`
`
`
` 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, for intravenous use
`
`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-dose vial, and 200 mcg/50 mL,
`
`
`
`
`400 mcg/100 mL, and 1,000 mcg/250 mL single-dose 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
`
`
`
`
`glass vial Ready to use (3)
`
`
`
`
`
`Precedex in 0 9% Sodium Chloride Injection, 200 mcg/50 mL (4 mcg/mL) in
`
`
`
`a glass bottle Ready to use (3)
`
`
`
`
`Precedex in 0 9% Sodium Chloride Injection, 400 mcg/100 mL (4 mcg/mL) in
`
`
`
`a glass bottle Ready to use (3)
`
`
`
`
`
`
`Precedex in 0 9% Sodium Chloride Injection, 1,000 mcg/250 mL (4 mcg/mL)
`
`
`
`
`in a glass bottle Ready to use (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)
`
`
` Tolerance and Tachyphylaxis: 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 >2%) are hypotension,
`
`bradycardia, and dry mouth (6 1)
`
` Adverse reactions associated with infusions >24 hours in duration include
`
`
`
`
`
`
`
`
`ARDS, respiratory failure, and agitation (6 1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc.
`at 1-800-441-4100, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`------------------------------ DRUG INTERACTIONS------------------------------
`
`
`Anesthetics, Sedatives, Hypnotics, Opioids: Enhancement of
`
`
`pharmacodynamic effects Reduction in dosage of Precedex or the
`
`concomitant medication may be required (7 1)
`
`
`
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`
`
` 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)
`
`
`
` Geriatric Patients: Dose reduction should be considered (2 2, 2 3, 5 2,
`
`
`
`
`
`8 5)
`
`
` Hepatic Impairment: Dose reduction should be considered (2 2, 2 3, 5 7,
`
`
`
`
`8 6)
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`Revised: 02/2020
`
`
`8
`
`9
`
`
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`Pregnancy
`8 1
`
`Labor and Delivery
`8 2
`
`Nursing Mothers
`8 3
`
`Pediatric Use
`8 4
`
`Geriatric Use
`8 5
`
`
`Hepatic Impairment
`8 6
`
`
`DRUG ABUSE AND DEPENDENCE
`
`Controlled Substance
`9 1
`
`Dependence
`9 3
`
`10 OVERDOSAGE
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`
`12 1 Mechanism of Action
`
`Pharmacodynamics
`12 2
`Pharmacokinetics
`12 3
`
`13 NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13 1
`
`
`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
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`INDICATIONS AND USAGE
`1 1
`Intensive Care Unit Sedation
`
`1 2
`Procedural Sedation
`
`DOSAGE AND ADMINISTRATION
`Dosing Guidelines
`2 1
`
`
`Dosage Information
`2 2
`
`Dosage Adjustment
`2 3
`
`
`Preparation of Solution
`2 4
`
`Administration with Other Fluids
`2 5
`
`Compatibility with Natural Rubber
`2 6
`
`
`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
`
`Arousability
`5 4
`
`5 5 Withdrawal
`
`Tolerance and Tachyphylaxis
`5 6
`
`
`Hepatic Impairment
`5 7
`
`
`ADVERSE REACTIONS
`
`
`Clinical Trials Experience
`6 1
`
`6 2
`Postmarketing Experience
`
`
`DRUG INTERACTIONS
`
`Anesthetics, Sedatives, Hypnotics, Opioids
`7 1
`
`
`7 2
`Neuromuscular Blockers
`
`6
`
`7
`
`
`
`Reference ID: 4554684
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`INDICATIONS AND USAGE
`1
`
`Intensive Care Unit Sedation
`1.1
`
`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.
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`Dosing Guidelines
`2.1
`
`
`• 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
`
`
`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.
`
`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)].
`
`
`
`
`
`
`
`
`Reference ID: 4554684
`
`

