Last Time Saved: 9/26/12 2:39 PM
`Document Name: QEN-3116v1.indd
`
`PMS Black
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use dexmedetomidine
`hydrochloride safely and effectively. See full prescribing information for Precedex.
`Precedex (dexmedetomidine hydrochloride) injection
`For intravenous infusion
`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 vial contents in 0.9% sodium chloride solution to achieve required
`concentration (4 mcg/mL) prior to administration. (2.4)
`For Intensive Care Unit Sedation: Generally initiate at 1 mcg/kg over 10 minutes,
`followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/hr. (2.2)
`For Procedural Sedation: Generally initiate at 1 mcg/kg over 10 minutes, followed by a
`maintenance infusion initiated at 0.6 mcg/kg/hr and titrated to achieve desired clinical
`effect with doses ranging from 0.2 to 1 mcg/kg/hr.
`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)
` 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: 09/2012
`
`Table 4: 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
`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.
`
`Midazolam
`(N = 122)
`56%
`27%
`19%
`1%
`42%
`44%
`10%
`15%
`15%
`30%
`13%
`2%
`6%
`2%
`6%
`6%
`3%
`1%
`1%
`6%
`7%
`
`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%).
`
`Table 5. Number (%) of 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
`
`>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%
`
`Procedural Sedation
`
`Adverse reaction information is derived from the two trials for procedural sedation
`
`in which 318 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.
`
`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
`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.
`
`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.
`
`EN-3116
`
`Precedex™
`
`Rx only
`(dexmedetomidine hydrochloride) injection
`
`For Intravenous Infusion
`
`Hospira, Inc., Lake Forest, IL 60045 USA
`
`Table 2: Adverse Reactions with an Incidence >2%—Intensive Care Unit Sedation
`Population <24 hours*
`Randomized
`All Precedex
`Precedex
`Placebo
`Propofol
`(N = 1007)
`(N = 798)
`(N = 400)
`(N = 188)
`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 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).
`
`Table 3: Treatment-Emergent Adverse Events Occurring in >1% Of All Dexmedetomidine-
`Treated 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%
`
`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
`
`Placebo
`(N = 379)
`13%
`18%
`9%
`3%
`4%
`6%
`3%
`4%
`5%
`4%
`2%
`1%
`3%
`3%
`3%
`2%
`2%
`2%
`1%
`<1%
`<1%
`
`In a controlled clinical trial, Precedex was compared to midazolam for ICU sedation
`
`exceeding 24 hours duration. 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.
`
`DOSAGE FORMS AND STRENGTHS
`3
`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
`4
`None
`
`WARNINGS AND PRECAUTIONS
`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 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 subjects
`experienced at least 1 event related to withdrawal within the first 24 hours after
`discontinuing study drug and 7 (3%) Precedex subjects experienced at least 1 event 24 to
`48 hours after end of study drug. The most common events were nausea, vomiting, and
`agitation.
`
`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
`
`Withdrawal symptoms were not seen after discontinuation of short term infusions
`of Precedex (<6 hours).
`5.6
`Tolerance and Tachyphylaxis
`
`Use of dexmedetomidine beyond 24 hours has been associated with tolerance and
`tachyphylaxis and a dose-related increase in adverse reactions [see Adverse Reactions (6.1)].
`5.7
`Hepatic Impairment
`
`Since 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 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)].
`
`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.
`•
`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
`
`Table 1: Dosage Information
`DOSAGE AND ADMINISTRATION
`For adult patients: a loading infusion of 1 mcg/kg over
`10 minutes.
`For patients being converted from alternate sedative therapy:
`a loading dose may not be required [see Dosage and Administration:
`Maintenance of Intensive Care Unit Sedation (2.2)].
`For patients over 65 years of age: a dose reduction should be
`considered [see Use in Specific Populations (8.5)].
`For 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/hr.
`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 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 1 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 patients: a loading infusion of
`1 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 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/hr and titrated to achieve desired clinical effect with
`doses ranging from 0.2 to 1 mcg/kg/hr. The rate of the maintenance
`infusion should be adjusted to achieve the targeted level of
`sedation.
`For awake fiberoptic intubation patients: a maintenance
`infusion of 0.7 mcg/kg/hr 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 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 patients with hepatic
`impairment, and geriatric patients [see Warnings and Precautions (5.7), Use in Specific
`Populations (8.6), Clinical Pharmacology (12.3)].
`2.4
`Preparation of Solution
`
`Strict aseptic technique must always be maintained during handling of Precedex.
`
`Parenteral drug products should be inspected visually for particulate matter and
`discoloration prior to administration, whenever solution and container permit.
`
`Precedex Injection, Concentrate, 200 mcg/2 mL (100 mcg/mL)
`
`Precedex must be diluted in 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 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/50 mL (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.
`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
`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.
