and adult offspring weights, decreased F1 grip strength, increased early implantation loss and decreased viability of second-generation offspring) occurred when pregnant rats were subcutaneously administered dexmedetomidine at doses less than the clinical dose from late pregnancy through lactation and weaning ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively. Data Animal Data Increased post-implantation losses and reduced live fetuses in the presence of maternal toxicity (i.e. decreased body weight) were noted in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine 200 mcg/kg/day (equivalent to 1.8 times the intravenous MRHD of 17.8 mcg/kg/day based on body surface area [BSA]) during the period of organogenesis (Gestation Day [GD] 6 to 15). No malformations were reported. No malformations or embryo-fetal toxicity were noted in a rabbit embryo-fetal development study in which pregnant does were administered dexmedetomidine intravenously at doses of up to 96 mcg/kg/day (approximately half the human exposure at the MRHD based on AUC) during the period of organogenesis (GD 6 to 18). Reduced pup and adult offspring birth weights, and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at doses of 8 mcg/kg/day (0.07 times the MRHD based on BSA) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21).
delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21). In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously. 8.2 Lactation Risk Summary Available published literature reports the presence of dexmedetomidine in human milk following intravenous administration (see Data). There is no information regarding the effects of dexmedetomidine on the breastfed infant or the effects on milk production. Advise women to monitor the breastfed infant for irritability. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for dexmedetomidine and any potential adverse effects on the breastfed infant from dexmedetomidine or from the underlying condition. Data In two published clinical studies, a total of 14 women were given intravenous dexmedetomidine 6 mcg/kg/hour for 10 minutes after delivery followed by continuous infusion of 0.2–0.7 mcg/kg/hour. Breast milk and maternal blood samples were collected at 0, 6, 12, and 24 hours after discontinuation of dexmedetomidine. Plasma and milk dexmedetomidine concentrations were detectable up to 6 hours in most subjects, up to 12 hours in one subject and undetectable in all at 24 hours. The milk-to-plasma ratio from single paired maternal milk and plasma concentrations at each time point ranged from 0.53 to 0.95. The relative infant dose was estimated to range from 0.02 to 0.098%. 8.4 Pediatric Use Safety and efficacy of dexmedetomidine injection have not been established for Procedural or ICU Sedation in pediatric patients. 8.5 Geriatric Use Intensive Care Unit Sedation A total of 729 patients in the clinical studies were 65 years of age and over. A total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of dexmedetomidine injection [ see Warnings and Precautions (5.1, 5.2)]. Therefore a dose reduction may be considered in patients over 65 years of age [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Procedural Sedation A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in dexmedetomidine injection-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age. 8.6 Hepatic Impairment Since dexmedetomidine clearance decreases with increasing severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see Dosage and Administration (2.2, 2.3), Clinical Pharmacology (12.3)] .
8.1 Pregnancy Risk Summary Available data from published randomized controlled trials and case reports over several decades of use with intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of the available data are based on studies with exposures that occurred at the time of caesarean section delivery, and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available data indicate that dexmedetomidine crosses the placenta. In animal reproduction studies, fetal toxicity that lower fetal viability and reduced live fetuses occurred with subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 1.8 times the maximum recommended human dose (MRHD) of 17.8 mcg/kg/day. Developmental toxicity (low pup weights and adult offspring weights, decreased F1 grip strength, increased early implantation loss and decreased viability of second-generation offspring) occurred when pregnant rats were subcutaneously administered dexmedetomidine at doses less than the clinical dose from late pregnancy through lactation and weaning ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15- 20%, respectively. Data Animal Data Increased post-implantation losses and reduced live fetuses in the presence of maternal toxicity (i.e. decreased body weight) were noted in a rat embryo-fetal development study in which pregnant dams were administered subcutaneous doses of dexmedetomidine 200 mcg/kg/day (equivalent to 1.8 times the intravenous MRHD of 17.8 mcg/kg/day based on body surface area [BSA]) during the period of organogenesis (Gestation Day [GD] 6 to 15). No malformations were reported. No malformations or embryo-fetal toxicity were noted in a rabbit embryo-fetal development study in which pregnant does were administered dexmedetomidine intravenously at doses of up to 96 mcg/kg/day (approximately half the human exposure at the MRHD based on AUC) during the period of organogenesis (GD 6 to 18). Reduced pup and adult offspring birth weights, and grip strength were reported in a rat developmental toxicology study in which pregnant females were administered dexmedetomidine subcutaneously at doses of 8 mcg/kg/day (0.07 times the MRHD based on BSA) during late pregnancy through lactation and weaning (GD 16 to postnatal day [PND] 25). Decreased viability of second generation offspring and an increase in early implantation loss along with delayed motor development occurred in the 32 mcg/kg/day group (equivalent to less than the clinical dose based on BSA) when first generation offspring were allowed to mate. This study limited dosing to hard palate closure (GD 15 to 18) through weaning instead of dosing from implantation (GD 6 to 7) to weaning (PND 21). In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously.
