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)
`10/2024
`
` --------------------------- INDICATIONS AND USAGE ----------------------------
`PRECEDEX is a alpha2-adrenergic receptor agonist indicated for:
`
`• Sedation of initially intubated and mechanically ventilated adult patients
`during treatment in an intensive care setting. Administer PRECEDEX by
`continuous infusion not to exceed 24 hours. (1.1)
`
`• Sedation of non-intubated adult patients prior to and/or during surgical and
`other procedures. (1.2)
`
`• Sedation of non-intubated pediatric patients aged 1 month to less than
`18 years prior to and during non-invasive 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 and single-
`dose flexible containers do not require further dilution prior to
`administration. (2.4)
`
`• For Adult Intensive Care Unit Sedation: Initiate at one mcg/kg over
`10 minutes, followed by a maintenance infusion of 0.2 mcg/kg/hour to
`0.7 mcg/kg/hour. (2.2)
`
`• For Adult Procedural Sedation: 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 mcg/kg/hour to 1 mcg/kg/hour. (2.2)
`
`• For Sedation of Pediatric Patients During Non-invasive Procedures:
`Patients 1 month to less than 2 years old initiate at 1.5 mcg/kg over
`10 minutes followed by a maintenance infusion of 1.5 mcg/kg/hour and
`titrated to achieve desired clinical effect with dosage ranging from
`0.5 mcg/kg/hour to 1.5 mcg/kg/hour; patients 2 to less than 18 years old
`initiate at 2 mcg/kg over 10 minutes followed by a maintenance infusion of
`1.5 mcg/kg/hour and titrated to achieve desired clinical effect with dosage
`ranging from 0.5 mcg/kg/hour to 1.5 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)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`
`2
`
`INDICATIONS AND USAGE
`1.1
`Intensive Care Unit Sedation
`1.2
`Procedural Sedation
`DOSAGE AND ADMINISTRATION
`2.1
`Administration Instructions
`2.2
`Recommended Dosage
`2.3
`Dosage Adjustment
`2.4
`Preparation of Solution
`2.5
`Administration with Other Fluids
`2.6
`Compatibility with Natural Rubber
`DOSAGE FORMS AND STRENGTHS
`3
`CONTRAINDICATIONS
`4
`5 WARNINGS AND PRECAUTIONS
`5.1
`Drug Administration
`5.2
`Hypotension, Bradycardia, and Sinus Arrest
`5.3
`Transient Hypertension
`5.4
`Arousability
`
`• PRECEDEX in 0.9% Sodium Chloride Injection, 80 mcg/20 mL
`(4 mcg/mL) in a single-dose vial. Ready to use. (3)
`
`• 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)
`
`• 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
`flexible containers. 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%) in adults are
`hypotension, bradycardia, and dry mouth. (6.1)
`
`• The most common adverse reactions (incidence >5%) in pediatric patients
`aged 1 month to less than 17 years are bradypnea, bradycardia,
`hypertension, and hypotension. (6.1)
`
`• Adverse reactions in adults, 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: 10/2024
`
`
`
`5.5 Withdrawal
`5.6
`Tolerance and Tachyphylaxis
`5.7
`Hyperthermia or Pyrexia
`5.8
`Hepatic Impairment
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`DRUG INTERACTIONS
`7.1
`Anesthetics, Sedatives, Hypnotics, Opioids
`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
`
`6
`
`7
`
`8
`
`9
`
`1
`
`Reference ID: 5461471
`
`