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`8
`
`1.1
`Intensive Care Unit Sedation
`
`
`1.2 Procedural Sedation
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosing Guidelines
`
`
`2.2 Dosage Information
`
`
`2.3 Dosage Adjustment
`9
`
`2.4 Preparation of Solution
`
`2.5
` Administration with Other
`
`Fluids
`
` Compatibility with Natural
`10
`Rubber
`11
`DOSAGE FORMS AND STRENGTHS
`12
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`5.1 Drug Administration
`
`5.2
` Hypotension, Bradycardia, and
`13
`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
`
`2.6
`
`
`
`3
`4
`5
`
`
`
`
`
`
`
`
`6
`
`
`7
`
`
`
`
`Reference ID: 3276639
`
`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
`DRUG ABUSE AND DEPENDENCE
`9.1 Controlled Substance
`9.3 Dependence
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis,
`Impairment of Fertility
`13.2 Animal Pharmacology and/or
`Toxicology
`CLINICAL STUDIES
`14.1 Intensive Care Unit Sedation
`14.2 Procedural Sedation
` HOW SUPPLIED/STORAGE AND
`HANDLING
` PATIENT COUNSELING INFORMATION
`17
`* Sections or subsections omitted from the
`full prescribing information are not listed
`
`14
`
`
`16
`
`
`
`

`

`between the Precedex and comparator groups. Efficacy results showed that Precedex was
`more effective than the comparator group when used to sedate non-intubated patients
`requiring monitored anesthesia care during surgical and other procedures (see Table 13).
`
`In Study 2, the sedative properties of Precedex were evaluated by comparing
`the percent of patients requiring rescue midazolam to achieve or maintain a specified
`level of sedation using the Ramsay Sedation Scale score ≥2 (see Table 9). Patients were
`randomized to receive a loading infusion of Precedex 1 mcg/kg or placebo (normal saline)
`given over 10 minutes and followed by a fixed maintenance infusion of 0.7 mcg/kg/hr.
`After achieving the desired level of sedation, topicalization of the airway occurred. Patients
`were allowed to receive rescue midazolam as needed to achieve and/or maintain a Ramsay
`Sedation Scale ≥2. Demographic characteristics were similar between the Precedex and
`comparator groups. For efficacy results see Table 13.
`
`Table 13: Key Efficacy Results of Procedural Sedation Studies
`Mean (SD)
`Total Dose
`(mg) of
`Rescue
`Midazolam
`Required
`
`% Not
`Requiring
`Midazolam
`Rescue
`
`Confidenceb
`Interval
`on the
`Difference vs.
`Placebo
`
`Number of
`Patients
`Enrolleda
`
`Confidenceb
`Intervals of
`the Mean
`Rescue Dose
`
`Last Time Saved: 9/26/12 2:39 PM
`Document Name: QEN-3116v1.indd
`
`PMS Black
`
`Cardiovascular Disorders, General
`
`Central and Peripheral Nervous
`System Disorders
`Gastrointestinal System Disorders
`Heart Rate and Rhythm Disorders
`
`Liver and Biliary System Disorders
`
`Table 7: Adverse Reactions Experienced During Post-approval Use of Precedex
`Body System
`Preferred Term
`Body as a Whole
`Fever, hyperpyrexia, hypovolemia, light anesthesia, 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
`Metabolic and Nutritional Disorders 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
`
`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.
`7.2
`Neuromuscular Blockers
`
`In one study of 10 healthy volunteers, administration of Precedex for 45 minutes
`at a plasma concentration of 1 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
`
`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.
`8.3
`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
`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
`
`The efficacy, safety, and pharmacokinetics of Precedex in pediatric patients less
`than 18 years of age have not been established. Therefore, Precedex should not be used in
`this population.
`8.5
`Geriatric Use
`
`Intensive Care Unit Sedation
`
`A total of 729 patients in the clinical studies were 65 years of age and over. A total
`of 200 patients were 75 years of age and over. In patients greater than 65 years of age, a
`higher incidence of bradycardia and hypotension was observed following administration
`of Precedex [see Warnings and Precautions (5.2)]. Therefore a dose reduction may be
`considered in patients over 65 years of age [see Dosage and Administration (2.2) and Clinical
`Pharmacology (12.3)].
`
`Procedural Sedation
`
`A total of 131 patients in the clinical studies were 65 years of age and over. A total
`of 47 patients were 75 years of age and over. Hypotension occurred in a higher incidence in
`Precedex-treated patients 65 years or older (72%) and 75 years or older (74%) as compared
`to patients <65 years (47%). A reduced loading dose of 0.5 mcg/kg given over 10 minutes
`is recommended and a reduction in the maintenance infusion should be considered for
`patients greater than 65 years of age.
`8.6
`Hepatic Impairment
`
`Since Precedex clearance decreases with increasing severity of hepatic impairment,
`dose reduction should be considered in patients with impaired hepatic function [see
`Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
`9
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance
`
`Precedex (dexmedetomidine hydrochloride) is not a controlled substance.
`
`Reference ID: 3276639
`
`Dependence
`9.3
`The dependence potential of Precedex has not been stu