NDC 42023-146 Dexmedetomidine Hydrochloride

Dexmedetomidine Hydrochloride

NDC Product Code 42023-146

NDC 42023-146-25

Package Description: 25 VIAL in 1 CARTON > 2 mL in 1 VIAL

NDC Product Information

Dexmedetomidine Hydrochloride with NDC 42023-146 is a a human prescription drug product labeled by Par Pharmaceutical, Inc.. The generic name of Dexmedetomidine Hydrochloride is dexmedetomidine hydrochloride. The product's dosage form is injection, solution, concentrate and is administered via intravenous form. The RxNorm Crosswalk for this NDC code indicates multiple RxCUI concepts are associated to this product: 1718906, 1718909 and 309710.

Dosage Form: Injection, Solution, Concentrate - A sterile preparation for parenteral use which, upon the addition of suitable solvents, yields a solution conforming in all respects to the requirements for Injections.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Dexmedetomidine Hydrochloride Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SODIUM CHLORIDE (UNII: 451W47IQ8X)
  • WATER (UNII: 059QF0KO0R)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Intravenous - Administration within or into a vein or veins.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Adrenergic alpha2-Agonists - [MoA] (Mechanism of Action)
  • Central alpha-2 Adrenergic Agonist - [EPC] (Established Pharmacologic Class)
  • General Anesthesia - [PE] (Physiologic Effect)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Par Pharmaceutical, Inc.
Labeler Code: 42023
FDA Application Number: ANDA203972 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 08-19-2014 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2022 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

* Please review the disclaimer below.

Dexmedetomidine Hydrochloride Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1 Intensive Care Unit Sedation

Dexmedetomidine hydrochloride injection is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Dexmedetomidine hydrochloride injection should be administered by continuous infusion not to exceed 24 hours. Dexmedetomidine hydrochloride injection has been continuously infused in mechanically ventilated patients prior to extubation, during extubation, and post-extubation. It is not necessary to discontinue dexmedetomidine hydrochloride injection prior to extubation.

1.2 Procedural Sedation

Dexmedetomidine hydrochloride injection is indicated for sedation of non-intubated patients prior to and/or during surgical and other procedures.

2.1 Dosing Guidelines

  • Dexmedetomidine hydrochloride injection dosing should be individualized and titrated to desired clinical response.Dexmedetomidine hydrochloride injection is not indicated for infusions lasting longer than 24 hours.Dexmedetomidine hydrochloride injection should be administered using a controlled infusion device.

2.2 Dosage Information

Table 1: Dosage InformationINDICATIONDOSAGE AND ADMINISTRATION Initiation of Intensive CareUnit 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: a dose reduction should be considered   [see Use in Specific Populations (8.5)].For adult patients with impaired hepatic function:  a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].  Maintenance of Intensive CareUnit 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: a dose reduction should be considered[see Use in Specific Populations (8.5)].For adult patients with impaired hepatic function:  a  dose  reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Initiation of Procedural Sedation For adult patients: a loading infusion of one mcg/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable. For awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes. For patients over 65 years of age: a loading infusion of 0.5 mcg/kg over 10 minutes [see Use in Specific Populations (8.5)]. For adult patients with impaired hepatic function: a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Maintenance of Procedural Sedation For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation.  For awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/hour is recommended until the endotracheal tube is secured.  For patients over 65 years of age: a dose reduction should be considered [see Use in Specific Populations (8.5)].  For adult patients with impaired hepatic function: a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.3 Dosage Adjustment

Due to possible pharmacodynamic interactions, a reduction in dosage of dexmedetomidine hydrochloride injection or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered [see Drug Interactions (7.1)].Dosage reductions may need to be considered for adult patients with hepatic impairment, and geriatric patients [see Warnings and Precautions (5.7), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.4 Preparation Of Solution

Strict aseptic technique must always be maintained during handling of dexmedetomidine hydrochloride injection.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.Dexmedetomidine Hydrochloride Injection, 200 mcg/2 mL (100 mcg/mL)Dexmedetomidine Hydrochloride Injection must be diluted with 0.9% sodium chloride injection to achieve required concentration (4 mcg/mL) prior to administration. Preparation of solutions is the same, whether for the loading dose or maintenance infusion.To prepare the infusion, withdraw 2 mL of dexmedetomidine hydrochloride injection, and add to 48 mL of 0.9% sodium chloride injection to a total of 50 mL. Shake gently to mix well.Dexmedetomidine Hydrochloride in 0.9% Sodium Chloride Injection, 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 are necessary.

