`
`
`
`
`
`
`
`----------------------------- CONTRAINDICATIONS -----------------------------
`
`
`None. (4)
`
`
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`
`
`
`• Monitoring: Continuously monitor patients while receiving Precedex. (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)
`
`
`• Prolonged exposure to dexmedetomidine beyond 24 hours may be
`
`
`
`
`associated with tolerance and tachyphylaxis and a dose-related increase in
`
`
`
`
`adverse events. (5.6)
`
`
`------------------------------ ADVERSE REACTIONS -----------------------------
`
`
`• The most common adverse reactions (incidence greater than 2%) are
`
`
`
`
`hypotension, bradycardia, and dry mouth. (6.1)
`
`• Adverse reactions associated with infusions greater than 24 hours in
`
`
`
`duration include ARDS, respiratory failure, and agitation. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc.
`
`at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`
`------------------------------ DRUG INTERACTIONS -----------------------------
`
`
`Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of
`
`
`
`pharmacodynamic effects. Reduction in dosage of Precedex or the
`
`
`
`concomitant medication may be required. (7.1)
`
`----------------------- USE IN SPECIFIC POPULATIONS ---------------------
`
`
`• Geriatric Patients: Dose reduction should be considered. (2.2, 2.3, 5.1, 8.5)
`
`
`
`
`
`
`• Hepatic Impairment: Dose reduction should be considered. (2.1, 2.2, 2.3,
`
`
`
`
`
`5.7, 8.6)
`
`• Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
`
`
`• Nursing Mothers: Caution should be exercised when administered to a
`
`
`
`nursing woman. (8.3)
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`These highlights do not include all the information needed to use
`
`
`
`
`PRECEDEX safely and effectively. See full prescribing information for
`
`PRECEDEX.
`PrecedexTM (dexmedetomidine hydrochloride) Injection
`
`
`
`For intravenous use.
`
`
`PrecedexTM (dexmedetomidine hydrochloride) in 0.9% Sodium Chloride
`
`
`
`Injection
`
`Initial U.S. Approval: 1999
`
`--------------------------- INDICATIONS AND USAGE ---------------------------
`
`
`Precedex is a relatively selective alpha2-adrenergic agonist indicated for:
`
`
`
`
`• Sedation of initially intubated and mechanically ventilated patients during
`
`
`
`treatment in an intensive care setting. Administer Precedex by continuous
`
`
`
`
`infusion not to exceed 24 hours. (1.1)
`
`
`• Sedation of non-intubated patients prior to and/or during surgical and other
`
`
`
`procedures. (1.2)
`
`---------------------- DOSAGE AND ADMINISTRATION ----------------------
`
`
`• Individualize and titrate Precedex dosing to desired clinical effect. (2.1)
`
`
`
`
`• Administer Precedex using a controlled infusion device. (2.1)
`
`
`
`• Dilute the 200 mcg/2 mL (100 mcg/mL) vial contents in 0.9% sodium
`
`
`
`
`
`
`chloride solution to achieve required concentration (4 mcg/mL) prior to
`
`
`
`administration. (2.4)
`
`• The 80 mcg/20 mL single-use vial, and 200 mcg/50mL and
`
`
`
`
`400 mcg/100 mL single-use bottles, do not require further dilution prior to
`
`
`
`
`administration. (2.4)
`
`
`For Adult Intensive Care Unit Sedation: Generally 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: Generally initiate at one mcg/kg over
`
`
`
`
`
`
`10 minutes, followed by a maintenance infusion initiated at 0.6 mcg/kg/hour
`
`
`
`and titrated to achieve desired clinical effect with doses ranging from 0.2 to
`
`
`
`1 mcg/kg/hour. (2.2)
`
`
`
`Alternative Doses: Recommended for patients over 65 years of age and
`
`
`
`
`awake fiberoptic intubation patients. (2.2)
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`
`
`Precedex Injection, 200 mcg/2 mL (100 mcg/mL) in a glass vial. To be used
`
`
`
`
`
`
`
`after dilution. (3)
`
`
`
