These Highlights Do Not Include All The Information Needed To Use Dexmedetomidine Hydrochloride In 0.9% Sodium Chloride Injection Safely And Effectively. See Full Prescribing Information For Dexmedetomidine Hydrochloride In 0.9% Sodium Chloride Injection.

Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection

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

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

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

PACKAGE LABEL - PRINCIPAL DISPLAY - DEXMEDETOMIDINE HCl 20 mL Single-Dose Vial Label

NDC 63323-671-02        671020

Dexmedetomidine HCl

in 0.9% Sodium Chloride Injection

80 mcg per 20 mL*

(4 mcg per mL)*

For intravenous infusion.

Preservative free.

20 mL

Single-Dose Vial                Rx only

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.

Five adult patients received an overdose of dexmedetomidine hydrochloride 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 hydrochloride (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a sterile, nonpyrogenic, ready to use solution suitable for intravenous infusion. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection contains dexmedetomidine hydrocholoride as the active pharmaceutical ingredient Dexmedetomidine hydrochloride is a central alpha₂-adrenergic agonist. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H- imidazole monohydrochloride, 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 in 0.9% sodium chloride injection is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7.0. Each mL contains 4.72 mcg of dexmedetomidine hydrochloride equivalent to 4 mcg (0.004 mg) of dexmedetomidine, 9 mg sodium chloride, 119.4 mcg of sodium acetate trihydrate and 5.4 mcg of acetic acid in water and is ready to be used. The solution is preservative-free.

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

Some patients receiving dexmedetomidine hydrochloride 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.

Sedation for Non-Invasive Procedures

The safety and effectiveness of Dexmedetomidine Injection have not been established in pediatric patients less than 1 month of age.

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.

ICU Sedation

The safety and efficacy of Dexmedetomidine Injection have not been established in pediatric patients for ICU sedation. 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 Injection for these patient populations.

The safety and efficacy of dexmedetomidine hydrochloride has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1,185 adult patients.

None.

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)]

Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine hydrochloride or the concomitant medication may be required. (7.1)

In a study in healthy adult volunteers (N = 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when dexmedetomidine hydrochloride was administered by intravenous infusion at doses within the recommended dose range (0.2-0.7 mcg/kg/hr).

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 to 0.7 mcg/kg/hr when administered to adults by intravenous infusion for up to 24 hours. Table 10 shows the main pharmacokinetic parameters when dexmedetomidine hydrochloride 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 in adults after dexmedetomidine hydrochloride maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetic (PK) parameters after dexmedetomidine hydrochloride maintenance dosing for <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.

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)].

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.

Since dexmedetomidine hydrochloride 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)].

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, 2.3), Clinical Pharmacology (12.3)].

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a alpha₂-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 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)

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.

Dexmedetomidine hydrochloride 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 hydrochloride, patients should be continuously monitored while receiving dexmedetomidine hydrochloride.

Dexmedetomidine hydrochloride is a relatively selective centrally acting 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 (≥1,000 mcg/kg) or with rapid intravenous administration.

Dexmedetomidine hydrochloride is not a controlled substance.

• Monitoring: Continuously monitor patients while receiving dexmedetomidine hydrochloride. (5.1)
• Bradycardia and Sinus Arrest: Have occurred in young healthy volunteers with high vagal tone or with different routes of administration, e.g., rapid intravenous or bolus administration. (5.2)
• Hypotension and Bradycardia: May necessitate medical intervention. May be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension, and in the elderly. Use with caution in patients with advanced heart block or severe ventricular dysfunction. (5.2)
• Co-administration with Other Vasodilators or Negative Chronotropic Agents: Use with caution due to additive pharmacodynamic effects. (5.2)
• Transient Hypertension: Observed primarily during the loading dose. Consider reduction in loading infusion rate. (5.3)
• Arousability: Patients can become aroused/alert with stimulation; this alone should not be considered as lack of efficacy. (5.4)
• Tolerance and Tachyphylaxis: Prolonged exposure to dexmedetomidine beyond 24 hours may be associated with tolerance and tachyphylaxis and a dose-related increase in adverse events. (5.6)

Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of dexmedetomidine hydrochloride. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable.