`

`INDICATION
`Maintenance of Procedural
`Sedation
`
`
`
`DOSAGE AND ADMINISTRATION
`For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/hour
`
`
`
`and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1
`mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the
`
`targeted level of sedation.
`
`For awake fiberoptic intubation in adult patients: a maintenance infusion of
`
`0.7 mcg/kg/hour is recommended until the endotracheal tube is secured.
`
`
`
`
`For patients over 65 years of age: a dose reduction should be considered [see Use in
`
`Specific Populations (8.5)].
`
`
`For adult patients with impaired hepatic function: a dose reduction should be
`
`
`considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
`
`
`
`
`
` Dosage Adjustment
`2.3
`
`
`
`
`
` Due to possible pharmacodynamic interactions, a reduction in dosage of Precedex or other concomitant
`
` anesthetics, sedatives, hypnotics or opioids may be required when co-administered [see Drug
`
`
` Interactions (7.1)].
` Dosage reductions may need to be considered for adult patients with hepatic impairment, and geriatric patients
`
`
`
`
`
`
`
`
` [see Warnings and Precautions (5.7), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
` Preparation of Solution
`2.4
`
`
` Strict aseptic technique must always be maintained during handling of Precedex.
`
`
` Parenteral drug products should be inspected visually for particulate matter and discoloration prior to
`
`administration, whenever solution and container permit.
`
`
`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),
`
`400 mcg/100 mL (4 mcg/mL), and 1,000 mcg/250 mL (4 mcg/mL)
`
`
`
`
`
`
`Precedex in 0.9% Sodium Chloride Injection is supplied in glass containers containing a premixed, ready to use
`
`
`
`
`
`dexmedetomidine hydrochloride solution in 0.9% sodium chloride in water. No further dilution of these
`
`preparations are necessary.
`
`
`
`Administration with Other Fluids
`2.5
`
`Precedex infusion should not be co-administered through the same intravenous catheter with blood or plasma
`
`because physical compatibility has not been established.
`Precedex has been shown to be incompatible when administered with the following drugs: amphotericin B,
`
`diazepam.
`
`
`
`
`
`Precedex has been shown to be compatible when administered with the following intravenous fluids:
`• 0.9% sodium chloride in water
`• 5% dextrose in water
`• 20% mannitol
`
`• Lactated Ringer’s solution
`
`• 100 mg/mL magnesium sulfate solution
`
`• 0.3% potassium chloride solution
`
`
`
`Reference ID: 4554684
`
`

`

`
`
` Commented [A1]: Added as per FDA IR received on 13-Dec­
`
`2019 and in line with CFR 201 57(c)(4)(ii)
`
`
`
`Commented [A2]: Added as per FDA IR received on 13-Dec­
`
`
`2019
`
`
` 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.
` DOSAGE FORMS AND STRENGTHS
`
`
`3
`Precedex Injection is clear and colorless and is available as follows.
`
`
`
`
`
`
`Precedex Injection
`
`
`Precedex Injection, 200 mcg dexmedetomidine/2 mL (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) in a glass vial. Ready to use.
`
`
`
`
`Precedex Injection, 200 mcg dexmedetomidine/50 mL (4 mcg/mL) in a glass bottle. Ready to use.
`
`
`
`
`
`
`
`Precedex Injection, 400 mcg dexmedetomidine/100 mL (4 mcg/mL) in a glass bottle. Ready to use.
`
`
`
`
`
`
`
`
`
`
`Precedex Injection, 1,000 mcg dexmedetomidine/250 mL (4 mcg/mL) in a glass bottle. Ready to use.
`
`
`CONTRAINDICATIONS
`4
`None.
`
`5
`WARNINGS AND PRECAUTIONS
`
`
`5.1
`Drug Administration
`Precedex should be administered only by persons skilled in the management of patients in the intensive care or
`
`
`
`
`
`
`operating room setting. Due to the known pharmacological effects of Precedex, patients should be continuously
`
`monitored while receiving Precedex.
`
`
`5.2 Hypotension, Bradycardia, and Sinus Arrest
`
`
`
`
`Clinically significant episodes of bradycardia and sinus arrest have been reported with Precedex administration
`
`
`in young, healthy adult volunteers with high vagal tone or with different routes of administration including
`
`
`rapid intravenous or bolus administration.
`
`
`
`
`
`
`Reports of hypotension and bradycardia have been associated with Precedex infusion. Some of these cases have
`
`resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the
`infusion of Precedex, increasing the rate of intravenous fluid administration, elevation of the lower extremities,
`
`
`
`
`
`and use of pressor agents. Because Precedex has the potential to augment bradycardia induced by vagal stimuli,
`
`
`
`
`
`clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g.,
`
`
`
`glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine
`
`were effective in the treatment of most episodes of Precedex-induced bradycardia. However, in some patients
`
`with significant cardiovascular dysfunction, more advanced resuscitative measures were required.
`
`
`
`
`Caution should be exercised when administering Precedex to patients with advanced heart block and/or severe
`
`
`
`ventricular dysfunction. Because Precedex decreases sympathetic nervous system activity, hypotension and/or
`
`
`
`
`bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic
`
`
`hypertension and in elderly patients.
`
`
`
`
`
`In clinical trials where other vasodilators or negative chronotropic agents were co-administered with Precedex
`
`
`
`
`
`
`an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents
`
`are administered concomitantly with Precedex.
`
`
`
`Reference ID: 4554684
`
`

