`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`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, 5.6, 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: 06/2013
`
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`
`
`•
`
`
`•
`
`•
`
`•
`
`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.
`
`
`Precedex (dexmedetomidine hydrochloride) Injection
`Precedex (dexmedetomidine hydrochloride) Injection, Concentrate
`
`For intravenous infusion of injection following dilution of concentrate
`
`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.
`
`
`
`
`The 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, Concentrate, 200 mcg/2 mL (100 mcg/mL) in a glass
`
`
`
`vial. (3)
`Precedex Injection 200 mcg/50 mL (4 mcg/mL) in a 50 mL glass bottle. (3)
`
`Precedex Injection 400 mcg/100 mL (4 mcg/mL) in a 100 mL glass bottle. (3)
`--------------------------CONTRAINDICATIONS-----------------------------
`None (4)
`----------------------WARNINGS AND PRECAUTIONS-------------------
`
`
`
`• Monitoring: Continuously monitor patients while receiving Precedex.
`
`
`
`(5.1)
`
`
`•
`
`
`
`
`
`Reference ID: 3326669
`
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`1
`
`1.1
`Intensive Care Unit Sedation
`
`
`1.2 Procedural Sedation
`
` DOSAGE AND ADMINISTRATION
`
`
` 2.1 Dosing Guidelines
`
`
`
`2.2 Dosage Information
`
`
` 2.3 Dosage Adjustment
`
`
`
`2.4 Preparation of Solution
`
`
`2.5 Administration With Other Fluids
`
`
`2.6 Compatibility with Natural Rubber
`
`
` DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`4
` CONTRAINDICATIONS
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Drug Administration
`
`
` 5.2 Hypotension, Bradycardia, and Sinus Arrest
`
`
`5.3 Transient Hypertension
`
`
` 5.4 Arousability
`
`
`
` 5.5 Withdrawal
`
`
`
`
` 5.6 Tolerance and Tachyphylaxis
`
`
` 5.7 Hepatic Impairment
`
`
` ADVERSE REACTIONS
`
`
` 6.1 Clinical Studies Experience
`
`
`
`6.2 Postmarketing Experience
`
` DRUG INTERACTIONS
`
`
` 7.1 Anesthetics, Sedatives, Hypnotics, Opioids
`
`
` 7.2 Neuromuscular Blockers
`
`
`
`
`
`
`
`8
`
`
`9
`
`USE IN SPECIFIC POPULATIONS
`
`
`
`8.1
`Pregnancy
`
`
`
`8.2
`Labor and Delivery
`
`
`
`8.3 Nursing Mothers
`
`
`
`Pediatric Use
`
`8.4
`
`8.5 Geriatric Use
`
`
`
`8.6 Hepatic Impairment
`
`
`DRUG ABUSE AND DEPENDENCE
`Controlled Substance
`9.1
`
`Dependence
`9.2
`10 OVERDOSAGE
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`14 CLINICAL STUDIES
`
`
`Intensive Care Unit Sedation
`
`14.1
`
`14.2 Procedural Sedation
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`
`*
`
`
`Sections or subsections omitted from the full prescribing
`
`information are not listed.
`
`
`2
`
`
`6
`
`
`7
`
`
`
`
`
`
`
`Reference ID: 3326669
`
`
`
`
`
`
`
`
`
`
`
`
`
` FULL PRESCRIBING INFORMATION
` 1
`
`INDICATIONS AND USAGE
`
`
`Intensive Care Unit Sedation
`1.1
`Precedex(TM) 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.
`
`2
`
`2.1
`
`DOSAGE AND ADMINISTRATION
`
`
`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.
`
`
`•
`
`•
`
`•
`
`
`
`
`
`
`Reference ID: 3326669
`
`
`
`Page 3 of 24
`
`
`
`
`
` Dosage Information
`
`2.2
`
`
`
`INDICATION
`
`
`Initiation of Intensive Care
`
`Unit Sedation
`
`Maintenance of Intensive Care
`
`Unit Sedation
`
`
`Initiation of Procedural
`Sedation
`
`
`Maintenance of Procedural
`Sedation
`
`
`
`
`
`
`Reference ID: 3326669
`
`
`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)].
`
`
`
`
`Page 4 of 24
`
`
`
` 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)].