In one study of 10 healthy adult volunteers, administration of dexmedetomidine hydrochloride 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.

• 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/20 mL single-dose vial, and 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)

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/20 mL (4 mcg/mL), 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/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.

Dexmedetomidine hydrochloride may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue dexmedetomidine hydrochloride if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes.

Dexmedetomidine Hydrochloride is clear and colorless and is available as follows.

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.

• 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 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.

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.

• 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.

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)].

Dexmedetomidine hydrochloride in 0.9% sodium chloride 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 should be administered by continuous infusion not to exceed 24 hours.

Dexmedetomidine hydrochloride in 0.9% sodium chloride 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 prior to extubation.

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 hydrochloride 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 hydrochloride 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 12.

In the first study, 175 adult patients were randomized to receive placebo and 178 to receive dexmedetomidine hydrochloride 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 hydrochloride (see Table 13).

A second prospective primary analysis assessed the sedative effects of dexmedetomidine hydrochloride by comparing the percentage of adult patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of adult patients in the dexmedetomidine hydrochloride group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 13).

A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine hydrochloride and placebo groups. On average, dexmedetomidine hydrochloride -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 hydrochloride 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 hydrochloride 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.

Adult patients randomized to placebo received significantly more propofol than adult patients randomized to dexmedetomidine hydrochloride (see Table 14).

A significantly greater percentage of adult patients in the dexmedetomidine hydrochloride group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see Table 14).

A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine hydrochloride and placebo groups. On average, dexmedetomidine hydrochloride-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 hydrochloride patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.

In a controlled clinical trial, dexmedetomidine hydrochloride was compared to midazolam for ICU sedation exceeding 24 hours duration. Dexmedetomidine hydrochloride 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 hydrochloride for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [see Adverse Reactions (6.1)].

Dexmedetomidine hydrochloride is indicated for short-term intravenous sedation. Dosage must be individualized and titrated to the desired clinical effect. Blood pressure, heart rate and oxygen levels will be monitored both continuously during the infusion of dexmedetomidine hydrochloride and as clinically appropriate after discontinuation.

• When dexmedetomidine hydrochloride is infused for more than 6 hours, patients should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours.
• Additionally, patients should be informed to report symptoms that may occur within 48 hours after the administration of dexmedetomidine hydrochloride such as: weakness, confusion, excessive sweating, weight loss, abdominal pain, salt cravings, diarrhea, constipation, dizziness or light- headedness.
• Advise breastfeeding mothers who were exposed to dexmedetomidine hydrochloride to monitor breastfed neonates for irritability [see Use in Specific Populations (8.2)].

Lake Zurich, IL 60047

www.fresenius-kabi.com/us

Package Insert Part Number Pending

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is available as:

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]

The container closure is not made with natural rubber latex.

Discard unused portion. Do not freeze.

Do not used if product is discolored or if precipitate matter is present.

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/mL magnesium sulfate solution
• 0.3% potassium chloride solution

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.

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.

Clinically significant episodes of bradycardia and sinus arrest have been reported with dexmedetomidine hydrochloride 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 hydrochloride infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine hydrochloride, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because dexmedetomidine hydrochloride 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-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.

Caution should be exercised when administering dexmedetomidine hydrochloride to patients with advanced heart block and/or severe ventricular dysfunction. Because dexmedetomidine hydrochloride 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 hydrochloride an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine hydrochloride.

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.

Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection

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

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

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

PACKAGE LABEL - PRINCIPAL DISPLAY - DEXMEDETOMIDINE HCl 20 mL Single-Dose Vial Label

NDC 63323-671-02        671020

Dexmedetomidine HCl

in 0.9% Sodium Chloride Injection

80 mcg per 20 mL*

(4 mcg per mL)*

For intravenous infusion.

