Dexmedetomidine Hydrochloride In 0.9% Sodium Chloride

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 80 mcg per 20 mL single-dose vial, 200 mcg per 50 mL, and 400 mcg per 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 mcg/kg/ hour to 0.7 mcg/kg/ hour . (2.2) For Adult Procedural Sedation: Initiate at one mcg/kg over 10 minutes , followed by a maintenance infusion initiated at 0.6 mcg/kg/ hour and titrated to achieve desired clinical effect with doses ranging from 0.2 mcg/kg/ hour to 1 mcg/kg/ hour . (2.2) Alternative Doses: Recommended for patients over 65 years of age and awake fiberoptic intubation patients. (2.2) 2.1 Administration Instructions Dexmedetomidine hydrochloride in 0.9% sodium chloride injection dosing should be individualized and titrated to desired clinical response. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is not indicated for infusions lasting longer than 24 hours. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection should be administered using a controlled infusion device. 2.2 Recommended Dosage Table 1: Recommended Dosage in Adult Patients INDICATION DOSAGE AND ADMINISTRATION Initiation of Intensive Care Unit Sedation For adult patients: a loading infusion of one mcg/kg over 10 minutes . For adult patients being converted from alternate sedative therapy: a loading dose may not be required. For patients over 65 years of age: Consider a dose reduction [ see Use in Specific Populations (8.5) ]. For adult patients with impaired hepatic function: Consider a dose reduction [ see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. Maintenance of Intensive Care Unit Sedation For adult patients: a maintenance infusion of 0.2 mcg/kg/ hour to 0.7 mcg/kg/ hour . The rate of the maintenance infusion should be adjusted to achieve the desired level of sedation. For patients over 65 years of age: Consider a dose reduction [ see Use in Specific Populations (8.5) ] . For adult patients with impaired hepatic function: Consider a dose reduction [ see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. Initiation of Procedural Sedation For adult patients: a loading infusion of one mcg/kg over 10 minutes . For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable. For awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes . For patients over 65 years of age: a loading infusion of 0.5 mcg/kg over 10 minutes [ see Use in Specific Populations (8.5) ] . For adult patients with impaired hepatic function: Consider a dose reduction [ see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. Maintenance of Procedural Sedation For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/ hour and titrated to achieve desired clinical effect with doses ranging from 0.2 mcg/kg/ hour to 1 mcg/kg/ hour . Adjust the rate of the maintenance infusion to achieve the targeted level of sedation. For awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/ hour is recommended until the endotracheal tube is secured. For patients over 65 years of age: Consider a dose reduction [ see Use in Specific Populations (8.5) ] . For adult patients with impaired hepatic function: Consider a dose reduction [ see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. 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, 80 mcg per 20 mL (4 mcg per mL), 200 mcg per 50 mL (4 mcg per mL) and 400 mcg per 100 mL (4 mcg per mL) Dexmedetomidine hydrochloride 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 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 per 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.

