PRECEDEX Adverse Reactions

(dexmedetomidine hydrochloride injection)

6 ADVERSE REACTIONS

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 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 EventAll PRECEDEX
(N = 1007)
(%)
Randomized PRECEDEX
(N = 798)
(%)
Placebo
(N = 400)
(%)
Propofol
(N = 188)
(%)
*
26 subjects in the all PRECEDEX group and 10 subjects in the randomized PRECEDEX group had exposure for greater than 24 hours.

Hypotension

25%

24%

12%

13%

Hypertension

12%

13%

19%

4%

Nausea

9%

9%

9%

11%

Bradycardia

5%

5%

3%

0

Atrial Fibrillation

4%

5%

3%

7%

Pyrexia

4%

4%

4%

4%

Dry Mouth

4%

3%

1%

1%

Vomiting

3%

3%

5%

3%

Hypovolemia

3%

3%

2%

5%

Atelectasis

3%

3%

3%

6%

Pleural Effusion

2%

2%

1%

6%

Agitation

2%

2%

3%

1%

Tachycardia

2%

2%

4%

1%

Anemia

2%

2%

2%

2%

Hyperthermia

2%

2%

3%

0

Chills

2%

2%

3%

2%

Hyperglycemia

2%

2%

2%

3%

Hypoxia

2%

2%

2%

3%

Post-procedural Hemorrhage

2%

2%

3%

4%

Pulmonary Edema

1%

1%

1%

3%

Hypocalcemia

1%

1%

0

2%

Acidosis

1%

1%

1%

2%

Urine Output Decreased

1%

1%

0

2%

Sinus Tachycardia

1%

1%

1%

2%

Ventricular Tachycardia

<1%

1%

1%

5%

Wheezing

<1%

1%

0

2%

Edema Peripheral

<1%

0

1%

2%

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 EventRandomized Dexmedetomidine
(N = 387)
Placebo
(N = 379)

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

2%

<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.

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
Adverse EventDexmedetomidine
(N = 244)
Midazolam
(N = 122)
*
Hypertension 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.
Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value.
Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100mmHg 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.
Includes any type of hypertension

Hypotension*

56%

56%

Hypotension Requiring Intervention

28%

27%

Bradycardia

42%

19%

Bradycardia Requiring Intervention

5%

1%

Systolic Hypertension

28%

42%

Tachycardia§

25%

44%

Tachycardia Requiring Intervention

10%

10%

Diastolic Hypertension

12%

15%

Hypertension

11%

15%

Hypertension Requiring Intervention

19%

30%

Hypokalemia

9%

13%

Pyrexia

7%

2%

Agitation

7%

6%

Hyperglycemia

7%

2%

Constipation

6%

6%

Hypoglycemia

5%

6%

Respiratory Failure

5%

3%

Renal Failure Acute

2%

1%

Acute Respiratory Distress Syndrome

2%

1%

Generalized Edema

2%

6%

Hypomagnesemia

1%

7%

The following adverse events occurred between 2 and 5% for PRECEDEX and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%).

Table 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
PRECEDEX (mcg/kg/hr)
Adverse Event≤0.7*
(N = 95)
>0.7 to ≤1.1*
(N = 78)
>1.1*
(N = 71)
*
Average maintenance dose over the entire study drug administration.

Constipation

6%

5%

14%

Agitation

5%

8%

14%

Anxiety

5%

5%

9%

Edema Peripheral

3%

5%

7%

Atrial Fibrillation

2%

4%

9%

Respiratory Failure

2%

6%

10%

Acute Respiratory Distress Syndrome

1%

3%

9%

Adult Procedural Sedation

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
Adverse EventPRECEDEX
(N = 318)
(%)
Placebo
(N = 113)
(%)
*
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.
Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or >25% decrease from baseline.
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)].
§
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.
#
Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline.

Hypotension*

54%

30%

Respiratory Depression

37%

32%

Bradycardia

14%

4%

Hypertension§

13%

24%

Tachycardia

5%

17%

Nausea

3%

2%

Dry Mouth

3%

1%

Hypoxia#

2%

3%

Bradypnea

2%

4%

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)].

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.

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‑specified criteria for the vital signs to be reported as adverse events are footnoted below the table.