`

`Dependence
`9.3
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2
`Pharmacodynamics
`12.3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`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: 5461471
`
`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 adult 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 adult 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 adult patients prior to and/or during surgical and other
`procedures.
`
`PRECEDEX is indicated for sedation of non-intubated pediatric patients aged 1 month to less than 18 years
`prior to and during non-invasive procedures.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1
`
`Administration Instructions
`
`• 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.
`
`2.2
`
`Recommended Dosage
`
`INDICATION
`
`DOSAGE AND ADMINISTRATION
`
`Table 1: Recommended Dosage in Adult Patients
`
`Initiation of Intensive Care
`Unit Sedation
`
`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: Consider a dose reduction [see Use in Specific
`Populations (8.5)].
`
`For adult patients with impaired hepatic function: Consider a dose reduction [see Use
`in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
`Maintenance of Intensive
`Care Unit Sedation
`
`For adult patients: a maintenance infusion of 0.2 mcg/kg/hour 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: Consider a dose reduction [see Use in Specific
`Populations (8.5)].
`
`For adult patients with impaired hepatic function: Consider a dose reduction [see Use
`in Specific Populations (8.6), Clinical Pharmacology (12.3)]
`
`Reference ID: 5461471
`
`3
`
`

`

`INDICATION
`
`DOSAGE AND ADMINISTRATION
`
`Initiation of Procedural
`Sedation
`
`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: Consider a dose reduction [see Use
`in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
`Maintenance of Procedural
`Sedation
`
`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 mcg/kg/hour
`to 1 mcg/kg/hour. Adjust the rate of the maintenance infusion 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: Consider a dose reduction [see Use in Specific
`Populations (8.5)].
`
`For adult patients with impaired hepatic function: Consider a dose reduction [see Use
`in Specific Populations (8.6), Clinical Pharmacology (12.3)].
`
`Table 2: Recommended Dosage in Pediatric Patients
`
`INDICATION
`
`DOSAGE AND ADMINISTRATION
`
`Initiation of Sedation
`During Non-invasive
`Procedures
`
`Maintenance of Sedation
`During Non-invasive
`Procedures
`
`For pediatric patients:
`
`• 1 month to less than 2 years: a loading infusion of 1.5 mcg/kg over 10 minutes.
`• 2 to less than 18 years: a loading infusion of 2 mcg/kg over 10 minutes.
`
`Consider a reduction in dosage if clinically indicated.
`
`For pediatric patients:
`
`• 1 month to less than 18 years: the maintenance infusion is generally initiated at
`1.5 mcg/kg/hour and titrated to achieve desired clinical effect with dosage ranging
`from 0.5 mcg/kg/hour to 1.5 mcg/kg/hour.
`
`As clinically warranted, titrate the maintenance dose to individual patient clinical
`response.
`
`
`
`
`
`2.3
`
`Dosage Adjustment
`
`Due to possible pharmacodynamic interactions, a reduction in dosage of PRECEDEX or other concomitant
`anesthetics, sedatives, hypnotics or opioids may be required when co-administered [see Drug
`Interactions (7.1)].
`
`Dosage reductions may need to be considered for adult patients with hepatic impairment, and geriatric patients
`[see Warnings and Precautions (5.8), 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.
`
`Reference ID: 5461471
`
`4
`
`

`

`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 Presentations Requiring Dilution:
`
`• 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 Presentations that are Ready to Use:
`
`PRECEDEX in 0.9% Sodium Chloride Injection is supplied in glass containers and flexible containers:
`
`• 80 mcg/20 mL (4 mcg/mL) in glass vials
`• 200 mcg/50 mL (4 mcg/mL) in glass bottles and flexible containers
`• 400 mcg/100 mL (4 mcg/mL) in glass bottles and flexible containers
`• 1,000 mcg/250 mL (4 mcg/mL) in glass bottles and flexible containers
`
`These presentations contain a premixed, ready to use dexmedetomidine hydrochloride solution in 0.9% sodium
`chloride in water. No further dilution of these preparations is necessary.
`
`Instructions for Use for Flexible Containers:
`
`1. Tear outer wrap at the notch and remove solution container.
`
`2. Check the container for minute leaks by squeezing it firmly. If leaks are found, or if the seal is not intact,
`discard the solution as the sterility may be compromised.
`
`3. Do not use if the solution is cloudy or a precipitate is present.
`
`4. Use aseptic technique.
`
`Preparation for Administration:
`
`1. Close flow control clamp of administration set.
`
`2. Remove twist-off cap from administration port at bottom of flexible container.
`
`3. Insert spike of administration set into administration port with a twisting motion until the spike is firmly
`seated. NOTE: See full directions on administration set carton.
`
`4. Suspend container from hanger.
`
`5. Squeeze and release drip chamber to establish proper fluid level in chamber during infusion.
`
`6. Open flow control clamp to expel air from set. Close clamp.
`
`7. Regulate rate of administration with flow control clamp.
`
`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:
`
`Reference ID: 5461471
`
`5
`
`

