`
` 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 sodium chloride
`
`injection, for intravenous use
`Initial U.S. Approval: 1999
`
`--------------------------- RECENT MAJOR CHANGES ---------------------------
`
`
`
`Dosage and Administration, Preparation of Solution (2.4)
`08/2022
`
`
`Warnings and Precautions, Hyperthermia or Pyrexia (5.7)
`08/2022
`--------------------------- INDICATIONS AND USAGE ----------------------------
`
`PRECEDEX is a alpha2-adrenergic receptor 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 single-dose vial.
`
`
`To be used after dilution. (3)
`
`
` PRECEDEX in 0.9% Sodium Chloride Injection, 80 mcg/20 mL
`
`(4 mcg/mL) in a single-dose vial. Ready to use. (3)
`FULL PRESCRIBING INFORMATION: CONTENTS*
`INDICATIONS AND USAGE
`1
`
`Intensive Care Unit Sedation
`1.1
`1.2
`Procedural Sedation
`DOSAGE AND ADMINISTRATION
`
`Dosing Guidelines
`2.1
`
`Dosage Information
`2.2
`2.3
`Dosage Adjustment
`2.4
`Preparation of Solution
`
`Administration with Other Fluids
`2.5
`2.6
`Compatibility with Natural Rubber
`3
`DOSAGE FORMS AND STRENGTHS
`
`4
`CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`Drug Administration
`5.1
`
`Hypotension, Bradycardia, and Sinus Arrest
`5.2
`Transient Hypertension
`5.3
`
`5.4
`Arousability
`5.5 Withdrawal
`5.6
`Tolerance and Tachyphylaxis
`
`5.7
`Hyperthermia or Pyrexia
`5.8
`Hepatic Impairment
`ADVERSE REACTIONS
`
`Clinical Trials Experience
`6.1
`
`Postmarketing Experience
`6.2
`DRUG INTERACTIONS
`
`
`Anesthetics, Sedatives, Hypnotics, Opioids
`7.1
`
`
`2
`
`6
`
`7
`
`
`
`
`
`
` PRECEDEX in 0.9% Sodium Chloride Injection, 200 mcg/50 mL,
`
`400 mcg/100 mL, and 1,000 mcg/250 mL (4 mcg/mL) in single-dose glass
`
`
`
`
`bottles. 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 -----------------------
`
`
`
` 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, 5.8,
`
`8.6)
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`
`
`
`Revised: 08/2022
`
`
`
`8
`
`9
`
`7.2
`Neuromuscular Blockers
`
`
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`8.6
`Hepatic Impairment
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance
`9.3
`Dependence
`10 OVERDOSAGE
`
`11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.1
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`14 CLINICAL STUDIES
`14.1
`Intensive Care Unit Sedation
`
`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.
`
`Reference ID: 5029338
`
`1
`
`
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`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
`
`
`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: 5029338
`
`2
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`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 (5.8), 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. Do not use if product is discolored or if precipitate
`matter is present.
`
`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 is 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
`
`Reference ID: 5029338
`
`3
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`• 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.
`3
`DOSAGE FORMS AND STRENGTHS
`PRECEDEX (dexmedetomidine hydrochloride) injection is a clear and colorless solution, to be used after
`dilution. It is available as:
`
` 200 mcg/2 mL (100 mcg/mL) single-dose vial.
`PRECEDEX (dexmedetomidine hydrochloride) in 0.9% sodium chloride injection is a clear and colorless
`solution, ready to use. It is available as:
`
` PRECEDEX 80 mcg/20 mL (4 mcg/mL) single-dose vial.
`
` PRECEDEX 200 mcg/50 mL (4 mcg/mL) single-dose glass bottle.
`
` PRECEDEX 400 mcg/100 mL (4 mcg/mL) single-dose glass bottle.
`
` PRECEDEX 1,000 mcg/250 mL (4 mcg/mL) single-dose glass bottle.
`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.
`4
`
`Reference ID: 5029338
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`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.
`5.4
`Arousability
`Some patients receiving PRECEDEX have been observed to be arousable and alert when stimulated. This alone
`should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms.
`5.5 Withdrawal
`Intensive Care Unit Sedation
`
`With administration up to 7 days, regardless of dose, 12 (5%) PRECEDEX adult subjects experienced at least 1
`event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) PRECEDEX
`adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events
`were nausea, vomiting, and agitation.
`In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug
`discontinuation occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after discontinuation
`of PRECEDEX supportive therapy is indicated.
`Procedural Sedation
`In adult subjects, withdrawal symptoms were not seen after discontinuation of short-term infusions of
`PRECEDEX (<6 hours).