8.5 Geriatric Use Intensive Care Unit Sedation A total of 729 patients in the clinical studies were 65 years of age and over. A total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a higher incidence of bradycardia and hypotension was observed following administration of dexmedetomidine injection [ see Warnings and Precautions (5.1, 5.2)]. Therefore a dose reduction may be considered in patients over 65 years of age [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. Procedural Sedation A total of 131 patients in the clinical studies were 65 years of age and over. A total of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in dexmedetomidine injection-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and a reduction in the maintenance infusion should be considered for patients greater than 65 years of age.
9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Dexmedetomidine is not a controlled substance. 9.3 Dependence The dependence potential of dexmedetomidine injection has not been studied in humans. However, since studies in rodents and primates have demonstrated that dexmedetomidine injection exhibits pharmacologic actions similar to those of clonidine, it is possible that dexmedetomidine injection may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [ see Warnings and Precautions (5.5) ].
9.3 Dependence The dependence potential of dexmedetomidine injection has not been studied in humans. However, since studies in rodents and primates have demonstrated that dexmedetomidine injection exhibits pharmacologic actions similar to those of clonidine, it is possible that dexmedetomidine injection may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [ see Warnings and Precautions (5.5) ].
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.
11 DESCRIPTION Dexmedetomidine Injection, USP is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. Dexmedetomidine Injection contains the dexmedetomidine as active pharmaceutical ingredient in the form of the hydrochloride salt form. Dexmedetomidine hydrochloride is a central alpha-2 adrenergic agonist. Structurally it is the S -enantiomer of medetomidine and is chemically described as 4-[( S )-α,2,3-Trimethylbenzyl]imidazole monohydrochloride. 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 crystalline 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 Injection is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7. Each mL contains 118 mcg of dexmedetomidine hydrochloride USP, equivalent to 100 mcg (0.1 mg) of dexmedetomidine, 1.6 mg of methylparaben NF and 0.2 mg of propylparaben NF, as preservatives and 9 mg of sodium chloride USP, as tonicity agent in water for injection. Image
12 CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics In a study in healthy adult volunteers (N = 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when dexmedetomidine injection was administered by intravenous infusion at doses within the recommended dose range (0.2–0.7 mcg/kg/hr). 12.3 Pharmacokinetics Following intravenous administration to adults, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t 1/2 ) of approximately 6 minutes; a terminal elimination half-life (t 1/2 ) of approximately 2 hours; and steady-state volume of distribution (V ss ) of approximately 118 liters. Clearance is estimated to be approximately 39 L/hour. The mean body weight associated with this clearance estimate was 72 kg. Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered to adults by intravenous infusion for up to 24 hours. Table 8 shows the main pharmacokinetic parameters when dexmedetomidine injection was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours. Table 8: Mean ± SD Pharmacokinetic Parameters in Adults Parameter Loading Infusion (min)/Total Infusion Duration (hrs) 10 min/12 hrs 10 min/24 hrs 10 min/24 hrs 35 min/24 hrs Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr) 0.3/0.17 0.3/0.17 0.6/0.33 1.25/0.70 t 1/2 *, hour 1.78 ± 0.30 2.22 ± 0.59 2.23 ± 0.21 2.50 ± 0.61 CL, liter/hour 46.3 ± 8.3 43.1 ± 6.5 35.3 ± 6.8 36.5 ± 7.5 V ss , liter 88.7 ± 22.9 102.4 ± 20.3 93.6 ± 17.0 99.6 ± 17.8 Avg Css #, ng/mL 0.27 ± 0.05 0.27 ± 0.05 0.67 ± 0.10 1.37 ± 0.20 Abbreviations: t 1/2 = half-life, CL = clearance, Vss = steady-state volume of distribution. * Presented as harmonic mean and pseudo standard deviation. # Mean Css = Average steady-state concentration of dexmedetomidine. The mean Css was calculated based on post- dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions. The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively. Dexmedetomidine pharmacokinetic parameters in adults after dexmedetomidine maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetics (PK) parameters after dexmedetomidine injection maintenance dosing for < 24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t 1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively. Distribution The steady-state volume of distribution (V ss ) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects.