`

`• 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.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`PRECEDEX Presentations Requiring Dilution:
`
`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 Presentations that are Ready To Use:
`
`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.
`• PRECEDEX 200 mcg/50 mL (4 mcg/mL) single-dose flexible container.
`• PRECEDEX 400 mcg/100 mL (4 mcg/mL) single-dose flexible container.
`• PRECEDEX 1,000 mcg/250 mL (4 mcg/mL) single-dose flexible container.
`
`4
`
`CONTRAINDICATIONS
`
`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
`
`6
`
`Reference ID: 5461471
`
`

`

`bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced
`resuscitative measures were required.
`
`Caution should be exercised when administering PRECEDEX to patients with advanced heart block and/or
`severe ventricular dysfunction. Because PRECEDEX decreases sympathetic nervous system activity,
`hypotension and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes
`mellitus, or chronic hypertension and in elderly patients.
`
`In clinical trials where other vasodilators or negative chronotropic agents were co-administered with
`PRECEDEX an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when
`such agents are administered concomitantly with PRECEDEX.
`
`5.3
`
`Transient Hypertension
`
`Transient hypertension has been observed primarily during the loading dose in association with the initial
`peripheral vasoconstrictive effects of PRECEDEX. Treatment of the transient hypertension has generally not
`been necessary, although reduction of the loading infusion rate may be desirable.
`
`5.4
`
`Arousability
`
`Some patients receiving PRECEDEX have been observed to be arousable and alert when stimulated. This alone
`should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms.
`
`5.5 Withdrawal
`
`Intensive Care Unit Sedation
`
`With administration up to 7 days, regardless of dose, 12 (5%) PRECEDEX adult subjects experienced at least 1
`event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) PRECEDEX
`adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events
`were nausea, vomiting, and agitation [see Adverse Reactions (6.1)].
`
`In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug
`discontinuation occurred at frequencies of <5%.
`
`Procedural Sedation
`
`In adult subjects, withdrawal symptoms were not seen after discontinuation of short-term infusions of
`PRECEDEX (<6 hours).
`
`In pediatric patients, mild transient withdrawal symptoms of emergence delirium or agitation were seen after
`discontinuation of short-term infusions of PRECEDEX (<2 hours) [see Adverse Reactions (6.1)].
`
`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)].
`
`6
`
`ADVERSE REACTIONS
`
`The following clinically significant adverse reactions are described elsewhere in the labeling:
`
`Reference ID: 5461471
`
`7
`
`