Preservative free.

20 mL

Single-Dose Vial                Rx only

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.

Five adult patients received an overdose of dexmedetomidine hydrochloride 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 hydrochloride (19.4 mcg/kg), had cardiac arrest from which he was successfully resuscitated.

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a sterile, nonpyrogenic, ready to use solution suitable for intravenous infusion. Dexmedetomidine hydrochloride in 0.9% sodium chloride injection contains dexmedetomidine hydrocholoride as the active pharmaceutical ingredient Dexmedetomidine hydrochloride is a central alpha₂-adrenergic agonist. Dexmedetomidine hydrochloride is the S-enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2,3-dimethylphenyl)ethyl]-1H- imidazole monohydrochloride, 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 in 0.9% sodium chloride injection is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7.0. Each mL contains 4.72 mcg of dexmedetomidine hydrochloride equivalent to 4 mcg (0.004 mg) of dexmedetomidine, 9 mg sodium chloride, 119.4 mcg of sodium acetate trihydrate and 5.4 mcg of acetic acid in water and is ready to be used. The solution is preservative-free.

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

Some patients receiving dexmedetomidine hydrochloride 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.

Sedation for Non-Invasive Procedures

The safety and effectiveness of Dexmedetomidine Injection have not been established in pediatric patients less than 1 month of age.

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.

ICU Sedation

The safety and efficacy of Dexmedetomidine Injection have not been established in pediatric patients for ICU sedation. 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 Injection for these patient populations.

The safety and efficacy of dexmedetomidine hydrochloride has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1,185 adult patients.

None.

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)]

Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine hydrochloride or the concomitant medication may be required. (7.1)

In a study in healthy adult volunteers (N = 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when dexmedetomidine hydrochloride was administered by intravenous infusion at doses within the recommended dose range (0.2-0.7 mcg/kg/hr).

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 to 0.7 mcg/kg/hr when administered to adults by intravenous infusion for up to 24 hours. Table 10 shows the main pharmacokinetic parameters when dexmedetomidine hydrochloride 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 in adults after dexmedetomidine hydrochloride maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the pharmacokinetic (PK) parameters after dexmedetomidine hydrochloride maintenance dosing for <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.

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)].

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.

Since dexmedetomidine hydrochloride 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)].

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, 2.3), Clinical Pharmacology (12.3)].

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is a alpha₂-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 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)

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.

Dexmedetomidine hydrochloride 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 hydrochloride, patients should be continuously monitored while receiving dexmedetomidine hydrochloride.

Dexmedetomidine hydrochloride is a relatively selective centrally acting 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 (≥1,000 mcg/kg) or with rapid intravenous administration.

Dexmedetomidine hydrochloride is not a controlled substance.

• Monitoring: Continuously monitor patients while receiving dexmedetomidine hydrochloride. (5.1)
• Bradycardia and Sinus Arrest: Have occurred in young healthy volunteers with high vagal tone or with different routes of administration, e.g., rapid intravenous or bolus administration. (5.2)
• Hypotension and Bradycardia: May necessitate medical intervention. May be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension, and in the elderly. Use with caution in patients with advanced heart block or severe ventricular dysfunction. (5.2)
• Co-administration with Other Vasodilators or Negative Chronotropic Agents: Use with caution due to additive pharmacodynamic effects. (5.2)
• Transient Hypertension: Observed primarily during the loading dose. Consider reduction in loading infusion rate. (5.3)
• Arousability: Patients can become aroused/alert with stimulation; this alone should not be considered as lack of efficacy. (5.4)
• Tolerance and Tachyphylaxis: Prolonged exposure to dexmedetomidine beyond 24 hours may be associated with tolerance and tachyphylaxis and a dose-related increase in adverse events. (5.6)

Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of dexmedetomidine hydrochloride. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable.