clearance (CL), volume of distribution (V), and t 1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively. Distribution The steady-state volume of distribution (V ss ) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of dexmedetomidine that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects. The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro , and negligible changes in the plasma protein binding of dexmedetomidine were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine was explored in vitro and none of these compounds appeared to be significantly displaced by dexmedetomidine. Elimination Metabolism Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy- dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N- methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide. Excretion The terminal elimination half-life (t1/2) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy- dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified. Specific Populations Male and Female Patients There was no observed difference in dexmedetomidine pharmacokinetics due to sex. Geriatric Patients The pharmacokinetic profile of dexmedetomidine injection was not altered by age. There were no differences in the pharmacokinetics of dexmedetomidine injection in young (18–40 years), middle age (41–65 years), and elderly (>65 years) subjects . Patients with Hepatic Impairment In adult subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for dexmedetomidine were lower than in healthy subjects.
inetics of dexmedetomidine injection in young (18–40 years), middle age (41–65 years), and elderly (>65 years) subjects . Patients with Hepatic Impairment In adult subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for dexmedetomidine were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy adult subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy adult subjects, respectively. Although dexmedetomidine is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see Dosage and Administration (2.2), Warnings and Precautions (5.8)] . Patients with Renal Impairment Dexmedetomidine pharmacokinetics (C max , T max , AUC, t 1/2 , CL, and Vss) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects. Drug Interaction Studies In Vitro Studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.
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.
12.2 Pharmacodynamics In a study in healthy adult volunteers (N = 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when dexmedetomidine injection was administered by intravenous infusion at doses within the recommended dose range (0.2–0.7 mcg/kg/hr).
12.3 Pharmacokinetics Following intravenous administration to adults, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t 1/2 ) of approximately 6 minutes; a terminal elimination half-life (t 1/2 ) of approximately 2 hours; and steady-state volume of distribution (V ss ) of approximately 118 liters. Clearance is estimated to be approximately 39 L/hour. The mean body weight associated with this clearance estimate was 72 kg. Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered to adults by intravenous infusion for up to 24 hours. Table 8 shows the main pharmacokinetic parameters when dexmedetomidine injection was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours. Table 8: Mean ± SD Pharmacokinetic Parameters in Adults Parameter Loading Infusion (min)/Total Infusion Duration (hrs) 10 min/12 hrs 10 min/24 hrs 10 min/24 hrs 35 min/24 hrs Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr) 0.3/0.17 0.3/0.17 0.6/0.33 1.25/0.70 t 1/2 *, hour 1.78 ± 0.30 2.22 ± 0.59 2.23 ± 0.21 2.50 ± 0.61 CL, liter/hour 46.3 ± 8.3 43.1 ± 6.5 35.3 ± 6.8 36.5 ± 7.5 V ss , liter 88.7 ± 22.9 102.4 ± 20.3 93.6 ± 17.0 99.6 ± 17.8 Avg Css #, ng/mL 0.27 ± 0.05 0.27 ± 0.05 0.67 ± 0.10 1.37 ± 0.20 Abbreviations: t 1/2 = half-life, CL = clearance, Vss = steady-state volume of distribution. * Presented as harmonic mean and pseudo standard deviation. # Mean Css = Average steady-state concentration of dexmedetomidine. The mean Css was calculated based on post- dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions. The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively. Dexmedetomidine pharmacokinetic parameters in adults after dexmedetomidine maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetics (PK) parameters after dexmedetomidine injection maintenance dosing for < 24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t 1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively. Distribution The steady-state volume of distribution (V ss ) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of dexmedetomidine that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects. The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro , and negligible changes in the plasma protein binding of dexmedetomidine were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine was explored in vitro and none of these compounds appeared to be significantly displaced by dexmedetomidine.
changes in the plasma protein binding of dexmedetomidine were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by dexmedetomidine was explored in vitro and none of these compounds appeared to be significantly displaced by dexmedetomidine. Elimination Metabolism Dexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with a minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy- dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N- methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide. Excretion The terminal elimination half-life (t1/2) of dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy- dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was a minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified. Specific Populations Male and Female Patients There was no observed difference in dexmedetomidine pharmacokinetics due to sex. Geriatric Patients The pharmacokinetic profile of dexmedetomidine injection was not altered by age. There were no differences in the pharmacokinetics of dexmedetomidine injection in young (18–40 years), middle age (41–65 years), and elderly (>65 years) subjects . Patients with Hepatic Impairment In adult subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for dexmedetomidine were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy adult subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy adult subjects, respectively. Although dexmedetomidine is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see Dosage and Administration (2.2), Warnings and Precautions (5.8)] . Patients with Renal Impairment Dexmedetomidine pharmacokinetics (C max , T max , AUC, t 1/2 , CL, and Vss) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects.
nt [see Dosage and Administration (2.2), Warnings and Precautions (5.8)] . Patients with Renal Impairment Dexmedetomidine pharmacokinetics (C max , T max , AUC, t 1/2 , CL, and Vss) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects. Drug Interaction Studies In Vitro Studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.