`Precedex in 0.9% Sodium Chloride Injection 80 mcg/20 mL (4 mcg/mL) in a
`
`
`
`
`
`
`20 mL glass vial. Ready to use. (3)
`
`
`
`Precedex in 0.9% Sodium Chloride Injection 200 mcg/50 mL (4 mcg/mL) in a
`
`
`
`
`
`50 mL glass bottle. Ready to use. (3)
`
`
`
`
`Precedex in 0.9% Sodium Chloride Injection 400 mcg/100 mL (4 mcg/mL) in
`
`
`
`
`
`a 100 mL glass bottle. Ready to use. (3)
`
`
`
`_______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`Pregnancy
`
`
`1
`INDICATIONS AND USAGE
`
`
`8.2
`Labor and Delivery
`
`
`Intensive Care Unit Sedation
`1.1
`
`
`8.3
`Nursing Mothers
`
`
`1.2
`Procedural Sedation
`
`
`8.4
`Pediatric Use
`
`
`DOSAGE AND ADMINISTRATION
`
`8.5
`Geriatric Use
`
`
`2.1
`Dosing Guidelines
`
`
`8.6
`Hepatic Impairment
`
`
`2.2
`Dosage Information
`
`
`DRUG ABUSE AND DEPENDENCE
`
`2.3
`Dosage Adjustment
`
`
`9.1
`Controlled Substance
`
`
`2.4
`Preparation of Solution
`
`
`9.3
`Dependence
`
`
`2.5
`Administration with Other Fluids
`
`
`2.6
`Compatibility with Natural Rubber
`
`
`
`10 OVERDOSAGE
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`11 DESCRIPTION
`
`
`CONTRAINDICATIONS
`4
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`Pharmacodynamics
`12.2
`
`
`5.1
`Drug Administration
`
`
`12.3
`Pharmacokinetics
`
`
`5.2
`Hypotension, Bradycardia, and Sinus Arrest
`
`
`5.3
`Transient Hypertension
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`5.4
`Arousability
`
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`
`
`
`5.5 Withdrawal
`
`
`13.2 Animal Pharmacology and/or Toxicology
`
`
`
`
`
`5.6
`Tolerance and Tachyphylaxis
`
`
`14 CLINICAL STUDIES
`
`
`5.7
`Hepatic Impairment
`
`
`Intensive Care Unit Sedation
`14.1
`
`
`ADVERSE REACTIONS
`
`14.2
`Procedural Sedation
`
`
`Clinical Studies Experience
`6.1
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`6.2
`Postmarketing Experience
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`DRUG INTERACTIONS
`
`* Sections or subsections omitted from the full prescribing information are
`
`
`Anesthetics, Sedatives, Hypnotics, Opioids
`7.1
`
`
`not listed.
`
`7.2
`Neuromuscular Blockers
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`
`
`
`
`8
`
`
`9
`
`
`2
`
`
`6
`
`
`7
`
`
`Reference ID: 3915582
`
`Revised: 3/2016
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
` INDICATIONS AND USAGE
` 1
` 1.1
`
`
` Intensive Care Unit Sedation
` Precedex™ is indicated for sedation of initially intubated and mechanically ventilated patients during
`
`
`
`
` treatment in an intensive care setting. Precedex should be administered by continuous infusion not to
`
` exceed 24 hours.
`
` Precedex has been continuously infused in mechanically ventilated patients prior to extubation, during
`
` extubation, and post-extubation. It is not necessary to discontinue Precedex prior to extubation.
`
`
` Procedural Sedation
` 1.2
` Precedex is indicated for sedation of non-intubated patients prior to and/or during surgical and other
`
`
` procedures.
`DOSAGE AND ADMINISTRATION
`
` 2
`
`
` 2.1
` Dosing Guidelines
` • Precedex dosing should be individualized and titrated to desired clinical response.
`
`
` • Precedex is not indicated for infusions lasting longer than 24 hours.
`
`
` • Precedex should be administered using a controlled infusion device.
`
`
`
`
`
`
`
`
`wEN-4004v02
`
`
`Reference ID: 3915582
`
`
`
`Page 2 of 23
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2.2
`
`
`
` Dosage Information
`
`
` INDICATION
`
`Initiation of Intensive Care
`
` Unit Sedation
`
`Maintenance of Intensive
`
` Care Unit Sedation
`
`
`
` Initiation of Procedural
`
` Sedation
`
`
`
` Maintenance of Procedural
`
` Sedation
`
`
`
`
`
`
`
`
`Table 1: Dosage Information
` DOSAGE AND ADMINISTRATION
`
`
` 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 [see Dosage and Administration (2.2)].