2.5 Administration With Other Fluids

  • Dexmedetomidine hydrochloride infusion should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established.Dexmedetomidine hydrochloride has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam.Dexmedetomidine hydrochloride has been shown to be compatible when administered with the following intravenous fluids:0.9% sodium chloride in water5% dextrose in water20% mannitolLactated Ringer's solution100 mg/mL magnesium sulfate solution0.3% potassium chloride solution

2.6 Compatibility With Natural Rubber

Compatibility studies have demonstrated the potential for absorption of dexmedetomidine hydrochloride to some types of natural rubber. Although dexmedetomidine hydrochloride is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.

4 Contraindications

None

5.1 Drug Administration

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

5.2 Hypotension, Bradycardia, And Sinus Arrest

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 hydrochloride-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.

5.3 Transient Hypertension

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.

5.4 Arousability

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.

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 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)].

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 hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Hypotension and bradycardia were the most common adverse reactions associated with the use of dexmedetomidine hydrochloride during post approval use of the drug.Table 7: Adverse Reactions Experienced During Post-approval Use of Dexmedetomidine HydrochlorideSystem Organ ClassPreferred TermBlood and Lymphatic System DisordersAnemiaCardiac DisordersArrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardiaEye DisordersPhotopsia, visual impairmentGastrointestinal DisordersAbdominal pain, diarrhea, nausea, vomitingGeneral Disorders and Administration Site ConditionsChills, hyperpyrexia, pain, pyrexia, thirstHepatobiliary DisordersHepatic function abnormal, hyperbilirubinemiaInvestigationsAlanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolongedMetabolism and Nutrition DisordersAcidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremiaNervous System DisordersConvulsion, dizziness, headache, neuralgia, neuritis, speech disorderPsychiatric DisordersAgitation, confusional state, delirium, hallucination, illusionRenal and Urinary DisordersOliguria, polyuria Respiratory, Thoracic and Mediastinal DisordersApnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosisSkin and Subcutaneous Tissue DisordersHyperhidrosis, pruritus, rash, urticariaSurgical and Medical ProceduresLight anesthesiaVascular DisordersBlood pressure fluctuation, hemorrhage, hypertension, hypotension

7.1 Anesthetics, Sedatives, Hypnotics, Opioids

Co-administration of dexmedetomidine hydrochloride 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 hydrochloride and isoflurane, propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions, when co-administered with dexmedetomidine hydrochloride injection, a reduction in dosage of dexmedetomidine hydrochloride 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 hydrochloride 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.

8.2 Labor And Delivery

The safety of dexmedetomidine hydrochloride during labor and delivery has not been studied.

8.3 Nursing Mothers

It is not known whether dexmedetomidine hydrochloride is excreted in human milk. Radio-labeled dexmedetomidine administered subcutaneously to lactating female rats was excreted in milk. Because many drugs are excreted in human milk, caution should be exercised when dexmedetomidine hydrochloride 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 hydrochloride for this patient population. The use of dexmedetomidine hydrochloride for procedural sedation in pediatric patients has not been evaluated.

8.6 Hepatic Impairment

Since dexmedetomidine 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)].

9.1 Controlled Substance

Dexmedetomidine hydrochloride is not a controlled substance.

9.3 Dependence

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)].

10 Overdosage

The tolerability of dexmedetomidine hydrochloride was studied in one study in which healthy adult subjects were administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hr. The maximum blood concentration achieved in this study was approximately 13 times the upper boundary of the therapeutic range. The most notable effects observed in two subjects who achieved the highest doses were first degree atrioventricular block and second degree heart block. No hemodynamic compromise was noted with the atrioventricular block and the heart block resolved spontaneously within one minute.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.