<table ID="ID118" width="569" styleCode="Noautorules"><caption/><col width="82"/><col width="118"/><col width="104"/><col width="104"/><col width="161"/><tbody><tr><td rowspan="4" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"> <content styleCode="bold"> Parameter</content> </td><td colspan="4" valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Loading Infusion (min)/Total Infusion Duration (hrs)</content> </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 10 min/12 hrs</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 10 min/24 hrs</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 10 min/24 hrs</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 35 min/24 hrs</content> </td></tr><tr><td colspan="4" valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Dexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr)</content> </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 0.3/0.17</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 0.3/0.17</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 0.6/0.33</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> 1.25/0.70</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> t<sub>1/2</sub>*, hour</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.78 ± 0.30 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2.22 ± 0.59 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2.23 ± 0.21 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2.50 ± 0.61 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> CL, liter/hour</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 46.3 ± 8.3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 43.1 ± 6.5 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 35.3 ± 6.8 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 36.5 ± 7.5 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> V<sub>ss</sub>, liter</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 88.7 ± 22.9 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 102.4 ± 20.3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 93.6 ± 17.0 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 99.6 ± 17.8 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Avg Css #, ng/mL</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.27 ± 0.05 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.27 ± 0.05 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.67 ± 0.10 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.37 ± 0.20 </td></tr><tr><td colspan="5" valign="top" styleCode="Lrule Botrule Rrule" align
td valign="top" styleCode=" Botrule Rrule" align="center"> 0.27 ± 0.05 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.67 ± 0.10 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1.37 ± 0.20 </td></tr><tr><td colspan="5" valign="top" styleCode="Lrule Botrule Rrule" align ="left"> Abbreviations: t<sub>1/2 </sub>= half-life, CL = clearance, Vss = steady-state volume of distribution. <sup>*</sup> Presented as harmonic mean and pseudo standard deviation. <sup>#</sup> Mean Css = Average steady-state concentration of dexmedetomidine. The mean Css was calculated based on post- dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions. The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively. </td></tr></tbody></table>
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Animal carcinogenicity studies have not been performed with dexmedetomidine. Mutagenesis Dexmedetomidine was not mutagenic in vitro , in either the bacterial reverse mutation assay ( E. coli and Salmonella typhimurium ) or the mammalian cell forward mutation assay (mouse lymphoma). Dexmedetomidine was clastogenic in the in vitro human lymphocyte chromosome aberration test with, but not without, rat S9 metabolic activation. In contrast, dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test with or without human S9 metabolic activation. Although dexmedetomidine was clastogenic in an in vivo mouse micronucleus test in NMRI mice, there was no evidence of clastogenicity in CD-1 mice. Impairment of Fertility Fertility in male or female rats was not affected after daily subcutaneous injections of dexmedetomidine at doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m 2 basis) administered from 10 weeks prior to mating in males, and 3 weeks prior to mating and during mating in females. 13.2 Animal Pharmacology and/or Toxicology There were no differences in the adrenocorticotropic hormone (ACTH)-stimulated cortisol response in dogs following a single dose of dexmedetomidine compared to saline control. However, after continuous subcutaneous infusions of dexmedetomidine at 3 mcg/kg/hour and 10 mcg/kg/hour for one week in dogs (exposures estimated to be within the clinical range), the ACTH-stimulated cortisol response was diminished by approximately 27% and 40%, respectively, compared to saline-treated control animals indicating a dose-dependent adrenal suppression.
13.2 Animal Pharmacology and/or Toxicology There were no differences in the adrenocorticotropic hormone (ACTH)-stimulated cortisol response in dogs following a single dose of dexmedetomidine compared to saline control. However, after continuous subcutaneous infusions of dexmedetomidine at 3 mcg/kg/hour and 10 mcg/kg/hour for one week in dogs (exposures estimated to be within the clinical range), the ACTH-stimulated cortisol response was diminished by approximately 27% and 40%, respectively, compared to saline-treated control animals indicating a dose-dependent adrenal suppression.