6 ADVERSE REACTIONS The most common adverse reactions (incidence greater than 2%) in adults are hypotension, bradycardia, and dry mouth. (6.1) Adverse reactions in adults, associated with infusions greater than 24 hours in duration include ARDS, respiratory failure, and agitation. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Most common treatment-emergent adverse reactions, occurring in greater than 2% of adult patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia and dry mouth. Intensive Care Unit Sedation Adverse reaction information is derived from the continuous infusion trials of dexmedetomidine for sedation in the Intensive Care Unit setting in which 1,007 adult patients received dexmedetomidine. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6) 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 greater than 2% are provided in Table 3 . The most frequent adverse reactions were hypotension, bradycardia and dry mouth [ see Warnings and Precautions (5.2) ]. Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of dexmedetomidine for sedation in the surgical intensive care unit setting in which 387 adult patients received dexmedetomidine for less than 24 hours. The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 4 ). Table 4: Treatment-Emergent Adverse Events Occurring in Greater than 1% of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion Less than 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% Less than 1% Thirst 2% Less than 1% In a controlled clinical trial, dexmedetomidine was compared to midazolam for ICU sedation exceeding 24 hours duration in adult patients. Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated adult patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 5 . The number (%) of adult subjects who had a dose-related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the dexmedetomidine group is provided in Table 6 . Table 5: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation Study * Includes any type of hypertension † Hypotension was defined in absolute terms as Systolic blood pressure of less than 80 mmHg or Diastolic blood pressure of less than 50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value ‡ Bradycardia was defined in absolute terms as less than 40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value § Hypertension was defined in absolute terms as Systolic blood pressure greater than 180 mmHg or Diastolic blood pressure of greater than 100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value ¶ Tachycardia was defined in absolute terms as greater than 120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value Adverse Event Dexmedetomidine (N = 244) (%) Midazolam (N = 122) (%) Hypotension† 56% 56% Hypotension Requiring Intervention 28% 27% Bradycardia‡ 42% 19% Bradycardia Requiring Intervention 5% 1% Systolic Hypertension§ 28% 42% Tachycardia¶ 25% 44% Tachycardia Requiring Intervention 10% 10% Diastolic Hypertension§ 12% 15% Hypertension§ 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 and midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%). Table 6: Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Dexmedetomidine Group Dexmedetomidine (mcg/kg/hr) Adverse Event ≤0.7 Average maintenance dose over the entire study drug administration (N = 95) (%) Greater than 0.7 to ≤1.1 (N = 78) (%) Greater than 1.1 (N = 71) (%) Constipation 6% 5% 14% Agitation 5% 8% 14% Anxiety 5% 5% 9% Edema Peripheral 3% 5% 7% Atrial Fibrillation 2% 4% 9% Respiratory Failure 2% 6% 10% Acute Respiratory Distress Syndrome 1% 3% 9% Adult Procedural Sedation Adverse reaction information is derived from the two trials for adult procedural sedation [ see Clinical Studies (14.2) ] in which 318 adult patients received dexmedetomidine. 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 greater than 2% are provided in Table 7 . The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [ see Warnings and Precautions (5.2) ]. Pre-specified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. The decrease in respiratory rate and hypoxia was similar between dexmedetomidine and comparator groups in both studies. Table 7: Adverse Reactions with an Incidence Greater than 2%—Adult Procedural Sedation Population Adverse Event Dexmedetomidine (N = 318) (%) Placebo (N = 113) (%) * Hypotension was defined in absolute and relative terms as Systolic blood pressure of less than 80 mmHg or ≤30% lower than pre-study drug infusion value, or Diastolic blood pressure of less than 50 mmHg † Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) less than 8 beats per minute or greater than 25% decrease from baseline ‡ Bradycardia was defined in absolute and relative terms as less than 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)] . § Hypertension was defined in absolute and relative terms as Systolic blood pressure greater than 180 mmHg or ≥30% higher than pre-study drug infusion value or Diastolic blood pressure of greater than 100 mmHg ¶ Tachycardia was defined in absolute and relative terms as greater than 120 beats per minute or ≥30% greater than pre-study drug infusion value # Hypoxia was defined in absolute and relative terms as SpO 2 less than 90% or 10% decrease from baseline Hypotension * 54% 30% Respiratory Depression † 37% 32% Bradycardia ‡ 14% 4% Hypertension § 13% 24% Tachycardia ¶ 5% 17% Nausea 3% 2% Dry Mouth 3% 1% Hypoxia # 2% 3% Bradypnea 2% 4% table3 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. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypotension and bradycardia were the most common adverse reactions associated with the use of dexmedetomidine during post-approval use of the drug. Table 9: Adverse Reactions Experienced During Post-Approval Use of Dexmedetomidine System Organ Class Preferred Term Blood and Lymphatic System Disorders Anemia Cardiac Disorders Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia Eye Disorders Photopsia, visual impairment Gastrointestinal Disorders Abdominal pain, diarrhea, nausea, vomiting General Disorders and Administration Site Conditions Chills, hyperpyrexia, pain, pyrexia, thirst Hepatobiliary Disorders Hepatic function abnormal, hyperbilirubinemia Investigations Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged Metabolism and Nutrition Disorders Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia 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

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 mcg/kg/hr to 0.7 mcg/kg/hr when administered to adults by intravenous infusion for up to 24 hours. Table 1 0 shows the main pharmacokinetic parameters when dexmedetomidine 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 0.7 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 1.25/0.7 t 1/2 *, hour 1.78 ± 0.3 2.22 ± 0.59 2.23 ± 0.21 2.5 ± 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 99.6 ± 17.8 Avg C ss † , ng/mL 0.27 ± 0.05 0.27 ± 0.05 0.67 ± 0.1 1.37 ± 0.2 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 The loading doses for each of the above indicated groups were 0.5 mcg/kg, 0.5 mcg/kg, 1 mcg/kg and 2.2 mcg/kg, respectively. Dexmedetomidine pharmacokinetic parameters in adults after dexmedetomidine maintenance doses of 0.2 mcg/kg/hr to 1.4 mcg/kg/hr for greater than 24 hours were similar to the pharmacokinetic (PK) parameters after dexmedetomidine maintenance dosing for less than 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. 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 (greater than 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 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: less than 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.