`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`•
`
`
`
`
`
`
`
`
`
`
`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)
`
`
`
`----------------------------- CONTRAINDICATIONS -----------------------------
`None. (4)
`_______________________________________________________________________________________________________________________________________
`FULL PRESCRIBING INFORMATION: CONTENTS*
` INDICATIONS AND USAGE
`1
`
`Intensive Care Unit Sedation
`1.1
`1.2
`Procedural Sedation
` DOSAGE AND ADMINISTRATION
`
`Dosing Guidelines
`2.1
`
`Dosage Information
`2.2
`2.3
`Dosage Adjustment
`2.4
`Preparation of Solution
`
`Administration with Other Fluids
`2.5
`2.6
`Compatibility with Natural Rubber
`3
`DOSAGE FORMS AND STRENGTHS
`
`4
` CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`Drug Administration
`5.1
`
`Hypotension, Bradycardia, and Sinus Arrest
`5.2
`Transient Hypertension
`5.3
`
`5.4
`Arousability
`5.5 Withdrawal
`5.6
`Tolerance and Tachyphylaxis
`5.7
`Hepatic Impairment
` ADVERSE REACTIONS
`
`Clinical Studies Experience
`6.1
`6.2
`Postmarketing Experience
`
`
`
`
`
`
`
`
`
`•
`
`•
`
`2
`
`6
`
`
`
`Reference ID: 3658226
`
`----------------------- 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 electronically at
`
`ProductComplaintsPP@hospira.com, 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.
`
`
`Revised: 1/2014
`
`7
`
`8
`
` DRUG INTERACTIONS
`
`
`Anesthetics, Sedatives, Hypnotics, Opioids
`7.1
`
`Neuromuscular Blockers
`7.2
`
`
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Labor and Delivery
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Hepatic Impairment
`9 DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance
`9.3
`Dependence
`
`10 OVERDOSAGE
`
` DESCRIPTION
`11
`
` CLINICAL PHARMACOLOGY
`12
`
`
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`
`Pharmacokinetics
`12.3
`
` NONCLINICAL TOXICOLOGY
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`
`
`13.2 Animal Pharmacology and/or Toxicology
` CLINICAL STUDIES
`
`14.1
`Intensive Care Unit Sedation
`
`13
`
`14
`
`
`
`
`
`Procedural Sedation
`14.2
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`_______________________________________________________________________________________________________________________________________
`
` * Sections or subsections omitted from the full prescribing information are
`
`not listed.
`
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`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`
`
`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.
`1.2
`Procedural Sedation
`Precedex is indicated for sedation of non-intubated patients prior to and/or during surgical and
`other procedures.
`2
`DOSAGE AND ADMINISTRATION
`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.
`
`
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`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)].
`
`
`2.3
`
`Dosage Adjustment
`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.
`
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`
` 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.
`2.5
`Administration with Other Fluids
`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
`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.
`3
`DOSAGE FORMS AND STRENGTHS
`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.
`4
`CONTRAINDICATIONS
`
`None
`WARNINGS AND PRECAUTIONS
`
`Drug Administration
`
`
`2.6
`
`5
`5.1
`
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`
` 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. 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.
`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).
`5.6
`Tolerance and Tachyphylaxis
`
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`
`
`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)].
`
`ADVERSE REACTIONS
`6
`
`
`Clinical Studies Experience
`6.1
`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)].
`
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`Table 2: Adverse Reactions with an Incidence >2%—Adult Intensive Care Unit Sedation
`
`Population <24 hours*
`
`Randomized
`Propofol
`Placebo
`Precedex
`All Precedex
`
`(N = 188)
`(N = 400)
`(N = 798)
`(N = 1007)
`(%)
`(%)
`(%)
`(%)
`Adverse Event
`13%
`12%
`24%
`25%
`Hypotension
`4%
`19%
`13%
`12%
`Hypertension
`11%
`9%
`9%
`9%
`Nausea
`0
`3%
`5%
`5%
`Bradycardia
`7%
`3%
`5%
`4%
`Atrial Fibrillation
`4%
`4%
`4%
`4%
`Pyrexia
`1%
`1%
`3%
`4%
`Dry Mouth
`3%
`5%
`3%
`3%
`Vomiting
`5%
`2%
`3%
`3%
`Hypovolemia
`6%
`3%
`3%
`3%
`Atelectasis
`6%
`1%
`2%
`2%
`Pleural Effusion
`1%
`3%
`2%
`2%
`Agitation
`
`1%
`4%
`2%
`2%
`Tachycardia
`2%
`2%
`2%
`2%
`Anemia
`0
`3%
`2%
`2%
`Hyperthermia
`2%
`3%
`2%
`2%
`Chills
`3%
`2%
`2%
`2%
`Hyperglycemia
`3%
`2%
`2%
`2%
`Hypoxia
`4%
`3%
`2%
`2%
`Post-procedural Hemorrhage
`3%
`1%
`1%
`1%
`Pulmonary Edema
`
`2%
`0
`1%
`1%
`Hypocalcemia
`2%
`1%
`1%
`1%
`Acidosis
`2%
`0
`1%
`1%
`Urine Output Decreased
`2%
`1%
`1%
`1%
`Sinus Tachycardia
`5%
`1%
`1%
`<1%
`Ventricular Tachycardia
`2%
`0
`1%
`<1%
`Wheezing
`2%
`1%
`0
`<1%
`Edema Peripheral
`
` * 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).