`
`
` 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)].
`
`
` 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)].
`
`
` 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)].
`
`
`
` 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)].
`
`
`
`
`
`
`
`
`
`
`
` Dosage Adjustment
` 2.3
`
`
` Due to possible pharmacodynamic interactions, a reduction in dosage of Precedex 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)].
`
`
`
` Preparation of Solution
`
` 2.4
`
` Strict aseptic technique must always be maintained during handling of Precedex.
`
` Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
`
` administration, whenever solution and container permit.
`
`
`
`
`
`
`
`
`wEN-4004v02
`
`Reference ID: 3915582
`
`
`
`
`
`Page 3 of 23
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Precedex Injection, 200 mcg/2 mL (100 mcg/mL)
`
`
`
`
`
`
` Precedex 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 Precedex Injection, and add to 48 mL of 0.9% sodium chloride
` injection to a total of 50 mL. Shake gently to mix well.
`
`
`
` Precedex 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)
`
`
`
`
`
`
`
` Precedex 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.
` Administration with Other Fluids
`
`
`
`
` 2.5
` Precedex infusion should not be co-administered through the same intravenous catheter with blood or
`
`
`
` plasma because physical compatibility has not been established.
` Precedex has been shown to be incompatible when administered with the following drugs:
`
`
` amphotericin B, diazepam.
` Precedex has been shown to be compatible when administered with the following intravenous fluids:
`
`
` • 0.9% sodium chloride in water
`
` • 5% dextrose in water
`
`
` • 20% mannitol
`
`
`
` • Lactated Ringer’s solution
`
` • 100 mg/mL magnesium sulfate solution
`
` • 0.3% potassium chloride solution
`
`
`
` 2.6
` Compatibility with Natural Rubber
`
`
` Compatibility studies have demonstrated the potential for absorption of Precedex to some types of natural
` rubber. Although Precedex is dosed to effect, it is advisable to use administration components made with
`
`
`
`
` synthetic or coated natural rubber gaskets.
` DOSAGE FORMS AND STRENGTHS
`
` 3
`
`
` Precedex Injection
` Precedex Injection, 200 mcg/2 mL dexmedetomidine (100 mcg/mL) in a glass vial. To be used after
`
`
` dilution.
`
`
`
`
` Precedex in 0.9% Sodium Chloride Injection
`
`
` Precedex Injection, 80 mcg dexmedetomidine/20 mL (4 mcg/mL) dexmedetomidine in a 20 mL glass
`
` vial. Ready to use.
`
` Precedex Injection, 200 mcg dexmedetomidine/50 mL (4 mcg/mL) dexmedetomidine in a 50 mL glass
`
`
` bottle. Ready to use.
` Precedex Injection, 400 mcg dexmedetomidine/100 mL (4 mcg/mL) dexmedetomidine in a 100 mL glass
`
`
` bottle. Ready to use.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`wEN-4004v02
`
`
`Reference ID: 3915582
`
`
`
`Page 4 of 23
`
`
`
`
`
`
`
` CONTRAINDICATIONS
`
`
`
` 4
`
`
` None
`
` 5
` WARNINGS AND PRECAUTIONS
` 5.1
`
`
` Drug Administration
` Precedex 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 Precedex, patients should be
` continuously monitored while receiving Precedex.
`
`
`
` 5.2 Hypotension, Bradycardia, and Sinus Arrest
`
` Clinically significant episodes of bradycardia and sinus arrest have been reported with Precedex
`
`
`
`
`
` 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 Precedex infusion. Some of these
`cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or
`
`
`stopping the infusion of Precedex, increasing the rate of intravenous fluid administration, elevation of the
`
`
`
`lower extremities, and use of pressor agents. Because Precedex 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 Precedex
`
`induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more
`
`advanced resuscitative measures were required.
`
`
`Caution should be exercised when administering Precedex to patients with advanced heart block and/or
`
`
`severe ventricular dysfunction. Because Precedex 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
`
`
`Precedex an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used
`
`when such agents are administered concomitantly with Precedex.
`
`5.3
`Transient Hypertension
`
`
`Transient hypertension has been observed primarily during the loading dose in association with the initial
`peripheral vasoconstrictive effects of Precedex. 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 Precedex have been observed to be arousable and alert when stimulated. This
`
`
`alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and
`
`
`
`
`symptoms.