14 CLINICAL STUDIES The safety and efficacy of dexmedetomidine injection has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1,185 adult patients. 14.1 Intensive Care Unit Sedation Two randomized, double-blind, parallel-group, placebo-controlled multicenter clinical trials included 754 adult patients being treated in a surgical intensive care unit. All patients were initially intubated and received mechanical ventilation. These trials evaluated the sedative properties of dexmedetomidine injection by comparing the amount of rescue medication (midazolam in one trial and propofol in the second) required to achieve a specified level of sedation (using the standardized Ramsay Sedation Scale) between dexmedetomidine injection and placebo from onset of treatment to extubation or to a total treatment duration of 24 hours. The Ramsay Level of Sedation Scale is displayed in Table 9. Table 9: Ramsay Level of Sedation Scale Clinical Score Level of Sedation Achieved 6 Asleep, no response 5 Asleep, sluggish response to light glabellar tap or loud auditory stimulus 4 Asleep, but with brisk response to light glabellar tap or loud auditory stimulus 3 Patient responds to commands 2 Patient cooperative, oriented, and tranquil 1 Patient anxious, agitated, or restless In the first study, 175 adult patients were randomized to receive placebo and 178 to receive dexmedetomidine injection by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion rate was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive "rescue" midazolam as needed to augment the study drug infusion. In addition, morphine sulfate was administered for pain as needed. The primary outcome measure for this study was the total amount of rescue medication (midazolam) needed to maintain sedation as specified while intubated. Patients randomized to placebo received significantly more midazolam than patients randomized to dexmedetomidine injection (see Table 10). A second prospective primary analysis assessed the sedative effects of dexmedetomidine injection by comparing the percentage of adult patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of adult patients in the dexmedetomidine injection group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 10). Table 10: Midazolam Use as Rescue Medication During Intubation (ITT) Study One Placebo (N = 175) Dexmedetomidine Injection (N = 178) p-value Mean Total Dose (mg) of Midazolam 19 mg 5 mg 0.0011* Standard deviation 53 mg 19 mg Categorized Midazolam Use 0 mg 43 (25%) 108 (61%) <0.001** 0–4 mg 34 (19%) 36 (20%) >4 mg 98 (56%) 34 (19%) ITT (intent-to-treat) population includes all randomized patients. * ANOVA model with treatment center. ** Chi-square. A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine injection and placebo groups. On average, dexmedetomidine injection-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h).
** Chi-square. A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine injection and placebo groups. On average, dexmedetomidine injection-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h). In addition, 44% (79 of 178 patients) of dexmedetomidine injection patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group. In a second study, 198 adult patients were randomized to receive placebo and 203 to receive dexmedetomidine injection by intravenous infusion at a dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion was adjusted to maintain a Ramsay sedation score of ≥3. Patients were allowed to receive "rescue" propofol as needed to augment the study drug infusion. In addition, morphine sulfate was administered as needed for pain. The primary outcome measure for this study was the total amount of rescue medication (propofol) needed to maintain sedation as specified while intubated. Adult patients randomized to placebo received significantly more propofol than adult patients randomized to dexmedetomidine injection (see Table 11). A significantly greater percentage of adult patients in the dexmedetomidine injection group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see Table 11). Table 11: Propofol Use as Rescue Medication During Intubation (ITT) Study Two Placebo (N = 198) Dexmedetomidine Injection (N = 203) p-value Mean Total Dose (mg) of Propofol 513 mg 72 mg <0.0001 * Standard deviation 782 mg 249 mg Categorized Propofol Use 0 mg 47 (24%) 122 (60%) <0.001** 0–50 mg 30 (15%) 43 (21%) >50 mg 121 (61%) 38 (19%) * ANOVA model with treatment center. ** Chi-square. A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine injection and placebo groups. On average, dexmedetomidine injection-treated patients received less morphine sulfate for pain than placebo-treated patients (0.43 versus 0.89 mg/h). In addition, 41% (83 of 203 patients) of dexmedetomidine injection patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group. In a controlled clinical trial, dexmedetomidine injection was compared to midazolam for ICU sedation exceeding 24 hours duration. Dexmedetomidine injection was not shown to be superior to midazolam for the primary efficacy endpoint, the percent of time patients were adequately sedated (81% versus 81%). In addition, administration of dexmedetomidine injection for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [ see Adverse Reactions (6.1) ]. 14.2 Procedural Sedation Adult Patients The safety and efficacy of dexmedetomidine injection for sedation of non-intubated adult patients prior to and/or during surgical and other procedures was evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials. Study 1 evaluated the sedative properties of dexmedetomidine injection in adult patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated dexmedetomidine injection in adult patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.