Table 8: Treatment-Emergent Adverse Events with Incidence >5%—Pediatric Patients During Non-invasive Procedure
*
Bradypnea was defined as respiratory rate <1st centile of the age adjusted normal range.
Bradycardia was defined as a decrease in HR of 30% from baseline or absolute HR ≤1st centile of the age adjusted normal range.
For pediatric patients 1 month to less than 1 year old, hypertension was defined as supine systolic blood pressure ≥104 mm/Hg and/or diastolic blood pressure ≥56 mmHg measurements. For pediatric patients 1 to less than 17 years old: hypertension was defined as supine systolic blood pressure and/or diastolic blood pressure measurements ≥95th percentile for gender, age, and height.
§
Hypotension was defined as a decrease in systolic blood pressure ≥30% from baseline.
Hypoxia was defined as oxygen saturation <90% for any duration.

PRECEDEX

Low Dose

(N = 42)

PRECEDEX

Middle Dose

(N = 42)

PRECEDEX

High Dose

(N = 38)

Total

(N = 122)

Number (%) of Pediatric Patients

n (%)

n (%)

n (%)

n (%)

Adverse Event

Bradypnea*

33 (79)

27 (64)

22 (58)

82 (67)

Bradycardia

24 (57)

24 (57)

27 (71)

75 (62)

Hypertension

11 (26)

17 (41)

18 (47)

46 (38)

Hypotension§

13 (31)

11 (26)

6 (16)

30 (25)

Hypoxia

6 (14)

3 (7)

1 (3)

10 (8)

Diastolic Hypertension

3 (7)

3 (7)

4 (11)

10 (8)

Systolic Hypertension

1 (2)

5 (12)

3 (8)

9 (7)

Tachycardia

3 (7)

1 (2)

1 (3)

5 (4)

N=Number of pediatric patients evaluable for adverse events.

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 9: Adverse Reactions Experienced During Post-Approval Use of PRECEDEX
System Organ ClassPreferred 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

 
Eye Disorders

Photopsia, visual impairment

Gastrointestinal Disorders

Abdominal pain, diarrhea, nausea, vomiting

General Disorders and Administration Site Conditions

Chills, hyperpyrexia, pain, pyrexia, thirst

Hepatobiliary Disorders

Hepatic function abnormal, hyperbilirubinemia

Investigations

Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, 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 Disorders

Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis, pruritus, rash, urticaria

Surgical and Medical Procedures

Light anesthesia

Vascular Disorders

Blood pressure fluctuation, hemorrhage, hypertension, hypotension

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Adverse Reactions

6 ADVERSE REACTIONS

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 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 EventAll PRECEDEX
(N = 1007)
(%)
Randomized PRECEDEX
(N = 798)
(%)
Placebo
(N = 400)
(%)
Propofol
(N = 188)
(%)
*
26 subjects in the all PRECEDEX group and 10 subjects in the randomized PRECEDEX group had exposure for greater than 24 hours.

Hypotension

25%

24%

12%

13%

Hypertension

12%

13%

19%

4%

Nausea

9%

9%

9%

11%

Bradycardia

5%

5%

3%

0

Atrial Fibrillation

4%

5%

3%

7%

Pyrexia

4%

4%

4%

4%

Dry Mouth

4%

3%

1%

1%

Vomiting

3%

3%

5%

3%

Hypovolemia

3%

3%

2%

5%

Atelectasis

3%

3%

3%

6%

Pleural Effusion

2%

2%

1%

6%

Agitation

2%

2%

3%

1%

Tachycardia

2%

2%

4%

1%

Anemia

2%

2%

2%

2%

Hyperthermia

2%

2%

3%

0

Chills

2%

2%

3%

2%

Hyperglycemia

2%

2%

2%

3%

Hypoxia

2%

2%

2%

3%

Post-procedural Hemorrhage

2%

2%

3%

4%

Pulmonary Edema

1%

1%

1%

3%

Hypocalcemia

1%

1%

0

2%

Acidosis

1%

1%

1%

2%

Urine Output Decreased

1%

1%

0

2%

Sinus Tachycardia

1%

1%

1%

2%

Ventricular Tachycardia

<1%

1%

1%

5%

Wheezing

<1%

1%

0

2%

Edema Peripheral

<1%

0

1%

2%

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 EventRandomized Dexmedetomidine
(N = 387)
Placebo
(N = 379)

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

2%

<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.