`
`2.4
`
`
`
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior
`
`to administration, whenever solution and container permit.
`
`
`Preparation of Solution
`Strict aseptic technique must always be maintained during handling of Precedex.
`
`Precedex Injection, Concentrate, 200 mcg/2 mL (100 mcg/ml)
`Precedex must be diluted with 0.9% sodium chloride solution 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 Concentrate, and add to 48 mL of
`
`
`0.9% sodium chloride injection to a total of 50 mL. Shake gently to mix well.
`
`Precedex Injection, 200 mcg/50mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL)
`
`
`Precedex 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.
`
`
`
`fluids:
`
`
`•
`
`•
`
`•
`
`•
`
`•
`
`•
`
`Compatibility with Natural Rubber
`2.6
`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.
`
`
`Precedex has been shown to be compatible when administered with the following intravenous
`
`
`
`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
`
`
`
`
`Reference ID: 3326669
`
`
`
`Page 5 of 24
`
`
`
`
`3
`
`
`DOSAGE FORMS AND STRENGTHS
`
`Precedex Injection, Concentrate
`
`
`
` Precedex Injection, 200 mcg/2 mL (100 mcg/mL) in a glass vial
`
`
`Precedex Injection
`
`
`Precedex Injection, 200 mcg/50 mL (4 mcg/mL) in a 50 mL glass bottle
`
`Precedex Injection, 400 mcg/100 mL (4 mcg/mL) in a 100 mL glass bottle
`
`
`
`CONTRAINDICATIONS
`
`None
`
`WARNINGS AND PRECAUTIONS
`
`
`4
`
`
`
`5
`
`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. 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.
`
`Transient Hypertension
`5.3
`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.
`
`
`
`
`
`Reference ID: 3326669
`
`
`
`Page 6 of 24
`
`
`
`Arousability
`5.4
`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).
`
`
`
`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
`
`
`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.
`
`
`
`
`•
`
`
`•
`
`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.
`
`
`ADVERSE REACTIONS
`
`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)]
`
`
`
`
`Reference ID: 3326669
`
`
`
`Page 7 of 24
`
`
`
` 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)].
`
`
`Table 2: Adverse Reactions With an Incidence >2%—Adult Intensive Care Unit Sedation
`
`
`Population <24 hours*
`
`
`Randomized
`
`
`
`Precedex
`
`All Precedex
`Propofol
`Placebo
`
`(N = 798)
`(N = 1007)
`(N = 188)
`(N = 400)
`(%)
`(%)
`Adverse Event
`(%)
`(%)
`Hypotension
`25%
`24%
`12%
`13%
`Hypertension
`12%
`13%
`19%
`4%
`Nausea
`9%
`9%
`9%
`11%
`Bradycardia
`5%
`5%
`3%
`0
`Atrial fibrillation
`4%
`5%
`3%
`7%
`Pyrexia
`4%
`4%
`4%
`4%
`Dry mouth
`4%
`3%
`1%
`1%
`Vomiting
`3%
`3%
`5%
`3%
`Hypovolemia
`3%
`3%
`2%
`5%
`Atelectasis
`3%
`3%
`3%
`6%
`Pleural effusion
`2%
`2%
`1%
`6%
`Agitation
`2%
`2%
`3%
`1%
`
`Tachycardia
`2%
`2%
`4%
`1%
`Anemia
`2%
`2%
`2%
`2%
`Hyperthermia
`2%
`2%
`3%
`0
`Chills
`2%
`2%
`3%
`2%
`Hyperglycemia
`2%
`2%
`2%
`3%
`Hypoxia
`2%
`2%
`2%
`3%
`Post-procedural hemorrhage
`2%
`2%
`3%
`4%
`Pulmonary edema
`1%
`1%
`1%
`3%
`Hypocalcemia
`1%
`1%
`0
`2%
`Acidosis
`1%
`1%
`1%
`2%
`
`Urine output decreased
`1%
`1%
`0
`2%
`Sinus tachycardia
`1%
`1%
`1%
`2%
`Ventricular tachycardia
`<1%
`1%
`1%
`5%
`Wheezing
`<1%
`1%
`0
`2%
`Edema peripheral
`<1%
`0
`1%
`2%
`
`* 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
`
`
`
`
`
`Reference ID: 3326669
`
`
`
`Page 8 of 24
`
`
`
`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).
