Dexmedetomidine HCl

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION 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 p …

3 DOSAGE FORMS AND STRENGTHS Dexmedetomidine hydrochloride injection, 200 mcg/2 mL (100 mcg/mL) in a glass vial. To be used after dilution. Dexmedetomidine Hydrochloride Injection 200 mcg/2 mL (100 mcg/mL) in a glass vial. To be used after dilution. (3)

4 CONTRAINDICATIONS None None. (4)

6 ADVERSE REACTIONS 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 25% decrease from baseline 3 Bradycardia was defined in absolute and relative terms as 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, hyperbilirubin …

7 DRUG INTERACTIONS 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.

8 USE IN SPECIFIC POPULATIONS Geriatric patients: Dose reduction should be considered ( 2.2 , 2.3 , 5.1 , 8.5 ) Hepatic Impairment: Dose reduction should be considered (2.1 , 2.2 , 2.3 , 5.7 , 8.6 ) Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ) Nursing Mothers: Caution should be exercised when administered to a nursing woman ( 8.3 ) See 17 for PATIENT COUNSELING INFORMATION. Revised:05/2017 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of dexmedetomidine hydrochloride use in pregnant women. In an in vitro human placenta study, placental transfer of dexmedetomidine occurred. In a study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously. Thus, fetal exposure should be expected in humans, and dexmedetomidine hydrochloride should be used during pregnancy only if the potential benefits justify the potential risk to the fetus. Teratogenic effects were not observed in rats following subcutaneous administration of dexmedetomidine during the period of fetal organogenesis (from gestation day 5 to 16) with doses up to 200 mcg/kg (representing a dose approximately equal to the maximum recommended human intravenous dose based on body surface area) or in rabbits following intravenous administration of dexmedetomidine during the period of fetal organogenesis (from gestation day 6 to 18) with doses up to 96 mcg/kg (representing approximately half the human exposure at the maximum recommended dose based on plasma area under the time-curve comparison). However, fetal toxicity, as evidenced by increased post-implantation losses and reduced live pups, was observed in rats at a subcutaneous dose of 200 mcg/kg. The no-effect dose in rats was 20 mcg/kg (representing a dose less than the maximum recommended human intravenous dose based on a body surface area comparison). In another reproductive toxicity study when dexmedetomidine was administered subcutaneously to pregnant rats at 8 and 32 mcg/kg (representing a dose less than the maximum recommended human intravenous dose based on a body surface area comparison) from gestation day 16 through weaning, lower offspring weights were observed. Additionally, when offspring of the 32 mcg/kg group were allowed to mate, elevated fetal and embryocidal toxicity and delayed motor development was observed in second generation offspring. 8.2 Labor and Delivery The safety of dexmedetomidine hydrochloride during labor and delivery has not been studied. 8.3 Nursing Mothers It is not known whether dexmedetomidine hydrochloride is excreted in human milk. Radio-labeled dexmedetomidine administered subcutaneously to lactating female rats was excreted in milk. Because many drugs are excreted in human milk, caution should be exercised when dexmedetomidine hydrochloride is administered to a nursing woman. 8.4 Pediatric Use Safety and efficacy have not been established for Procedural Sedation in pediatric patients. The use of dexmedetomidine for procedural sedation in pediatric patients has not been evaluated. 8.5 Geriatric Use 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 hydrochloride-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 hydrochloride 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 ) and Clinical Pharmacology (12.3)].

12.1 Mechanism of Action Dexmedetomidine hydrochloride is a relatively selective 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 (≥1000 mcg/kg) or with rapid intravenous administration.

11 DESCRIPTION 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

10 OVERDOSAGE The tolerability of dexmedetomidine hydrochloride 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. One patient who received a loading bolus dose of undiluted dexmedetomidine hydrochloride (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.

16 HOW SUPPLIED/STORAGE AND HANDLING Dexmedetomidine Hydrochloride Injection is available as: NDC 0143-9532-25 - 200 mcg/2 mL (100 mcg/mL) in 2 mL clear glass vial, carton of 25. The strength is based on the dexmedetomidine base. Vials are intended for single use only. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].