`5.6
`Tolerance and Tachyphylaxis
`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 Hyperthermia or Pyrexia
`PRECEDEX may induce hyperthermia or pyrexia, which may be resistant to traditional cooling methods, such
`as administration of cooled intravenous fluids and antipyretic medications. Discontinue PRECEDEX if
`
`drug-related hyperthermia or pyrexia is suspected and monitor patients until body temperature normalizes.
`5.8 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.
`
`Reference ID: 5029338
`
`5
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

` 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
`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
`All
`Propofol
`Placebo
`PRECEDEX
`PRECEDEX
`(N = 188)
`(N = 400)
`(N = 798)
`(N = 1007)
`(%)
`(%)
`(%)
`(%)
`Adverse Event
`13%
`12%
`24%
`25%
`Hypotension
`4%
`19%
`13%
`12%
`Hypertension
`11%
`9%
`9%
`9%
`Nausea
`0
`3%
`5%
`5%
`Bradycardia
`7%
`3%
`5%
`4%
`Atrial Fibrillation
`4%
`4%
`4%
`4%
`Pyrexia
`1%
`1%
`3%
`4%
`Dry Mouth
`3%
`5%
`3%
`3%
`Vomiting
`5%
`2%
`3%
`3%
`Hypovolemia
`6%
`3%
`3%
`3%
`Atelectasis
`6%
`1%
`2%
`2%
`Pleural Effusion
`1%
`3%
`2%
`2%
`Agitation
`1%
`4%
`2%
`2%
`Tachycardia
`
`2%
`2%
`2%
`2%
`Anemia
`0
`3%
`2%
`2%
`Hyperthermia
`2%
`3%
`2%
`2%
`Chills
`3%
`2%
`2%
`2%
`Hyperglycemia
`3%
`2%
`2%
`2%
`Hypoxia
`4%
`3%
`2%
`2%
`Post-procedural Hemorrhage
`3%
`1%
`1%
`1%
`Pulmonary Edema
`2%
`0
`1%
`1%
`Hypocalcemia
`2%
`1%
`1%
`1%
`Acidosis
`2%
`0
`1%
`1%
`Urine Output Decreased
`2%
`1%
`1%
`1%
`Sinus Tachycardia
`5%
`1%
`1%
`<1%
`Ventricular Tachycardia
`2%
`0
`1%
`<1%
`Wheezing
`2%
`1%
`0
`<1%
`Edema Peripheral
`
` *
` 26 subjects in the all PRECEDEX group and 10 subjects in the randomized PRECEDEX group had exposure for greater than 24
`hours.
`Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of
`PRECEDEX for sedation in the surgical intensive care unit setting in which 387 adult patients received
`6
`
`
`
`
`
`
`
`Reference ID: 5029338
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`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
`Placebo
`Randomized Dexmedetomidine
`
`(N = 379)
`(N = 387)
`Adverse Event
`28%
`13%
`Hypotension
`16%
`18%
`
`Hypertension
`
`11%
`9%
`Nausea
`7%
`3%
`Bradycardia
`5%
`4%
`Fever
`4%
`6%
`Vomiting
`4%
`3%
`Atrial Fibrillation
`4%
`4%
`Hypoxia
`3%
`5%
`Tachycardia
`3%
`4%
`Hemorrhage
`3%
`2%
`Anemia
`3%
`1%
`Dry Mouth
`2%
`3%
`Rigors
`2%
`3%
`Agitation
`2%
`3%
`Hyperpyrexia
`2%
`2%
`Pain
`2%
`2%
`Hyperglycemia
`2%
`2%
`Acidosis
`2%
`1%
`Pleural Effusion
`2%
`<1%
`Oliguria
`2%
`<1%
`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.
`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%
`
`Adverse Event
`Hypotension1
`Hypotension Requiring Intervention
`Bradycardia2
`Bradycardia Requiring Intervention
`Systolic Hypertension3
`Tachycardia4
`Tachycardia Requiring Intervention
`
`Midazolam
`(N = 122)
`56%
`27%
`19%
`1%
`42%
`44%
`10%
`
`Reference ID: 5029338
`
`7
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`Dexmedetomidine
`(N = 244)
`12%
`11%
`19%
`9%
`7%
`7%
`7%
`6%
`5%
`5%
`2%
`2%
`2%
`1%
`
`Midazolam
`(N = 122)
`15%
`15%
`30%
`13%
`2%
`6%
`2%
`6%
`6%
`3%
`1%
`1%
`6%
`7%
`
`>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%
`
`Adverse Event
`Diastolic Hypertension3
`Hypertension3
`Hypertension Requiring Intervention†
`Hypokalemia
`Pyrexia
`Agitation
`Hyperglycemia
`Constipation
`Hypoglycemia
`Respiratory Failure
`Renal Failure Acute
`Acute Respiratory Distress Syndrome
`Generalized Edema
`Hypomagnesemia
`
` Includes any type of hypertension.