`

`
`
`
`
`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).
`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, 2.3)].
`
`
`
`ADVERSE REACTIONS
`6
`
`
`
`
`
`The following clinically significant adverse reactions are described elsewhere in the labeling:
`
` Hypotension, bradycardia and sinus arrest [see Warnings and Precautions (5.2)]
`
`
`
`
` Transient hypertension [see Warnings and Precautions (5.3)]
`
`
`
`
`6.1
`Clinical Trials Experience
`
`
`
`Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the
`
`
`
`
`clinical trials of a drug cannot be directly compared to rates in the 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.
`
`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 1,007 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
`
`
`
`Reference ID: 4554684
`
`

`

`
`
`
`
`
`
`
`
` 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
`
`24%
`25%
`13%
`12%
`Hypotension
`13%
`12%
`4%
`19%
`Hypertension
`
`9%
`9%
`11%
`9%
`Nausea
`
`5%
`5%
`0
`3%
`Bradycardia
`5%
`4%
`7%
`3%
`Atrial Fibrillation
`
`4%
`
` 4%
`4%
`4%
`Pyrexia
`3%
`4%
`1%
`1%
`Dry Mouth
`
`
`3%
`3%
`3%
`5%
`Vomiting
`
`3%
`3%
`5%
`2%
`Hypovolemia
`
`3%
`3%
`6%
`3%
`Atelectasis
`
`2%
`2%
`6%
`1%
`Pleural Effusion
`
`2%
`2%
`1%
`3%
`Agitation
`
`2%
`2%
`1%
`4%
`Tachycardia
`
`2%
`2%
`2%
`2%
`Anemia
`
`2%
`2%
`0
`3%
`Hyperthermia
`
`2%
`2%
`2%
`3%
`Chills
`
`2%
`2%
`3%
`2%
`Hyperglycemia
`
`2%
`2%
`3%
`2%
`Hypoxia
`
`2%
`
` 2%
`4%
`3%
` Post-procedural Hemorrhage
`1%
`1%
`3%
`1%
`Pulmonary Edema
`
`
`1%
`
` 1%
`2%
`0
`Hypocalcemia
`1%
`1%
`2%
`1%
`Acidosis
`
`1%
`
` 1%
`2%
`0
` Urine Output Decreased
`1%
`1%
`2%
`1%
`Sinus Tachycardia
`
`
`1%
`<1%
`5%
`1%
`Ventricular Tachycardia
`1%
`<1%
`2%
`0
`Wheezing
`0
`<1%
`2%
`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).
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4554684
`
`

`

`
`
`
`
`
`Midazolam
`
`(N = 122)
`56%
`27%
`19%
`1%
`42%
`44%
`10%
`15%
`15%
`
`
`
` 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
`Placebo
`
`(N = 387)
`(N = 379)
`
`
`
` Adverse Event
`
`Hypotension
`28%
`13%
`Hypertension
`16%
`18%
`Nausea
`11%
`9%
`Bradycardia
`7%
`3%
`Fever
`5%
`4%
`Vomiting
`4%
`6%
`Atrial Fibrillation
`4%
`3%
`Hypoxia
`4%
`4%
`
`Tachycardia
`
` 3%
`5%
`Hemorrhage
`3%
`4%
`
`Anemia
`3%
`2%
`Dry Mouth
`3%
`1%
`
`Rigors
`2%
`3%
`Agitation
`2%
`3%
`
` Hyperpyrexia
`
`2%
`3%
`Pain
`2%
`2%
`Hyperglycemia
`2%
`2%
`Acidosis
`2%
`2%
`Pleural Effusion
`2%
`1%
`
`Oliguria
`2%
`<1%
`Thirst
`<1%
`2%
`
`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.
`
`
`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%
`
`Adverse Event
`
`Hypotension1
`Hypotension Requiring Intervention
`Bradycardia2
`Bradycardia Requiring Intervention
`Systolic Hypertension3
`Tachycardia4
` Tachycardia Requiring Intervention
`Diastolic Hypertension3
`Hypertension3
`
`
`
`
`
`Reference ID: 4554684
`
`

