1.1 Intensive Care Unit Sedation

Dexmedetomidine HCl in 0.9% sodium chloride injection is indicated for sedation of initially intubated and mechanically ventilated 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 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 patients prior to and/or during surgical and other procedures.

2.1 Dosing Guidelines

• 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 Dosage Information

2.3 Dosage Adjustment

Due to possible pharmacodynamic interactions, a reduction in dosage of dexmedetomidine HCl 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 (5.7), 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 HCl 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.

Dexmedetomidine HCl in 0.9% sodium chloride injection, 80 mcg/20 mL (4 mcg/mL), 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL)

Dexmedetomidine HCl 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 are necessary.

2.5 Administration of Other Fluids

Dexmedetomidine HCl 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 HCl in 0.9% sodium chloride injection has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam.

Dexmedetomidine HCl 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 HCl in 0.9% sodium chloride injection to some types of natural rubber. Although dexmedetomidine HCl 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.

Dexmedetomidine HCl in 0.9% sodium chloride injection is clear and colorless and is available as follows:

Dexmedetomidine HCl in 0.9% sodium chloride injection, 80 mcg dexmedetomidine/20 mL (4 mcg/mL) dexmedetomidine in a glass vial. Ready to use.

Dexmedetomidine HCl in 0.9% sodium chloride injection, 200 mcg dexmedetomidine/50 mL (4 mcg/mL) dexmedetomidine in a glass bottle. Ready to use.

Dexmedetomidine HCl in 0.9% sodium chloride injection, 400 mcg dexmedetomidine/100 mL (4 mcg/mL) dexmedetomidine in a glass bottle. Ready to use.

5.1 Drug Administration

Dexmedetomidine HCl 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 HCl in 0.9% sodium chloride injection, patients should be continuously monitored while receiving dexmedetomidine HCl 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 HCl in 0.9% sodium chloride injection 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 HCl in 0.9% sodium chloride injection infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine HCl 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 HCl in 0.9% sodium chloride injection 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 HCl in 0.9% sodium chloride injection-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.

Caution should be exercised when administering dexmedetomidine HCl in 0.9% sodium chloride injection to patients with advanced heart block and/or severe ventricular dysfunction. Because dexmedetomidine HCl in 0.9% sodium chloride injection 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 HCl 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 HCl 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 HCl 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 HCl 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

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 Hepatic Impairment

Since dexmedetomidine HCl in 0.9% sodium chloride injection 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)].

6.1 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 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 patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia, and dry mouth.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of dexmedetomidine HCl 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 HCl in 0.9% sodium chloride injection during post approval use of the drug.

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.

8.1 Pregnancy

8.2 Labor and Delivery

The safety of dexmedetomidine HCl in 0.9% sodium chloride injection 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 HCl in 0.9% sodium chloride injection is administered to a nursing woman.

8.4 Pediatric Use

Safety and efficacy have not been established for Procedural or ICU Sedation in pediatric patients. 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 HCl in 0.9% sodium chloride injection for this patient population. The use of dexmedetomidine HCl in 0.9% sodium chloride injection for procedural sedation in pediatric patients has not been evaluated.

8.5 Geriatric Use

8.6 Hepatic Impairment

Since dexmedetomidine HCl in 0.9% sodium chloride injection 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) and Clinical Pharmacology (12.3)].

9.1 Controlled Substance

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection (dexmedetomidine hydrochloride) is not a controlled substance.

9.3 Dependence

The dependence potential of dexmedetomidine HCl in 0.9% sodium chloride injection has not been studied in humans. However, since studies in rodents and primates have demonstrated that dexmedetomidine HCl in 0.9% sodium chloride injection exhibits pharmacologic actions similar to those of clonidine, it is possible that dexmedetomidine HCl in 0.9% sodium chloride injection may produce a clonidine-like withdrawal syndrome upon abrupt discontinuation [see Warnings and Precautions (5.5)].

12.1 Mechanism of Action

Dexmedetomidine HCl in 0.9% sodium chloride injection is a relatively selective alpha2-adrenergic agonist with sedative properties. Alpha2 selectivity is observed in animals following slow intravenous infusion of low and medium doses (10–300 mcg/kg). Both alpha1 and alpha2 activity is observed following slow intravenous infusion of high doses (≥1000 mcg/kg) or with rapid intravenous administration.

12.2 Pharmacodynamics

In a study in healthy volunteers (N = 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when dexmedetomidine HCl in 0.9% sodium chloride 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, dexmedetomidine exhibits the following pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (t1/2) of approximately 6 minutes; a terminal elimination half-life (t1/2) of approximately 2 hours; and steady-state volume of distribution (Vss) 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 by intravenous infusion for up to 24 hours. Table 8 shows the main pharmacokinetic parameters when dexmedetomidine HCl 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.

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 after dexmedetomidine HCl 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 HCl in 0.9% sodium chloride injection maintenance dosing for < 24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

14.1 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 HCl 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 HCl 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 9.

In the first study, 175 adult patients were randomized to receive placebo and 178 to receive dexmedetomidine HCl 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 HCl in 0.9% sodium chloride injection (see Table 10).

A second prospective primary analysis assessed the sedative effects of dexmedetomidine HCl in 0.9% sodium chloride injection by comparing the percentage of patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of patients in the dexmedetomidine HCl in 0.9% sodium chloride injection group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 10).

A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the dexmedetomidine HCl in 0.9% sodium chloride injection and placebo groups. On average, dexmedetomidine HCl 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 HCl 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 HCl 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.

Patients randomized to placebo received significantly more propofol than patients randomized to dexmedetomidine HCl in 0.9% sodium chloride injection (see Table 11).

A significantly greater percentage of patients in the dexmedetomidine HCl 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 11).

A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the dexmedetomidine HCl in 0.9% sodium chloride injection and placebo groups. On average, dexmedetomidine HCl 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 HCl 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 HCl in 0.9% sodium chloride injection was compared to midazolam for ICU sedation exceeding 24 hours duration. Dexmedetomidine HCl 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 HCl 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

The safety and efficacy of dexmedetomidine HCl in 0.9% sodium chloride injection for sedation of non-intubated 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 HCl in 0.9% sodium chloride injection in patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated dexmedetomidine HCl in 0.9% sodium chloride injection in patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.

In Study 1, the sedative properties of dexmedetomidine HCl in 0.9% sodium chloride injection were evaluated by comparing the percent of 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).

Patients were randomized to receive a loading infusion of either dexmedetomidine HCl in 0.9% sodium chloride injection 1 mcg/kg, dexmedetomidine HCl 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). 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 HCl in 0.9% sodium chloride injection and comparator groups. Efficacy results showed that dexmedetomidine HCl 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 13).

In Study 2, the sedative properties of dexmedetomidine HCl in 0.9% sodium chloride injection were evaluated by comparing the percent of patients requiring rescue midazolam to achieve or maintain a specified level of sedation using the Ramsay Sedation Scale score ≥2 (see Table 9). Patients were randomized to receive a loading infusion of dexmedetomidine HCl 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. 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 HCl in 0.9% sodium chloride injection and comparator groups. For efficacy results see Table 13.

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.

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].