`
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`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
`13%
`28%
`Hypotension
`18%
`16%
`Hypertension
`
`9%
`11%
`Nausea
`
`3%
`7%
`Bradycardia
`4%
`5%
`Fever
`6%
`4%
`Vomiting
`3%
`4%
`Atrial Fibrillation
`4%
`4%
`Hypoxia
`5%
`3%
`Tachycardia
`4%
`3%
`Hemorrhage
`2%
`3%
`Anemia
`1%
`3%
`Dry Mouth
`3%
`2%
`Rigors
`3%
`2%
`Agitation
`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.
`
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`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%
`
`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.
`4 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%).
`
`Midazolam
`(N = 122)
`56%
`27%
`19%
`1%
`42%
`44%
`10%
`15%
`15%
`30%
`13%
`2%
`6%
`2%
`6%
`6%
`3%
`1%
`1%
`6%
`7%
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`>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%
`
`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*
`(N = 95)
`Adverse Event
`
`
`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.
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` Table 6: Adverse Reactions With an Incidence > 2%—Procedural Sedation Population
`Placebo
`
`
` Precedex
`(N = 113)
`(N = 318)
`(%)
`(%)
`Adverse Event
`Hypotension1
`54%
`30%
`Respiratory Depression2
`37%
`32%
`Bradycardia3
`14%
`4%
`Hypertension4
`13%
`24%
`Tachycardia5
`5%
`17%
`3%
`2%
`Nausea
`3%
`1%
`Dry Mouth
`Hypoxia6
`2%
`3%
`2%
`4%
`Bradypnea
`
` 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.
`5 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.
`
`
`
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`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.
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` 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
`
`Hepatic function abnormal, hyperbilirubinemia
`Alanine aminotransferase increased, aspartate aminotransferase
`increased, blood alkaline phosphatase increased, blood urea
`increased, electrocardiogram T wave inversion,
`gammaglutamyltransferase increased
`
`Metabolism and Nutrition Disorders Acidosis, hyperkalemia, hypoglycemia, hypovolemia
`
`Convulsion, dizziness, headache, neuralgia, neuritis, speech
`Nervous System Disorders
`disorder
`Agitation, confusional state, delirium, hallucination, illusion
`Oliguria
`Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation,
`hypoxia, pulmonary congestion, respiratory acidosis
`Hyperhidrosis
`
`
`Eye Disorders
`
`Gastrointestinal Disorders
`General Disorders and
`Administration Site Conditions
`
`Hepatobiliary Disorders
`Investigations
`
`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
`7.1
`
`
`DRUG INTERACTIONS
`Anesthetics, Sedatives, Hypnotics, Opioids
`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.
`8
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`Pregnancy Category C
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`8.3
`
`There are no adequate and well-controlled studies of Precedex use in pregnant women. In an in
`vitro human placenta study, placental transfer of dexmedetomidine occurred. In a study in the pregnant
`rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was
`administered subcutaneously. Thus, fetal exposure should be expected in humans, and Precedex should be
`used during pregnancy only if the potential benefits justify the potential risk to the fetus.
`Teratogenic effects were not observed in rats following subcutaneous administration of
`dexmedetomidine during the period of fetal organogenesis (from gestation day 5 to 16) with doses up to
`200 mcg/kg (representing a dose approximately equal to the maximum recommended human intravenous
`dose based on body surface area) or in rabbits following intravenous administration of dexmedetomidine
`during the period of fetal organogenesis (from gestation day 6 to 18) with doses up to 96 mcg/kg
`(representing approximately half the human exposure at the maximum recommended dose based on
`plasma area under the time-curve comparison). However, fetal toxicity, as evidenced by increased post-
`implantation losses and reduced live pups, was observed in rats at a subcutaneous dose of 200 mcg/kg.
`The no-effect dose in rats was 20 mcg/kg (representing a dose less than the maximum recommended
`human intravenous dose based on a body surface area comparison). In another reproductive toxicity study
`when dexmedetomidine was administered subcutaneously to pregnant rats at 8 and 32 mcg/kg
`(representing a dose less than the maximum recommended human intravenous dose based on a body
`surface area comparison) from gestation day 16 through weaning, lower offspring weights were observed.
`Additionally, when offspring of the 32 mcg/kg group were allowed to mate, elevated fetal and
`embryocidal toxicity and delayed motor development was observed in second generation offspring.
`8.2
`Labor and Delivery
`The safety of Precedex during labor and delivery has not been studied.
`Nursing Mothers
`It is not known whether Precedex is excreted in human milk. Radio-labeled dexmedetomidine
`administered subcutaneously to lactating female rats was excreted in mil