`
`5.5 Withdrawal
`
`
`Intensive Care Unit Sedation
`
`With administration up to 7 days, regardless of dose, 12 (5%) Precedex adult subjects experienced at least
`
`
`
`
`1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) Precedex
`
`
`adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common
`
`
`events were nausea, vomiting, and agitation.
`
`
`
`
`
`
`
`wEN-4004v02
`
`
`Reference ID: 3915582
`
`
`
`Page 5 of 23
`
`
`
`
`
`
`
`
`
`
`
` In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study
`
`
`
` drug discontinuation occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after
` discontinuation of Precedex supportive therapy is indicated.
`
`
` Procedural Sedation
`
` In adult subjects, withdrawal symptoms were not seen after discontinuation of short term infusions of
`
`
` Precedex (<6 hours).
` Tolerance and Tachyphylaxis
`
`
` 5.6
` 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 Precedex clearance decreases with severity of hepatic impairment, dose reduction should be
`
`
`
`
` considered in patients with impaired hepatic function [see Dosage and Administration (2.2)].
`
`
` 6
` ADVERSE REACTIONS
` 6.1
` Clinical Studies Experience
`
`
`
`
` Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in
` the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may
`
`
`
`
` not reflect the rates observed in practice.
`
` Use of Precedex has been associated with the following serious adverse reactions:
` • Hypotension, bradycardia and sinus arrest [see Warnings and Precautions (5.2)]
`
`
`
`
` • Transient hypertension [see Warnings and Precautions (5.3)]
`
`
` Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in both
`
`
`
` Intensive Care Unit and procedural sedation studies include hypotension, bradycardia and dry mouth.
` Intensive Care Unit Sedation
`
`
`
`
` Adverse reaction information is derived from the continuous infusion trials of Precedex for sedation in the
` Intensive Care Unit setting in which 1007 adult patients received Precedex. The mean total dose was
`
`
`
`
`
`
` 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean
` duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of
`
`
`
`
`
`
`
` age, 43% ≥65 years of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions
`
` occurring at an incidence of >2% are provided in Table 2. The most frequent adverse reactions were
`
`
` hypotension, bradycardia and dry mouth [see Warnings and Precautions (5.2)].
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`wEN-4004v02
`
`
`Reference ID: 3915582
`
`
`
`Page 6 of 23
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 2: Adverse Reactions with an Incidence >2%—Adult Intensive Care Unit Sedation
`
`
`
` Population <24 hours*
`
`Randomized
` Placebo
`
`
` Propofol
`
` Precedex
`
` All Precedex
`
` (N = 400)
`
` (N = 188)
`
` (N = 798)
`
` (N = 1007)
`
` (%)
`
` Adverse Event
`
` (%)
`
` (%)
`
` (%)
`
` 12%
`
` Hypotension
`
` 13%
`
` 24%
`
` 25%
`
` 19%
` Hypertension
`
` 4%
`
`
` 13%
`
` 12%
` 9%
`
`
` Nausea
` 11%
`
` 9%
`
` 9%
`
`
` 3%
` Bradycardia
`
`
`
` 5%
`
` 5%
` 0
`
` 3%
` Atrial Fibrillation
`
`
` 7%
`
` 5%
`
` 4%
`
` 4%
`
` Pyrexia
`
` 4%
`
` 4%
`
` 4%
`
` 1%
` Dry Mouth
`
` 1%
`
` 3%
`
` 4%
`
` 5%
`
` Vomiting
`
` 3%
`
` 3%
`
` 3%
`
` 2%
`
` Hypovolemia
`
` 5%
`
` 3%
`
` 3%
`
` 3%
`
` Atelectasis
`
` 6%
`
` 3%
`
` 3%
`
` 1%
` Pleural Effusion
`
`
` 6%
`
` 2%
`
` 2%
`
` 3%
`
` Agitation
`
` 1%
`
` 2%
`
` 2%
`
`
` 4%
`Tachycardia
`
` 1%
`
` 2%
`
` 2%
`
` 2%
`
` Anemia
`
` 2%
`
` 2%
`
` 2%
`
` 3%
` Hyperthermia
`
`
` 2%
`
` 2%
` 0
`
` 3%
`
` Chills
`
` 2%
`
` 2%
`
` 2%
`
` 2%
` Hyperglycemia
`
` 3%
`
` 2%
`
` 2%
`
` 2%
`
` Hypoxia
`
` 3%
`
` 2%
`
` 2%
`
` 3%
` Post-procedural Hemorrhage
`
` 4%
`
` 2%
`
` 2%
`
` 1%
`
` Pulmonary Edema
`
` 3%
`
` 1%
`
` 1%
`
` 0
`
` Hypocalcemia
`
` 2%
`
` 1%
`
` 1%
`
` 1%
`
` Acidosis
`
` 2%
`
` 1%
`
` 1%
`
` 0
` Urine Output Decreased
`
` 2%
`
` 1%
`
` 1%
`
` 1%
`
` Sinus Tachycardia
`
` 2%
`
` 1%
`
` 1%
`
` 1%
` Ventricular Tachycardia
`
` 5%
`
` 1%
`
` <1%
`
` 0
`
` Wheezing
`
` 2%
`
` 1%
`
` <1%
` 1%
` Edema Peripheral
`
` 2%
`
`
`
` <1%
`
` 0
`
` 26 subjects in the all Precedex group and 10 subjects in the randomized Precedex group had exposure for greater than 24
` *
`
` hours.