`

`• 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 adult 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
`incidence of >2% are provided in Table 3. The most frequent adverse reactions were hypotension, bradycardia
`and dry mouth [see Warnings and Precautions (5.2)].
`
`Table 3: Adverse Reactions with an Incidence >2%-Adult Intensive Care Unit Sedation Population
`<24 hours*
`
`Adverse Event
`Hypotension
`Hypertension
`Nausea
`Bradycardia
`Atrial Fibrillation
`Pyrexia
`Dry Mouth
`Vomiting
`Hypovolemia
`Atelectasis
`Pleural Effusion
`Agitation
`Tachycardia
`Anemia
`Hyperthermia
`Chills
`Hyperglycemia
`Hypoxia
`Post-procedural Hemorrhage
`Pulmonary Edema
`Hypocalcemia
`Acidosis
`
`All
`PRECEDEX
`(N = 1007)
`(%)
`25%
`12%
`9%
`5%
`4%
`4%
`4%
`3%
`3%
`3%
`2%
`2%
`2%
`2%
`2%
`2%
`2%
`2%
`2%
`1%
`1%
`1%
`
`Randomized
`PRECEDEX
`(N = 798)
`(%)
`24%
`13%
`9%
`5%
`5%
`4%
`3%
`3%
`3%
`3%
`2%
`2%
`2%
`2%
`2%
`2%
`2%
`2%
`2%
`1%
`1%
`1%
`
`8
`
`Reference ID: 5461471
`
`Placebo
`(N = 400)
`(%)
`12%
`19%
`9%
`3%
`3%
`4%
`1%
`5%
`2%
`3%
`1%
`3%
`4%
`2%
`3%
`3%
`2%
`2%
`3%
`1%
`0
`1%
`
`Propofol
`(N = 188)
`(%)
`13%
`4%
`11%
`0
`7%
`4%
`1%
`3%
`5%
`6%
`6%
`1%
`1%
`2%
`0
`2%
`3%
`3%
`4%
`3%
`2%
`2%
`
`

`

`Randomized
`All
`Propofol
`Placebo
`PRECEDEX
`PRECEDEX
`(N = 188)
`(N = 400)
`(N = 798)
`(N = 1007)
`(%)
`(%)
`(%)
`(%)
`Adverse Event
`2%
`0
`1%
`1%
`Urine Output Decreased
`2%
`1%
`1%
`1%
`Sinus Tachycardia
`5%
`1%
`1%
`<1%
`Ventricular Tachycardia
`2%
`0
`1%
`<1%
`Wheezing
`2%
`1%
`0
`<1%
`Edema Peripheral
`* 26 subjects in the all PRECEDEX group and 10 subjects in the randomized PRECEDEX group had exposure for greater than 24
`hours.
`
`Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of
`PRECEDEX for sedation in the surgical intensive care unit setting in which 387 adult patients received
`PRECEDEX for less than 24 hours. The most frequently observed treatment-emergent adverse events included
`hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia and anemia (see Table 4).
`
`Table 4: 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
`
`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
`
`Randomized Dexmedetomidine
`(N = 387)
`28%
`16%
`11%
`7%
`5%
`4%
`4%
`4%
`3%
`3%
`3%
`3%
`2%
`2%
`2%
`2%
`2%
`2%
`2%
`2%
`2%
`
`Placebo
`(N = 379)
`13%
`18%
`9%
`3%
`4%
`6%
`3%
`4%
`5%
`4%
`2%
`1%
`3%
`3%
`3%
`2%
`2%
`2%
`1%
`<1%
`<1%
`
`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 adult patients in the randomized active comparator continuous infusion long-term intensive care unit
`sedation study are provided in Table 5. The 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 is
`provided in Table 6.
`
`9
`
`Reference ID: 5461471
`
`

`

`Table 5: Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or
`Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion
`Long-Term Intensive Care Unit Sedation Study
`
`Dexmedetomidine
`(N = 244)
`56%
`28%
`42%
`5%
`28%
`25%
`10%
`12%
`11%
`19%
`9%
`7%
`7%
`7%
`6%
`5%
`5%
`2%
`2%
`2%
`1%
`
`Midazolam
`(N = 122)
`56%
`27%
`19%
`1%
`42%
`44%
`10%
`15%
`15%
`30%
`13%
`2%
`6%
`2%
`6%
`6%
`3%
`1%
`1%
`6%
`7%
`
`Adverse Event
`Hypotension1
`Hypotension Requiring Intervention
`Bradycardia2
`Bradycardia Requiring Intervention
`Systolic Hypertension3
`Tachycardia4
`Tachycardia Requiring Intervention
`Diastolic Hypertension3
`Hypertension3
`Hypertension Requiring Intervention†
`Hypokalemia
`Pyrexia
`Agitation
`Hyperglycemia
`Constipation
`Hypoglycemia
`Respiratory Failure
`Renal Failure Acute
`Acute Respiratory Distress Syndrome
`Generalized Edema
`Hypomagnesemia
`Includes any type of hypertension.
`1 Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or
`in relative terms as ≤30% lower than pre-study drug infusion value.
`2 Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value.
`3 Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or
`in relative terms as ≥30% higher than pre-study drug infusion value.
`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 6: 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
`
`Adverse Event
`Constipation
`Agitation
`Anxiety
`Edema Peripheral
`Atrial Fibrillation
`
`Reference ID: 5461471
`
`PRECEDEX (mcg/kg/hr)
`≤0.7*
`(N = 95)
`6%
`5%
`5%
`3%
`2%
`
`10
`
`>0.7 to ≤1.1*
`(N = 78)
`5%
`8%
`5%
`5%
`4%
`
`>1.1*
`(N = 71)
`14%
`14%
`9%
`7%
`9%
`
`