`

`Dexmedetomidine
`
` (N = 244)
`19%
`9%
`7%
`7%
`7%
`6%
`5%
`5%
`2%
`2%
`2%
`1%
`
` Midazolam
`
`(N = 122)
`30%
`13%
`2%
`6%
`2%
`6%
`6%
`3%
`1%
`1%
`6%
`7%
`
`
`
`
`
` Adverse Event
`
`Hypertension Requiring Intervention†
`Hypokalemia
`Pyrexia
`Agitation
`Hyperglycemia
`Constipation
`Hypoglycemia
` Respiratory Failure
`
`Renal Failure Acute
`
`Acute Respiratory Distress Syndrome
`
`Generalized Edema
`
`Hypomagnesemia
`
` Includes any type of hypertension
`†
`
`
`
`
`1 Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or
`
`
`in relative terms as ≤30% lower than pre-study drug infusion value
`
`
`
`
`
`
`2 Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value
`
`
`
`
`3 Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or
`
`
`
`in relative terms as ≥30% higher than pre-study drug infusion value
`
`
`
`
`
`Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value
`4
` 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 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.
`
`
`
`
`
`
`
`
`
`
`
` >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%
`
`
`
`Reference ID: 4554684
`
`

`

`
`
` The decrease in respiratory rate and hypoxia was similar between Precedex and comparator groups in both
`
` studies.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5
`
` 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
`
`
`
`
`Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion
`
`value
`
`
`
`6 Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline
`6.2
`
`
` Postmarketing Experience
` The following adverse reactions have been identified during post-approval use of Precedex. Because these
`
`
`
`
`
` reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably
` estimate their frequency or establish a causal relationship to drug exposure.
`
`
`
` Hypotension and bradycardia were the most common adverse reactions associated with the use of Precedex
`
`
` during post-approval use of the drug.
` Table 7: Adverse Reactions Experienced During Post-Approval Use of Precedex
`
`
` System Organ Class
` Preferred Term
`Blood and Lymphatic System Disorders Anemia
`
`
`
`Cardiac Disorders
`Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia,
`
`
`cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction,
`
`
`supraventricular tachycardia, tachycardia, ventricular arrhythmia,
`ventricular tachycardia
`Photopsia, visual impairment
`
` Abdominal pain, diarrhea, nausea, vomiting
`Chills, hyperpyrexia, pain, pyrexia, thirst
`
`
`
`
`
`
`
`Eye Disorders
`Gastrointestinal Disorders
`General Disorders and Administration
`
`
`Site Conditions
`
`Hepatobiliary Disorders
`Investigations
`
`
`Hepatic function abnormal, hyperbilirubinemia
`Alanine aminotransferase increased, aspartate aminotransferase
`increased, blood alkaline phosphatase increased, blood urea
`
`
`increased, electrocardiogram T wave inversion,
`
`
`
`
`Reference ID: 4554684
`
`

`

`
`
`
`
`
`
` Preferred Term
`
`
` gammaglutamyltransferase increased, electrocardiogram QT
`prolonged
` Metabolism and Nutrition Disorders
`
`Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia
`Nervous System Disorders
`Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder
`
`
`Psychiatric Disorders
`Agitation, confusional state, delirium, hallucination, illusion
`
`Renal and Urinary Disorders
`
`
` Oliguria, polyuria
`
` Respiratory, Thoracic and Mediastinal
`Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation,
`Disorders
`
`
` hypoxia, pulmonary congestion, respiratory acidosis
`
` Skin and Subcutaneous Tissue Disorders Hyperhidrosis, pruritus, rash, urticaria
` Surgical and Medical Procedures
`
`
`
` Light anesthesia
`Blood pressure fluctuation, hemorrhage, hypertension, hypotension
`Vascular 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 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.
`
`USE IN SPECIFIC POPULATIONS
`8
`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
`