`†
`1 Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or
`
`
`
`
`
`in relative terms as ≤30% lower than pre-study drug infusion value.
`
`
`2 Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value.
`
`
`
`
`
`3 Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or
`
`
`
`
`
`
`
`in relative terms as ≥30% higher than pre-study drug infusion value.
`
`
`Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.
`
`
`
`
`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.
`
`
`
`Reference ID: 5029338
`
`8
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`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
`
`Placebo
`PRECEDEX
`
`(N = 113)
`(N = 318)
`(%)
`(%)
`Adverse Event
`54%
`30%
`Hypotension1
`37%
`32%
`Respiratory Depression2
`14%
`4%
`Bradycardia3
`13%
`24%
`Hypertension4
`5%
`17%
`Tachycardia5
`3%
`2%
`Nausea
`3%
`1%
`Dry Mouth
`2%
`3%
`Hypoxia6
`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.
`
`
`
`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
`Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia,
`Cardiac Disorders
`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
`
`
`5
`
`Eye Disorders
`Gastrointestinal Disorders
`General Disorders and Administration
`Site Conditions
`Hepatobiliary Disorders
`
`Reference ID: 5029338
`
`
`Hepatic function abnormal, hyperbilirubinemia
`9
`
`This label may not be the latest approved by FDA.
`For current labeling information, please visit https://www.fda.gov/drugsatfda
`
`

`

`System Organ Class
`Investigations
`
`
`
`
`
`Preferred Term
`Alanine aminotransferase increased, aspartate aminotransferase
`increased, blood alkaline phosphatase increased, blood urea
`increased, electrocardiogram T wave inversion,
`gammaglutamyltransferase increased, electrocardiogram QT
`
` prolonged
`
` Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia
` Metabolism and Nutrition Disorders
`
` Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder
`Nervous System Disorders
`
` Agitation, confusional state, delirium, hallucination, illusion
`
` Psychiatric Disorders
`
` Oliguria, polyuria
`Renal and Urinary Disorders
`Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation,
`Respiratory, Thoracic and Mediastinal
`
` hypoxia, pulmonary congestion, respiratory acidosis
`Disorders
`Skin and Subcutaneous Tissue Disorders Hyperhidrosis, pruritus, rash, urticaria
`
`
` Surgical and Medical Procedures
` Light anesthesia
` Blood pressure fluctuation, hemorrhage, hypertension, hypotension
`Vascular Disorders
`7
` DRUG INTERACTIONS
`
`7.1
`Anesthetics, Sedatives, Hypnotics, Opioids
`Co-administration of PRECEDEX with anesthetics, sedatives, hypnotics, and opioids is likely to lead to an
`enhancement of effects. Specific studies have confirmed these effects with sevoflurane, isoflurane, propofol,
`alfentanil, and midazolam. No pharmacokinetic interactions between PRECEDEX and isoflurane, propofol,
`alfentanil and midazolam have been demonstrated. However, due to possible pharmacodynamic interactions,
`when co-administered with PRECEDEX, a reduction in dosage of PRECEDEX or the concomitant anesthetic,
`sedative, hypnotic or opioid may be required.
`7.2
`Neuromuscular Blockers
`In one study of 10 healthy adult volunteers, administration of PRECEDEX for 45 minutes at a plasma
`concentration of one ng/mL resulted in no clinically meaningful increases in the magnitude of neuromuscular
`blockade associated with rocuronium administration.
`8
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`Risk Summary
`Available data from published randomized controlled trials and case reports over several decades of use with
`intravenously administered dexmedetomidine during pregnancy have not identified a drug-associated risk of
`major birth defects and miscarriage; however, the reported exposures occurred after the first trimester. Most of
`the available data are based on studies with exposures that occurred at the time of caesarean section delivery,
`and these studies have not identified an adverse effect on maternal outcomes or infant Apgar scores. Available
`data indicate that dexmedetomidine crosses the placenta.
`In animal reproduction studies, fetal toxicity that lower fetal viability and reduced live fetuses occurred with
`subcutaneous administration of dexmedetomidine to pregnant rats during organogenesis at doses 1.8 times the
`maximum recommended human dose (MRHD) of 17.8 mcg/kg/day.
`Developmental toxicity (low pup weights and adult offspring weights, decreased F1 grip strength, increased
`early implantation loss and decreased viability of second-generation offspring) occurred when pregnant rats
`were subcutaneously administered dexmedetomidine at doses less than the clinical dose from late pregnancy
`through lactation and w