Dexmedetomidine Hydrochloride in Sodium Chloride

1. INDICATIONS AND USAGE Dexmedetomidine hydrochloride (HCl) 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 HCl 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 HCl 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 HCl in 0.9% sodium chloride injection should be administered by continuous infusion not to exceed 24 hours. Dexmedetomidine HCl 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 HCl in 0.9% sodium chloride injection prior to extubation. 1.2. Procedural Sedation Dexmedetomidine HCl 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 PRECEDEXTM (dexmedetomidine hydrochloride) injection and PRECEDEXTM (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 HCl in 0.9% sodium chloride injection dosing to desired clinical effect. ( 2.1 ) Administer dexmedetomidine HCl in 0.9% sodium chloride injection using a controlled infusion device. ( 2.1 ) The 80 mcg/20 mL single-dose vial, 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 ) Alternative Doses: Recommended for patients over 65 years of age and awake fiberoptic intubation patients. ( 2.2 ) 2.1. Administration Instructions Dexmedetomidine HCl in 0.9% sodium chloride injection dosing should be individualized and titrated to desired clinical response. Dexmedetomidine HCl in 0.9% sodium chloride injection is not indicated for infusions lasting longer than 24 hours. Dexmedetomidine HCl 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. 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 PRECEDEXTM (dexmedetomidine hydrochloride) injection and PRECEDEXTM (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. Dosa …

3. DOSAGE FORMS AND STRENGTHS Dexmedetomidine HCl in 0.9% sodium chloride injection is a clear and colorless solution, ready to use. It is available as: Dexmedetomidine HCl in 0.9% sodium chloride injection 80 mcg/20 mL (4 mcg/mL) single-dose glass vial. Dexmedetomidine HCl in 0.9% sodium chloride injection 200 mcg/50 mL (4 mcg/mL) single-dose glass bottle. Dexmedetomidine HCl in 0.9% sodium chloride injection 400 mcg/100 mL (4 mcg/mL) single-dose glass bottle. Dexmedetomidine HCl in 0.9% sodium chloride injection 80 mcg/20 mL (4 mcg/mL) in a single-dose glass vial. Ready to use. ( 3 ) Dexmedetomidine HCl in 0.9% sodium chloride injection 200 mcg/50 mL (4 mcg/mL) in a single-dose glass bottle. Ready to use. ( 3 ) Dexmedetomidine HCl in 0.9% sodium chloride injection 400 mcg/100 mL (4 mcg/mL) in a single-dose glass bottle. Ready to use. ( 3 )

4. CONTRAINDICATIONS None. None. ( 4 )

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 Precision Dose, Inc. at 1-844-668-3942, 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 HCl in 0.9% sodium chloride injection for sedation in the Intensive Care Unit setting in which 1,007 adult patients received dexmedetomidine HCl 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 1% Of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion 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 dexmedetomidine HCl 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 HCl in 0.9% Sodium Chloride Injection Group Dexmedetomidine HCl in 0.9% sodium chloride injection (mcg/kg/hr) Adverse Event ≤0.7 Average maintenance dose over the entire study drug administration. (N = 95) >0.7 to ≤1.1 (N = 78) >1.1 (N = 71) Constipation 6% 5% 14% Agitation 5% 8% 14% Anxiety 5% 5% 9% Edema Peripheral 3% 5% 7% Atrial Fibrillation 2% 4% 9% Respiratory Failure 2% 6% 10% Acute Respiratory Distress Syndrome 1% 3% 9% Adult Procedural Sedation Adverse reaction information is derived from the two trials for adult procedural sedation [ see Clinical Studies (14.2) ] in which 318 adult patients received dexmedetomidine HCl in 0.9% sodium chloride injection. The mean total dose was 1.6 mcg/kg (range: 0 …

7. DRUG INTERACTIONS Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine HCl 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 HCl 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 HCl in 0.9% sodium chloride injection and isoflurane, propofol, alfentanil, and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with dexmedetomidine HCl in 0.9% sodium chloride injection, a reduction in dosage of dexmedetomidine HCl 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 HCl 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 PRECEDEXTM (dexmedetomidine hydrochloride) injection and PRECEDEXTM (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 2-4% 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. 8.2. Lactation Risk Summary Available published literature reports the presence of dexmedetomidine in human milk following intravenou …

12.1. Mechanism of Action Dexmedetomidine HCl 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 (10–300 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.

11. DESCRIPTION Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a sterile, nonpyrogenic ready to use solution suitable for intravenous infusion. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole monohydrochloride. Dexmedetomidine HCl in 0.9% sodium chloride injection has a molecular weight of 236.7 and the empirical formula is C 13 H 16 N 2 ∙ HCl and the structural formula is: Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89. Dexmedetomidine HCl in 0.9% sodium chloride injection 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 (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. Chemical Structure

10. OVERDOSAGE The tolerability of dexmedetomidine HCl 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 HCl 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 HCl in 0.9% sodium chloride injection (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.

16. HOW SUPPLIED/STORAGE AND HANDLING Dexmedetomidine HCl in 0.9% sodium chloride injection Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is clear and colorless, and available as 80 mcg/20 mL (4 mcg/mL), 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL) in 20 mL clear glass vials, 50 mL, and 100 mL clear glass bottles, respectively. The strength is based on the dexmedetomidine base. Containers are intended for single-dose only. Discard unused portion. Unit of Sale Concentration NDC 68094-047-10 Carton of 10 single-dose clear glass vials 80mcg/20mL (4mcg/mL) NDC 68094-147-10 Carton of 20 single-dose clear glass bottles 200mcg/50mL (4mcg/mL) NDC 68094-247-10 Carton of 10 single-dose clear glass bottles 400mcg/100mL (4mcg/mL) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°C) [See USP Controlled Room Temperature].