`

`2%
`Respiratory Failure
`1%
`Acute Respiratory Distress Syndrome
`* Average maintenance dose over the entire study drug administration.
`
`Adult Procedural Sedation
`
`6%
`3%
`
`10%
`9%
`
`Adverse reaction information is derived from the two trials for adult 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 in adults at an incidence of >2% are provided in Table 7. 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 7: Adverse Reactions with an Incidence >2%—Adult Procedural Sedation Population
`
`Placebo
`PRECEDEX
`(N = 113)
`(N = 318)
`(%)
`(%)
`Adverse Event
`Hypotension1
`30%
`54%
`Respiratory Depression2
`32%
`37%
`Bradycardia3
`4%
`14%
`Hypertension4
`24%
`13%
`Tachycardia5
`17%
`5%
`2%
`3%
`Nausea
`1%
`3%
`Dry Mouth
`Hypoxia6
`3%
`2%
`4%
`2%
`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. Subjects in Study 2 were pretreated with glycopyrrolate 0.1 mg intravenously before receiving study drug [see Clinical
`Studies (14.2)].
`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.
`
`5
`
`Pediatric Sedation for Magnetic Resonance Imaging
`
`Adverse reaction information is derived from a trial for sedation of pediatric procedural during a non-invasive
`procedure [see Clinical Studies (14.2)] in which 122 pediatric patients aged 1 month to less than 17 years
`undergoing magnetic resonance imaging (MRI) scans received PRECEDEX. In pediatric patients 1 month to
`less than 2 years old, the median total dose for the PRECEDEX low, middle, and high dose treatment groups
`was 8.30, 18.90, and 22.75 mcg, respectively. The median duration of treatment ranged from 52.5 to 69 minutes
`across treatment groups. In pediatric patients 2 to less than 17 years old, the median total dose for the
`PRECEDEX low, middle, and high dose treatment groups was 21.30, 43.90, and 80.25 mcg, respectively. The
`median duration of treatment ranged from 56.5 to 66 minutes across treatment groups.
`
`Reference ID: 5461471
`
`11
`
`

`

`All-causality treatment-emergent adverse reactions occurring in the combined age group of pediatric patients
`during the procedure at an incidence of >5% are provided in Table 8. The most frequent treatment-emergent
`adverse events were bradypnea, bradycardia, hypertension, and hypotension [see Warnings and Precautions
`(5.2, 5.3)]. In the combined age group and in each age group, increased incidence in bradycardia and
`hypertension was observed with increasing PRECEDEX dose. Mild transient withdrawal symptoms of
`emergence delirium or agitation occurred in 3 of 122 patients after discontinuation of PRECEDEX infusion [see
`Warnings and Precautions (5.5)]. All reported treatment-emergent adverse reactions were mild to moderate in
`severity and the majority resolved without medical intervention. No subject in the study required airway
`intervention, including a jaw thrust or insertion of a nasal or oral airway. A similar profile was observed in the
`pediatric patients 1 month to less than 2 years old and in pediatric patients 2 to less than 17 years old.
`Pre-specifie