`
`
`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
`
`
`Randomized Dexmedetomidine
`(N = 387)
`28%
`16%
`
`11%
`7%
`5%
`4%
`4%
`4%
`3%
`3%
`3%
`3%
`2%
`2%
`2%
`2%
`2%
`2%
`2%
`2%
`
`2%
`
`
`
`Placebo
`(N = 379)
`13%
`18%
`9%
`3%
`4%
`6%
`3%
`4%
`5%
`4%
`2%
`1%
`3%
`3%
`3%
`2%
`2%
`2%
`1%
`<1%
`<1%
`
`Adverse Event
`Hypotension
`Hypertension
`Nausea
`Bradycardia
`
`Fever
`
`Vomiting
`Atrial Fibrillation
`Hypoxia
`Tachycardia
`
`Hemorrhage
`
`Anemia
`
`Dry Mouth
`Rigors
`Agitation
`Hyperpyrexia
`Pain
`
`Hyperglycemia
`Acidosis
`
`Pleural Effusion
`Oliguria
`
`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%
`
`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.
`
` 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%).
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`Reference ID: 3326669
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`Page 10 of 24
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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*
`
`Adverse Event
`N = 95
`
`
`6%
`Constipation
`5%
`Agitation
`5%
`Anxiety
`3%
`Oedema 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 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, 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
`
` Precedex
`Placebo
`
`N = 318
`N = 113
`
` (%)
` (%)
`Adverse Event
`Hypotension1
`54%
`30%
`Respiratory depression2
`37%
`32%
`Bradycardia3
`14%
`4%
`Hypertension4
`13%
`24%
`Tachycardia5
`5%
`17%
`Nausea
`3%
`2%
`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.
`
` 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.
`
`
`Postmarketing Experience
`6.2
`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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`Reference ID: 3326669
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`
` Cardiovascular Disorders, General
`
`
`
` Central and Peripheral Nervous System
`Disorders
`Gastrointestinal System Disorders
`
` Heart Rate and Rhythm Disorders
`
` Table 7: Adverse Reactions Experienced During Post-approval Use of Precedex
`Body System
`Preferred Term
`Fever, hyperpyrexia, hypovolemia, light anesthesia,
`Body as a Whole
`pain, rigors
`Blood pressure fluctuation, heart disorder,
`hypertension, hypotension, myocardial infarction
`Dizziness, headache, neuralgia, neuritis, speech
`disorder, convulsion
`
`Abdominal pain, diarrhea, vomiting, nausea
`Arrhythmia, ventricular arrhythmia, bradycardia,
`hypoxia, atrioventricular block, cardiac arrest,
`extrasystoles, atrial fibrillation, heart block, t wave
`inversion, tachycardia, supraventricular tachycardia,
`ventricular tachycardia
`Increased gamma-glutamyl transpepsidase, hepatic
`
`function abnormal, hyperbilirubinemia, alanine
`transaminase, aspartate aminotransferase
`
`Acidosis, respiratory acidosis, hyperkalemia,
`increased alkaline phosphatase, thirst, hypoglycemia
`Agitation, confusion, delirium, hallucination, illusion
`Anemia
`Blood urea nitrogen increased, oliguria
`Apnea, bronchospasm, dyspnea, hypercapnia,
`
`hypoventilation, hypoxia, pulmonary congestion
`
`Increased sweating
`Hemorrhage
`Photopsia, abnormal vision
`
`Liver and Biliary System Disorders
`
`Metabolic and Nutritional Disorders
`
` Psychiatric Disorders
`
`Red Blood Cell Disorders
`
`Renal Disorders
`Respiratory System Disorders
`
`Skin and Appendages Disorders
`Vascular Disorders
`Vision Disorders
`
`
`DRUG INTERACTIONS
`
`
`7
`
`
`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.
`
`
`Neuromuscular Blockers
`7.2
`
` 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.
`
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`Reference ID: 3326669
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`Page 13 of 24
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` USE IN SPECIFIC POPULATIONS
`
`8
`
`
`Pregnancy
`8.1
`Pregnancy Category C:
`
`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
`8.3
`It is not known whether Precedex 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 Precedex 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 effi