11 Description

Dexmedetomidine hydrochloride injection concentrate is a sterile, nonpyrogenic solution suitable for intravenous infusion following dilution. 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 hydrochloride has a molecular weight of 236.7 and the empirical formula is C13H16N2 • HCl and the structural formula is:Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in water and has a pKa of 7.1. Its partition coefficient in-octanol: water at pH 7.4 is 2.89. Dexmedetomidine hydrochloride is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7.0. Each mL contains 118 mcg of dexmedetomidine hydrochloride equivalent to 100 mcg (0.1 mg) of dexmedetomidine and 9 mg of sodium chloride in water and is to be used after dilution. The solution is preservative-free and contains no additives or chemical stabilizers.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 and 9 mg sodium chloride in water and is ready to be used.  The solution is preservative-free and contains no additives or chemical stabilizers.

12.1 Mechanism Of Action

Dexmedetomidine hydrochloride 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 (≥1,000 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 hydrochloride 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 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.Table 8: Mean ± SD Pharmacokinetic ParametersParameterLoading Infusion (min)/Total Infusion Duration (hrs)10 min/12 hrs10 min/24 hrs10 min/24 hrs35 min/24 hrsDexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr)0.3/0.170.3/0.170.6/0.331.25/0.70 t1/2Presented as harmonic mean and pseudo standard deviation., hour 1.78 ± 0.30 2.22 ± 0.59 2.23 ± 0.21 2.50 ± 0.61 CL, liter/hour 46.3 ± 8.3 43.1 ± 6.5 35.3 ± 6.8 36.5 ± 7.5 Vss, liter 88.7 ± 22.9 102.4 ± 20.3 93.6 ± 17.0 99.6 ± 17.8 Avg CssMean Css  = Average steady-state concentration of dexmedetomidine. The mean Css was calculated based on post-dose sampling from 2.5 to 9 hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions.The loading doses for each of the above indicated groups were 0.5, 0.5, 1 and 2.2 mcg/kg, respectively., ng/mL 0.27 ± 0.05 0.27 ± 0.05 0.67 ± 0.10 1.37 ± 0.20Abbreviations: t1/2 = half-life, CL = clearance, Vss = steady-state volume of distributionDexmedetomidine pharmacokinetic parameters 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 t1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

CarcinogenesisAnimal carcinogenicity studies have not been performed with dexmedetomidine.MutagenesisDexmedetomidine was not mutagenic in vitro,  in either the bacterial reverse mutation assay (E. coli and Salmonella typhimurium) or the mammalian cell forward mutation assay (mouse lymphoma). Dexmedetomidine was clastogenic in the in vitro human lymphocyte chromosome aberration test with, but not without, rat S9 metabolic activation. In contrast, dexmedetomidine was not clastogenic in the in vitro human lymphocyte chromosome aberration test with or without human S9 metabolic activation. Although dexmedetomidine was clastogenic in an in vivo mouse micronucleus test in NMRI mice, there was no evidence of clastogenicity in CD-1 mice.Impairment of FertilityFertility in male or female rats was not affected after daily subcutaneous injections of dexmedetomidine at doses up to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m2 basis) administered from 10 weeks prior to mating in males, and 3 weeks prior to mating and during mating in females.