evaluated the sedative properties of dexmedetomidine injection in adult patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated dexmedetomidine injection in adult patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure. In Study 1, the sedative properties of dexmedetomidine injection were evaluated by comparing the percent of adult patients not requiring rescue midazolam to achieve a specified level of sedation using the standardized Observer's Assessment of Alertness/Sedation Scale (see Table 12). Table 12: Observer's Assessment of Alertness/Sedation Assessment Categories Responsiveness Speech Facial Expression Eyes Composite Score Responds readily to name spoken in normal tone Normal Normal Clear, no ptosis 5 (alert) Lethargic response to name spoken in normal tone Mild slowing or thickening Mild relaxation Glazed or mild ptosis (less than half the eye) 4 Responds only after name is called loudly and/or repeatedly Slurring or prominent slowing Marked relaxation (slack jaw) Glazed and marked ptosis (half the eye or more) 3 Responds only after mild prodding or shaking Few recognizable words – – 2 Does not respond to mild prodding or shaking – – – 1 (deep sleep) Adult patients were randomized to receive a loading infusion of either dexmedetomidine 1 mcg/kg, dexmedetomidine 0.5 mcg/kg, or placebo (normal saline) given over 10 minutes and followed by a maintenance infusion started at 0.6 mcg/kg/hr. The maintenance infusion of study drug could be titrated from 0.2 mcg/kg/hr to 1 mcg/kg/hr to achieve the targeted sedation score (Observer's Assessment of Alertness/Sedation Scale ≤4). Adult patients were allowed to receive rescue midazolam as needed to achieve and/or maintain an Observer's Assessment of Alertness/Sedation Scale ≤4. After achieving the desired level of sedation, a local or regional anesthetic block was performed. Demographic characteristics were similar between the dexmedetomidine and comparator groups. Efficacy results showed that dexmedetomidine was more effective than the comparator group when used to sedate non-intubated patients requiring monitored anesthesia care during surgical and other procedures (see Table 13). In Study 2, the sedative properties of dexmedetomidine were evaluated by comparing the percent of adult patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see Table 9). Adult patients were randomized to receive a loading infusion of dexmedetomidine 1 mcg/kg or placebo (normal saline) given over 10 minutes and followed by a fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired level of sedation, topicalization of the airway occurred. Adult patients were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay Sedation Scale ≥2. Demographic characteristics were similar between the dexmedetomidine and comparator groups. For efficacy results see Table 13. Table 13: Key Efficacy Results of Adult Procedural Sedation Studies Study Loading Infusion Treatment Arm Number of Patients Enrolled a % Not Requiring Midazolam Rescue Confidence b Interval on the Difference vs. Placebo Mean (SD) Total Dose (mg) of Rescue Midazolam Required Confidence b Intervals of the Mean Rescue Dose Study 1 Dexmedetomidine 0.5 mcg/kg 134 40 37 (27, 48) 1.4 (1.7) -2.7 (-3.4, -2.0) Dexmedetomidine 1 mcg/kg 129 54 51 (40, 62) 0.9 (1.5) -3.1 (-3.8, -2.5) Placebo 63 3 – 4.1 (3.0) – Study 2 Dexmedetomidine 1 mcg/kg 55 53 39 (20, 57) 1.1 (1.5) -1.8 (-2.7, -0.9) Placebo 50 14 – 2.9 (3.0) – a Based on ITT population defined as all randomized and treated patients. b Normal approximation to the binomial with continuity correction
<table ID="ID129" width="438" styleCode="Noautorules"><caption/><col width="115"/><col width="323"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Clinical Score</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Level of Sedation Achieved</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> 6 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Asleep, no response </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> 5 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Asleep, sluggish response to light glabellar tap or loud auditory stimulus </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> 4 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Asleep, but with brisk response to light glabellar tap or loud auditory stimulus </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Patient responds to commands </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Patient cooperative, oriented, and tranquil </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Patient anxious, agitated, or restless </td></tr></tbody></table>
> 2 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Patient cooperative, oriented, and tranquil </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"> 1 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Patient anxious, agitated, or restless </td></tr></tbody></table> <table ID="ID131" width="614" styleCode="Noautorules"><caption/><col width="182"/><col width="158"/><col width="142"/><col width="132"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule"/><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo </content> <content styleCode="bold"> (N = 175)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Dexmedetomidine Injection </content> <content styleCode="bold"> (N = 178)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"> <content styleCode="bold"> p-value</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Mean Total Dose (mg) of Midazolam</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 0.0011* </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Standard deviation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 53 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 19 mg </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Categorized Midazolam Use</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 0 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 43 (25%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 108 (61%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> <0.001** </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 0–4 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 34 (19%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 36 (20%) </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> >4 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 98 (56%) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 34 (19%) </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"> ITT (intent-to-treat) population includes all randomized patients. <sup>*</sup> ANOVA model with treatment center. <sup>**</sup> Chi-square. </td></tr></tbody></table>