`
` Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of
` Precedex for sedation in the surgical intensive care unit setting in which 387 adult patients received
`
`
` Precedex for less than 24 hours. The most frequently observed treatment-emergent adverse events
`
`included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and
`
`
`
` anemia (see Table 3).
`
`
`
`
`
`
`
`wEN-4004v02
`
`Reference ID: 3915582
`
`
`
`
`
`Page 7 of 23
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 3: Treatment-Emergent Adverse Events Occurring in >1% Of All Dexmedetomidine-Treated
`
`
`
`
` Adult Patients in the Randomized Placebo-Controlled Continuous Infusion <24 Hours ICU
`
`
` Sedation Studies
`
` Placebo
`
` Randomized Dexmedetomidine
`
` (N = 379)
`
`
`
` (N = 387)
`
` Adverse Event
`
` Hypotension
`
` 13%
` 28%
`
` Hypertension
`
`
` 18%
`
` 16%
`
` Nausea
` 9%
`
`
` 11%
` Bradycardia
`
` 3%
` 7%
`
`
` Fever
`
` 4%
`
` 5%
` Vomiting
`
`
` 6%
`
` 4%
` Atrial Fibrillation
`
` 3%
`
` 4%
`
` Hypoxia
`
` 4%
`
` 4%
`
` Tachycardia
`
` 5%
`
` 3%
`
` Hemorrhage
`
` 4%
`
` 3%
`
` Anemia
`
` 2%
`
` 3%
` Dry Mouth
`
` 1%
`
` 3%
`
` Rigors
`
` 3%
`
` 2%
` Agitation
`
` 3%
`
` 2%
`
`
` 3%
`
` 2%
` Hyperpyrexia
`
` 2%
`
` 2%
`
` Pain
`
` 2%
`
` 2%
` Hyperglycemia
`
` 2%
`
` 2%
`
` Acidosis
`
` 1%
`
` 2%
` Pleural Effusion
`
` <1%
`
` 2%
`
` Oliguria
`
` <1%
`
` 2%
`
` Thirst
`
`
` In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours
`
`duration in adult patients. Key treatment emergent adverse events occurring in dexmedetomidine or
`
`
`
`
`
`midazolam treated patients in the randomized active comparator continuous infusion long-term intensive
`
`care unit sedation study are provided in Table 4. The number (%) of subjects who had a dose-related
`
`
`increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the Precedex
`
`
`group is provided in Table 5.