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 Clinical Studies

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

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 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 9.Table 9: Ramsay Level of Sedation ScaleClinical ScoreLevel of Sedation Achieved6Asleep, no response5Asleep, sluggish response to light glabellar tap or loud auditory stimulus4Asleep, but with brisk response to light glabellar tap or loud auditory stimulus3Patient responds to commands2Patient cooperative, oriented, and tranquil1Patient anxious, agitated, or restlessIn 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 10).A second prospective primary analysis assessed the sedative effects of dexmedetomidine hydrochloride 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 hydrochloride group maintained a Ramsay sedation score of ≥3 without receiving any midazolam rescue compared to the placebo group (see Table 10).Table 10: Midazolam Use as Rescue Medication During Intubation (ITT) Study OnePlacebo(N=175)Dexmedetomidine(N=178)p-valueMean Total Dose (mg) of Midazolam19 mg5mg0.0011*Standard deviation53 mg19 mgCategorized Midazolam Use0 mg43 (25%)108 (61%)<0.001**0-4 mg34 (19%)36 (20%)>4 mg98 (56%)34 (19%)ITT (intent-to-treat) population includes all randomized patients*    ANOVA model with treatment center**  Chi-squareA prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the dexmedetomidine hydrochloride and placebo groups. On average, dexmedetomidine-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.Patients randomized to placebo received significantly more propofol than patients randomized to dexmedetomidine hydrochloride (see Table 11).A significantly greater percentage of patients in the dexmedetomidine group compared to the placebo group maintained a Ramsay sedation score of ≥3 without receiving any propofol rescue (see Table 11).Table 11: Propofol Use as Rescue Medication During Intubation (ITT) Study TwoPlacebo(N=198)Dexmedetomidine(N=203)p-valueMean Total Dose (mg) of PropofolStandard deviation513 mg782 mg72 mg249 mg<0.0001*Categorized Propofol Use0 mg47 (24%)122 (60%)<0.001**0-50 mg30 (15%)43 (21%)>50 mg121 (61%)38 (19%)*     ANOVA model with treatment center**  Chi-squareA prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the dexmedetomidine and placebo groups. On average, dexmedetomidine -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 patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.In a controlled clinical trial, dexmedetomidine was compared to midazolam for ICU sedation exceeding 24 hours duration. dexmedetomidine 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 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 hydrochloride 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 hydrochloride in patients having a variety of elective surgeries/procedures performed under monitored anesthesia care. Study 2 evaluated dexmedetomidine hydrochloride in patients undergoing awake fiberoptic intubation prior to a surgical or diagnostic procedure.In Study 1, the sedative properties of dexmedetomidine hydrochloride 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).Table 12: Observer's Assessment of Alertness/SedationAssessment CategoriesResponsivenessSpeechFacial ExpressionEyesComposite Score Responds readily to name spoken in normal tone Normal Normal Clear, no ptosis 5 (alert) Lethargic response to name spoken in normal tone Mild slowing or thickening Mild relaxation Glazed or mild ptosis (less than half the eye) 4 Responds only after name is called loudly and/or repeatedly Slurring or prominent slowing Marked relaxation (slack jaw) Glazed and marked ptosis (half the eye or more) 3 Responds only after mild prodding or shaking Few recognizable words – – 2 Does not respond to mild prodding or shaking – – – 1 (deep sleep)Patients were randomized to receive a loading infusion of either dexmedetomidine hydrochloride 1 mcg/kg, dexmedetomidine hydrochloride 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 hydrochloride and comparator groups. Efficacy results showed that dexmedetomidine hydrochloride 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 hydrochloride 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 hydrochloride 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 hydrochloride and comparator groups. For efficacy results see Table 13.Table 13: Key Efficacy Results of Procedural Sedation StudiesStudyLoading Infusion Treatment ArmNumber of Patients EnrolledBased on ITT population defined as all randomized and treated patients.% Not Requiring Midazolam RescueConfidenceNormal approximation to the binomial with continuity correction.Interval on the Difference vs. PlaceboMean (SD) Total Dose (mg) of Rescue Midazolam RequiredConfidence Intervals of the Mean Rescue Dose Study1 Dexmedetomidine0.5 mcg/kg 134 40 37 (27, 48) 1.4 (1.7) -2.7 (-3.4, -2.0) Dexmedetomidine 1 mcg/kg 129 54 51 (40, 62) 0.9 (1.5) -3.1 (-3.8, -2.5) Placebo 63 3 – 4.1 (3.0) – Study2 Dexmedetomidine 1 mcg/kg 55 53 39 (20, 57) 1.1 (1.5) -1.8 (-2.7, -0.9)  Placebo 50 14 – 2.9 (3.0) –

17 Patient Counseling Information

  • Dexmedetomidine hydrochloride injection 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.

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