DEXMEDETOMIDINE HCL

Dexmedetomidine hydrochloride Injection is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine and is chemically described as 4-[( S )-a,2,3-trimethylbenzyl]imidazole monohydrochloride. Dexmedetomidine hydrochloride has a molecular weight of 236.74 and the molecular formula is C 13 H 16 N 2 • HCl and the structural formula is: Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89. Dexmedetomidine hydrochloride is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7.0. Each mL contains 118 mcg of dexmedetomidine hydrochloride equivalent to 100 mcg (0.1 mg) of dexmedetomidine and 9 mg of sodium chloride in water and is to be used after dilution. The solution is preservative-free and contains no additives or chemical stabilizers. Structural Formula

Dexmedetomidine hydrochloride injection is a relatively selective alpha 2 -adrenergic agonist indicated for: Sedation of non-intubated patients prior to and/or during surgical and other procedures. (1.1) 1.1 Procedural Sedation Dexmedetomidine hydrochloride injection is indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures.

Individualize and titrate dexmedetomidine hydrochloride injection dosing to desired clinical effect. (2.1) Administer dexmedetomidine hydrochloride injection using a controlled infusion device. (2.1) Dilute the 200 mcg/2mL (100 mcg/mL) vial contents in 0.9% sodium chloride solution to achieve required concentration (4 mcg/mL) prior to administration. (2.4) For Adult Procedural Sedation: Generally 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 Dosing Guidelines Dexmedetomidine hydrochloride injection dosing should be individualized and titrated to desired clinical response. Dexmedetomidine hydrochloride injection is not indicated for infusions lasting longer than 24 hours. Dexmedetomidine hydrochloride injection should be administered using a controlled infusion device. 2.2 Dosage Information Table 1: Dosage Information INDICATION DOSAGE AND ADMINISTRATION 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: a dose reduction should be considered [ 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 . The rate of the maintenance infusion should be adjusted 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: a dose reduction should be considered [ see Use in Specific Populations (8.5) ] . For adult patients with impaired hepatic function: a dose reduction should be considered [ 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 hydrochloride 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 (5.7), 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 injection. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Dexmedetomidine Hydrochloride Injection, 200 mcg/2 mL (100 mcg/mL) Dexmedetomidine hydrochloride injection must be diluted in 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 infusion, withdraw 2 mL of dexmedetomidine hydrochloride injection and add to 48 mL of 0.9% sodium chloride injection to a total of 50 mL. Shake gently to mix well. 2.5 Administration with Other Fluids Dexmedetomidine hydrochloride 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 injection has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam. Dexmedetomidine hydrochloride 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 injection to some types of natural rubber. Although dexmedetomidine hydrochloride injection is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.

None None. (4)

The most common adverse reactions (incidence greater than 2%) are hypotension, bradycardia, and dry mouth. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact West-Ward Pharmaceuticals Corp. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Studies 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 clinical trials of another drug and may not reflect the rates observed in practice. Use of dexmedetomidine hydrochloride has been associated with the following serious adverse reactions: Hypotension, bradycardia and sinus arrest [see Warnings and Precautions (5.2 )] Transient hypertension [see Warnings and Precautions (5.3 )] Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in procedural sedation studies include hypotension, bradycardia and dry mouth. Procedural Sedation Adverse reaction information is derived from the two trials for procedural sedation [ see Clinical Studies (14.1)] in which 318 adult patients received dexmedetomidine hydrochloride. 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 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 )] . 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 and comparator groups in both studies. Table 2. Adverse Reactions With an Incidence >2%— Procedural Sedation Population Adverse Event Dexmedetomidine hydrochloride 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. 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of dexmedetomidine hydrochloride. 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 during post approval use of the drug. Table 3: 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 Surgical and Medical Procedures Light anesthesia Vascular Disorders Blood pressure fluctuation, hemorrhage, hypertension, hypotension

Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine hydrochloride or the concomitant medication may be required. (7.1) 7.1 Anesthetics, Sedatives, Hypnotics, Opioids Co-administration of dexmedetomidine hydrochloride with anesthetics, sedatives, hypnotics, and opioids is likely to lead to an enhancement of effects. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions between dexmedetomidine hydrochloride and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with dexmedetomidine hydrochloride, a reduction in dosage of dexmedetomidine hydrochloride 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 for 45 minutes at a plasma concentration of 1 ng/mL resulted in no clinically meaningful increases in the magnitude of neuromuscular blockade associated with rocuronium administration.