"center"> 34 (19%) </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"> ITT (intent-to-treat) population includes all randomized patients. <sup>*</sup> ANOVA model with treatment center. <sup>**</sup> Chi-square. </td></tr></tbody></table> <table ID="ID133" width="492" styleCode="Noautorules"><caption/><col width="174"/><col width="92"/><col width="132"/><col width="94"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule"/><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Placebo</content> <content styleCode="bold"> (N = 198)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="center"><content styleCode="bold"> Dexmedetomidine Injection</content> <content styleCode="bold"> (N = 203)</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"> <content styleCode="bold"> p-value</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Mean Total Dose (mg) of Propofol</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 513 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 72 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> <0.0001<sup>*</sup> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Standard deviation </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 782 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 249 mg </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Categorized Propofol Use</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 0 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 47 (24%) </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 122 (60%) </td><td valign="top" styleCode=" Botrule Rrule" align="right"> <0.001** </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 0–50 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 30 (15%) </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 43 (21%) </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> >50 mg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 121 (61%) </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 38 (19%) </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><sup>*</sup> ANOVA model with treatment center. <sup>**</sup> Chi-square. </td></tr></tbody></table>
er"> 121 (61%) </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 38 (19%) </td><td valign="top" styleCode=" Botrule Rrule"/></tr><tr><td colspan="4" valign="top" styleCode="Lrule Botrule Rrule" align="left"><sup>*</sup> ANOVA model with treatment center. <sup>**</sup> Chi-square. </td></tr></tbody></table> <table ID="ID137" width="531" styleCode="Noautorules"><caption/><col width="114"/><col width="93"/><col width="96"/><col width="123"/><col width="104"/><tbody><tr><td colspan="5" valign="top" styleCode="Lrule Toprule Botrule Rrule" align="center"><content styleCode="bold"> Assessment Categories</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="center"><content styleCode="bold"> Responsiveness</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Speech</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Facial Expression</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Eyes</content> </td><td valign="top" styleCode=" Botrule Rrule" align="center"><content styleCode="bold"> Composite Score</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Responds readily to name spoken in normal tone </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Normal </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Normal </td><td valign="top" styleCode=" Botrule Rrule" align="center"> Clear, no ptosis </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 5 (alert) </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Lethargic response to name spoken in normal tone </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Mild slowing or thickening </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Mild relaxation </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Glazed or mild ptosis (less than half the eye) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 4 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Responds only after name is called loudly and/or repeatedly </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Slurring or prominent slowing </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Marked relaxation (slack jaw) </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Glazed and marked ptosis (half the eye or more) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Responds only after mild prodding or shaking </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Few recognizable words </td><td valign="top" styleCode=" Botrule Rrule" align="left"> – </td><td valign="top" styleCode=" Botrule Rrule" align="left"> – </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 2 </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> Does not respond to mild prodding or shaking </td><td valign="top" styleCode=" Botrule Rrule" align="left"> – </td><td valign="top" styleCode=" Botrule Rrule" align="left"> – </td><td valign="top" styleCode=" Botrule Rrule" align="left"> – </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (deep sleep) </td></tr></tbody></table>
td><td valign="top" styleCode=" Botrule Rrule" align="left"> – </td><td valign="top" styleCode=" Botrule Rrule" align="left"> – </td><td valign="top" styleCode=" Botrule Rrule" align="left"> – </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 1 (deep sleep) </td></tr></tbody></table> <table ID="ID139" width="588" styleCode="Noautorules"><caption/><col width="70"/><col width="102"/><col width="76"/><col width="85"/><col width="76"/><col width="85"/><col width="95"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"> <content styleCode="bold"> Study</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Loading Infusion</content> <content styleCode="bold"> Treatment Arm</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Number</content> <content styleCode="bold"> of Patients</content> <content styleCode="bold"> Enrolled<sup>a</sup></content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> % Not</content> <content styleCode="bold"> Requiring</content> <content styleCode="bold"> Midazolam</content> <content styleCode="bold"> Rescue</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Confidence<sup>b</sup></content> <content styleCode="bold"> Interval on</content> <content styleCode="bold"> the Difference</content> <content styleCode="bold"> vs.