`
`
`
`
`
`
`
`wEN-4004v02
`
`
`Reference ID: 3915582
`
`
`
`Page 8 of 23
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Table 4: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or
`
` Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion
`
`
`
`Long-Term Intensive Care Unit Sedation Study
`
`
`
` Dexmedetomidine
`
`
`
` (N = 244)
` 56%
`
`
` 28%
`
` 42%
` 5%
`
` 28%
`
`
` 25%
`
` 10%
`
` 12%
`
` 11%
`
` 19%
` 9%
`
`
` 7%
`
` 7%
`
` 7%
`
` 6%
`
` 5%
`
` 5%
`
` 2%
`
` 2%
`
` 2%
`
` 1%
`
` Midazolam
`
`
`
`
` (N = 122)
` 56%
`
`
` 27%
`
` 19%
` 1%
`
` 42%
`
`
` 44%
`
` 10%
`
` 15%
`
` 15%
`
` 30%
`
` 13%
` 2%
`
`
` 6%
`
` 2%
`
` 6%
`
` 6%
`
` 3%
`
` 1%
`
` 1%
`
` 6%
`
` 7%
`
`
` Adverse Event
`
` Hypotension1
` Hypotension Requiring Intervention
`
` Bradycardia2
`
` Bradycardia Requiring Intervention
`
` Systolic Hypertension3
`
` Tachycardia4
`
` Tachycardia Requiring Intervention
` Diastolic Hypertension3
`
`
` Hypertension3
` Hypertension Requiring Intervention†
`
` Hypokalemia
`
` Pyrexia
` Agitation
`
`
` Hyperglycemia
`
` Constipation
` Hypoglycemia
`
` Respiratory Failure
`
`
` Renal Failure Acute
` Acute Respiratory Distress Syndrome
`
` Generalized Edema
`
`
` Hypomagnesemia
`
`
` †
`
`
` Includes any type of hypertension.
`1 Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of
`
`
`
`
`<50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value.
`
`
`
`2 Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion
`
`
`
`
`value.
`
`3 Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of
`
`
`
`
`
`
`>100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value.
`
`Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion
`
`value.
` The following adverse events occurred between 2 and 5% for Precedex and Midazolam, respectively:
`
`
`
`
`
` renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure
`
` (4.5%, 3.3%).
`
`
`
`
`
`
`
`4
`
`
`
`
`
`
`wEN-4004v02
`
`Reference ID: 3915582
`
`
`
`
`
`Page 9 of 23
`
`
`
`
`
`
`
`
` Table 5. Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent
`
`
` Adverse Events by Maintenance Adjusted Dose Rate Range in the Precedex Group
`
`
`
`
` Precedex mcg/kg/hr
`
` ≤0.7*
`
` Adverse Event
`
` (N = 95)
`
`
` 6%
` Constipation
`
` 5%
`
` Agitation
`
` 5%
`
` Anxiety
`
` 3%
`
` Edema Peripheral
`
` 2%
`
` Atrial Fibrillation
`
` 2%
`
` Respiratory Failure
`
` 1%
`
` Acute Respiratory Distress Syndrome
`
` * Average maintenance dose over the entire study drug administration
`
` Procedural Sedation
`
` Adverse reaction information is derived from the two trials for procedural sedation [see Clinical Studies
`
` (14.2)] in which 318 adult patients received Precedex. The mean total dose was 1.6 mcg/kg (range:
`
`
` 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of infusion of
`
`
`
`
` 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93 years of age, ASA I-IV, 30% ≥65
`
`
`
`
` years of age, 52% male and 61% Caucasian.
`
`
`
` Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 6. The
`
` most frequent adverse reactions were hypotension, bradycardia, and dry mouth [see Warnings and
`
`
`
` Precautions (5.2)]. Pre-specified criteria for the vital signs to be reported as adverse reactions are
`
`
` footnoted below the table. The decrease in respiratory rate and hypoxia was similar between Precedex and
`
`
`
` comparator groups in both studies.
`
`
`
`
`
`
`
` >0.7 to ≤1.1*
`
`
` (N = 78)
`
` 5%
`
` 8%
`
` 5%
`
` 5%
`
` 4%
`
` 6%
`
` 3%
`
` >1.1*
`
`
` (N = 71)
`
` 14%
`
` 14%
` 9%
`
`
` 7%
`
` 9%
` 10%
`
` 9%
`
`
`
`
`
`
`
`
`
`
`wEN-4004v02
`
`Reference ID: 3915582
`
`
`
`
`
`Page 10 of 23
`
`
`
`
`
`
`
`
`
` Table 6: Adverse Reactions With an Incidence > 2%—Procedural Sedation Population
`
`
` Precedex
`
` Placebo
`
`
` (N = 318)
` (N = 113)
`
` Adverse Event
`
`
` (%)
` (%)
`
` Hypotension1
`
` 54%
`
` 30%
` Respiratory Depression2
`
` 37%
`
` 32%
`
` Bradycardia3
`
` 14%
` 4%
`
`
` Hypertension4
`
` 13%
` 24%
`
`
` Tachycardia5
` 5%
`
` 17%
`
`
`
` 3%
` 2%
`
` Nausea
` Dry Mouth
`
` 3%
`
` 1%
`
` Hypoxia6
`
` 2%
`
` 3%
` Bradypnea
`
` 2%
`
` 4%
`
`1 Hypotension was defined in absolute and relative terms as Systolic blood pressure of <80 mmHg or ≤30% lower than pre-
`
`
`
` study drug infusion value, or Diastolic blood pressure of <50 mmHg.