In one study of 10 healthy adult volunteers, administration of dexmedetomidine hydrochloride 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.

• 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/20 mL single-dose vial, and 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)

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/20 mL (4 mcg/mL), 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/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.

Dexmedetomidine hydrochloride may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such as administration of cooled intravenous fluids and antipyretic medications. Discontinue dexmedetomidine hydrochloride if drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes.

Dexmedetomidine Hydrochloride is clear and colorless and is available as follows.

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.

• 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 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.

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.

• 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.

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)].

Dexmedetomidine hydrochloride in 0.9% sodium chloride 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 should be administered by continuous infusion not to exceed 24 hours.

Dexmedetomidine hydrochloride in 0.9% sodium chloride 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 prior to extubation.

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 hydrochloride 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 hydrochloride 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 12.

In the first study, 175 adult patients were randomized to receive placebo and 178 to receive dexmedetomidine hydrochloride 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 hydrochloride (see Table 13).

A second prospective primary analysis assessed the sedative effects of dexmedetomidine hydrochloride by comparing the percentage of adult patients who achieved a Ramsay sedation score of ≥3 during intubation without the use of additional rescue medication. A significantly greater percentage of adult patients in the dexmedetomidine hydrochloride group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 13).

A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine hydrochloride and placebo groups. On average, dexmedetomidine hydrochloride -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 hydrochloride 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 hydrochloride 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.

Adult patients randomized to placebo received significantly more propofol than adult patients randomized to dexmedetomidine hydrochloride (see Table 14).

A significantly greater percentage of adult patients in the dexmedetomidine hydrochloride group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see Table 14).

A prospective secondary analysis assessed the dose of morphine sulfate administered to adult patients in the dexmedetomidine hydrochloride and placebo groups. On average, dexmedetomidine hydrochloride-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 hydrochloride patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.

In a controlled clinical trial, dexmedetomidine hydrochloride was compared to midazolam for ICU sedation exceeding 24 hours duration. Dexmedetomidine hydrochloride 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 hydrochloride for longer than 24 hours was associated with tolerance, tachyphylaxis, and a dose-related increase in adverse events [see Adverse Reactions (6.1)].

Dexmedetomidine hydrochloride is indicated for short-term intravenous sedation. Dosage must be individualized and titrated to the desired clinical effect. Blood pressure, heart rate and oxygen levels will be monitored both continuously during the infusion of dexmedetomidine hydrochloride and as clinically appropriate after discontinuation.

• When dexmedetomidine hydrochloride is infused for more than 6 hours, patients should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours.
• Additionally, patients should be informed to report symptoms that may occur within 48 hours after the administration of dexmedetomidine hydrochloride such as: weakness, confusion, excessive sweating, weight loss, abdominal pain, salt cravings, diarrhea, constipation, dizziness or light- headedness.
• Advise breastfeeding mothers who were exposed to dexmedetomidine hydrochloride to monitor breastfed neonates for irritability [see Use in Specific Populations (8.2)].

Lake Zurich, IL 60047

www.fresenius-kabi.com/us

Package Insert Part Number Pending

Dexmedetomidine hydrochloride in 0.9% sodium chloride injection is available as:

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature.]

The container closure is not made with natural rubber latex.

Discard unused portion. Do not freeze.

Do not used if product is discolored or if precipitate matter is present.

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/mL magnesium sulfate solution
• 0.3% potassium chloride solution

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.

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.

Clinically significant episodes of bradycardia and sinus arrest have been reported with dexmedetomidine hydrochloride 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 hydrochloride infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine hydrochloride, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because dexmedetomidine hydrochloride 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-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required.

Caution should be exercised when administering dexmedetomidine hydrochloride to patients with advanced heart block and/or severe ventricular dysfunction. Because dexmedetomidine hydrochloride 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 hydrochloride an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine hydrochloride.

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.