olam</content> <content styleCode="bold"> Rescue</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Confidence<sup>b</sup></content> <content styleCode="bold"> Interval on</content> <content styleCode="bold"> the Difference</content> <content styleCode="bold"> vs. Placebo</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Mean (SD)</content> <content styleCode="bold"> Total Dose (mg)</content> <content styleCode="bold"> of Rescue</content> <content styleCode="bold"> Midazolam</content> <content styleCode="bold"> Required</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"> <content styleCode="bold"> Confidence<sup>b</sup></content> <content styleCode="bold"> Intervals of</content> <content styleCode="bold"> the Mean</content> <content styleCode="bold"> Rescue Dose</content> </td></tr><tr><td rowspan="3" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Study 1</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Dexmedetomidine 0.5 mcg/kg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 134 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 40 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 37 (27, 48) </td><td valign="top" styleCode=" Botrule Rrule" align="right"> 1.4 (1.7) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -2.7 (-3.4, -2.0) </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="left"> Dexmedetomidine 1 mcg/kg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 129 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 54 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 51 (40, 62) </td><td valign="top" styleCode=" Botrule Rrule" align="right"> 0.9 (1.5) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -3.1 (-3.8, -2.5) </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="left"> Placebo </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 63 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 3 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> – </td><td valign="top" styleCode=" Botrule Rrule" align="right"> 4.1 (3.0) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> – </td></tr><tr><td rowspan="2" valign="top" styleCode="Lrule Botrule Rrule" align="left"><content styleCode="bold"> Study 2</content> </td><td valign="top" styleCode=" Botrule Rrule" align="left"> Dexmedetomidine 1 mcg/kg </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 55 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 53 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 39 (20, 57) </td><td valign="top" styleCode=" Botrule Rrule" align="right"> 1.1 (1.5) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> -1.8 (-2.7, -0.9) </td></tr><tr><td valign="top" styleCode=" Botrule Rrule" align="left"> Placebo </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 50 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> 14 </td><td valign="top" styleCode=" Botrule Rrule" align="center"> – </td><td valign="top" styleCode=" Botrule Rrule" align="right"> 2.9 (3.0) </td><td valign="top" styleCode=" Botrule Rrule" align="center"> – </td></tr></tbody></table>
16 HOW SUPPLIED/STORAGE AND HANDLING Dexmedetomidine Injection, USP is clear and colorless, and is available in a 100 mcg/mL strength in clear glass, multiple-dose vials as follows: NDC No. Strength Package 700069- 758 -04 400 mcg/4 mL (100 mcg/mL) 4 vials/carton 700069- 759 -04 1000 mcg/10 mL(100 mcg/mL) 4 vials/carton Store vials at 20℃ to 25°C (68℉ to 77°F); excursions permitted 15℃ to 30°C (59℉ to 86°F) [see USP Controlled Room Temperature]. Protect from light.
<table ID="ID143" width="444" styleCode="Noautorules"><caption/><col width="123"/><col width="217"/><col width="104"/><tbody><tr><td valign="top" styleCode="Lrule Toprule Botrule Rrule" align="left"><content styleCode="bold"> NDC No.</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Strength</content> </td><td valign="top" styleCode=" Toprule Botrule Rrule" align="left"><content styleCode="bold"> Package</content> </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 700069-<content styleCode="bold"> 758</content> -04 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 400 mcg/4 mL (100 mcg/mL) </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 4 vials/carton </td></tr><tr><td valign="top" styleCode="Lrule Botrule Rrule" align="left"> 700069-<content styleCode="bold"> 759</content> -04 </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 1000 mcg/10 mL(100 mcg/mL) </td><td valign="top" styleCode=" Botrule Rrule" align="left"> 4 vials/carton </td></tr></tbody></table>
17 PATIENT COUNSELING INFORMATION Dexmedetomidine is indicated for short-term intravenous sedation. Dosage must be individualized and titrated to the desired clinical effect. Blood pressure, heart rate and oxygen levels will be monitored both continuously during the infusion of dexmedetomidine and as clinically appropriate after discontinuation. When dexmedetomidine is infused for more than 6 hours, patients should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours. Additionally, patients should be informed to report symptoms that may occur within 48 hours after the administration of dexmedetomidine injection such as: weakness, confusion, excessive sweating, weight loss, abdominal pain, salt cravings, diarrhea, constipation, dizziness or light-headedness. Advise breastfeeding mothers who were exposed to dexmedetomidine to monitor breastfed neonates for irritability [see Use in Specific Populations (8.2)] .