`
`
`
`2 Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or > 25%
`
`
`
`
`
`
`decrease from baseline.
`3 Bradycardia was defined in absolute and relative terms as <40 beats per minute or ≤30% lower than pre-study drug
`
`
`
`infusion value.
`4 Hypertension was defined in absolute and relative terms as Systolic blood pressure >180 mmHg or ≥30% higher than pre-
`
`
`
`
`
`
`study drug infusion value or Diastolic blood pressure of >100 mmHg.
`
`
`Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug
`
`infusion value.
`6 Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline.
`
`
`
`
`
` 6.2
`
`
` Postmarketing Experience
` The following adverse reactions have been identified during post approval use of Precedex. 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
`
`
` Precedex during post approval use of the drug.
`
`
`
`5
`
`
`
`
`
`wEN-4004v02
`
`
`Reference ID: 3915582
`
`
`
`Page 11 of 23
`
`
`
`
`
`
`
` Table 7: Adverse Reactions Experienced During Post-approval Use of Precedex
`
`
` System Organ Class
` Preferred Term
` Blood and Lymphatic System
`
`
` Anemia
`
` Disorders
` Cardiac Disorders
`
`
`
`
` Arrhythmia, atrial fibrillation, atrioventricular block,
`
` bradycardia, cardiac arrest, cardiac disorder, extrasystoles,
`
` myocardial infarction, supraventricular tachycardia, tachycardia,
`
` ventricular arrhythmia, ventricular tachycardia
`
`
` Photopsia, visual impairment
`
` Abdominal pain, diarrhea, nausea, vomiting
`
` Chills, hyperpyrexia, pain, pyrexia, thirst
`
`
`
`
`
` Eye Disorders
`
`
` Gastrointestinal Disorders
`
`
` General Disorders and
` Administration Site Conditions
`
` Hepatobiliary Disorders
`
`
` Investigations
`
`
`
`
`
` Nervous System Disorders
`
`
`
`
`
`
`
` Hepatic function abnormal, hyperbilirubinemia
`
`
`
` Alanine aminotransferase increased, aspartate aminotransferase
` increased, blood alkaline phosphatase increased, blood urea
`
`
`
` increased, electrocardiogram T wave inversion,
` gammaglutamyltransferase increased, electrocardiogram QT
`
`
` prolonged
` Metabolism and Nutrition Disorders Acidosis, hyperkalemia, hypoglycemia, hypovolemia,
`
`
` hypernatremia
` Convulsion, dizziness, headache, neuralgia, neuritis, speech
`
` disorder
` Agitation, confusional state, delirium, hallucination, illusion
`
` Oliguria, polyuria
`
` Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation,
` hypoxia, pulmonary congestion, respiratory acidosis
`
`
`
`
` Hyperhidrosis
`
` Psychiatric Disorders
`
` Renal and Urinary Disorders
`
`Respiratory, Thoracic and
`
`
` Mediastinal Disorders
` Skin and Subcutaneous Tissue
`
`
` Disorders
` Surgical and Medical Procedures
`
` Vascular Disorders
`
`
`
`
`
`
`
`
` Light anesthesia
`
` Blood pressure fluctuation, hemorrhage, hypertension,
`
` hypotension
`
`
`
` 7
`
` DRUG INTERACTIONS
`
`
` Anesthetics, Sedatives, Hypnotics, Opioids
`
`
` 7.1
`Co-administration of Precedex 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 Precedex and isoflurane,
`
`propofol, alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic
`interactions, when co-administered with Precedex, a reduction in dosage of Precedex 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 Precedex 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.
`
`
`
`wEN-4004v02
`
`Reference ID: 3915582
`
`
`
`
`
`Page 12 of 23
`
`
`
`
`
` 8
` USE IN SPECIFIC