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
Adverse EventDexmedetomidine
(N = 244)
Midazolam
(N = 122)
*
Hypertension 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.
Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value.
Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100mmHg 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.
Includes any type of hypertension

Hypotension*

56%

56%

Hypotension Requiring Intervention

28%

27%

Bradycardia

42%

19%

Bradycardia Requiring Intervention

5%

1%

Systolic Hypertension

28%

42%

Tachycardia§

25%

44%

Tachycardia Requiring Intervention

10%

10%

Diastolic Hypertension

12%

15%

Hypertension

11%

15%

Hypertension Requiring Intervention

19%

30%

Hypokalemia

9%

13%

Pyrexia

7%

2%

Agitation

7%

6%

Hyperglycemia

7%

2%

Constipation

6%

6%

Hypoglycemia

5%

6%

Respiratory Failure

5%

3%

Renal Failure Acute

2%

1%

Acute Respiratory Distress Syndrome

2%

1%

Generalized Edema

2%

6%

Hypomagnesemia

1%

7%

The following adverse events occurred between 2 and 5% for PRECEDEX and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%).

Table 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
PRECEDEX (mcg/kg/hr)
Adverse Event≤0.7*
(N = 95)
>0.7 to ≤1.1*
(N = 78)
>1.1*
(N = 71)
*
Average maintenance dose over the entire study drug administration.

Constipation

6%

5%

14%

Agitation

5%

8%

14%

Anxiety

5%

5%

9%

Edema Peripheral

3%

5%

7%

Atrial Fibrillation

2%

4%

9%

Respiratory Failure

2%

6%

10%

Acute Respiratory Distress Syndrome

1%

3%

9%

Adult Procedural Sedation

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
Adverse EventPRECEDEX
(N = 318)
(%)
Placebo
(N = 113)
(%)
*
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.
Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or >25% decrease from baseline.
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)].
§
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.
#
Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline.

Hypotension*

54%

30%

Respiratory Depression

37%

32%

Bradycardia

14%

4%

Hypertension§

13%

24%

Tachycardia

5%

17%

Nausea

3%

2%

Dry Mouth

3%

1%

Hypoxia#

2%

3%

Bradypnea

2%

4%

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)].

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.

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‑specified criteria for the vital signs to be reported as adverse events are footnoted below the table.

Table 8: Treatment-Emergent Adverse Events with Incidence >5%—Pediatric Patients During Non-invasive Procedure
*
Bradypnea was defined as respiratory rate <1st centile of the age adjusted normal range.
Bradycardia was defined as a decrease in HR of 30% from baseline or absolute HR ≤1st centile of the age adjusted normal range.
For pediatric patients 1 month to less than 1 year old, hypertension was defined as supine systolic blood pressure ≥104 mm/Hg and/or diastolic blood pressure ≥56 mmHg measurements. For pediatric patients 1 to less than 17 years old: hypertension was defined as supine systolic blood pressure and/or diastolic blood pressure measurements ≥95th percentile for gender, age, and height.
§
Hypotension was defined as a decrease in systolic blood pressure ≥30% from baseline.
Hypoxia was defined as oxygen saturation <90% for any duration.

PRECEDEX

Low Dose

(N = 42)

PRECEDEX

Middle Dose

(N = 42)

PRECEDEX

High Dose

(N = 38)

Total

(N = 122)

Number (%) of Pediatric Patients

n (%)

n (%)

n (%)

n (%)

Adverse Event

Bradypnea*

33 (79)

27 (64)

22 (58)

82 (67)

Bradycardia

24 (57)

24 (57)

27 (71)

75 (62)

Hypertension

11 (26)

17 (41)

18 (47)

46 (38)

Hypotension§

13 (31)

11 (26)

6 (16)

30 (25)

Hypoxia

6 (14)

3 (7)

1 (3)

10 (8)

Diastolic Hypertension

3 (7)

3 (7)

4 (11)

10 (8)

Systolic Hypertension

1 (2)

5 (12)

3 (8)

9 (7)

Tachycardia

3 (7)

1 (2)

1 (3)

5 (4)

N=Number of pediatric patients evaluable for adverse events.

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 9: Adverse Reactions Experienced During Post-Approval Use of PRECEDEX
System Organ ClassPreferred 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

 
Eye Disorders

Photopsia, visual impairment

Gastrointestinal Disorders

Abdominal pain, diarrhea, nausea, vomiting

General Disorders and Administration Site Conditions

Chills, hyperpyrexia, pain, pyrexia, thirst

Hepatobiliary Disorders

Hepatic function abnormal, hyperbilirubinemia

Investigations

Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, 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 Disorders

Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis

Skin and Subcutaneous Tissue Disorders

Hyperhidrosis, pruritus, rash, urticaria

Surgical and Medical Procedures

Light anesthesia

Vascular Disorders

Blood pressure fluctuation, hemorrhage, hypertension, hypotension

Medication Guide

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