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PRECEDEX (dexmedetomidine hydrochloride injection) Adverse Reactions

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

Use of Precedex has been associated with the following serious adverse reactions:

Hypotension, bradycardia and sinus arrest [see Warnings and Precautions (5.2)]
Transient hypertension [see Warnings and Precautions (5.3)]

Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia and dry mouth.

Intensive Care Unit Sedation

Adverse reaction information is derived from the continuous infusion trials of Precedex for sedation in the Intensive Care Unit setting in which 1007 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*
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 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

Adverse Event

Randomized 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 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
   Includes any type of hypertension.
1   Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value.
2   Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value.
3   Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value.
4   Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value.

Adverse Event

Dexmedetomidine
(N = 244)

Midazolam
(N = 122)

Hypotension1

56%

56%

Hypotension Requiring Intervention

28%

27%

Bradycardia2

42%

19%

Bradycardia Requiring Intervention

5%

1%

Systolic Hypertension3

28%

42%

Tachycardia4

25%

44%

Tachycardia Requiring Intervention

10%

10%

Diastolic Hypertension3

12%

15%

Hypertension3

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 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
*
Average maintenance dose over the entire study drug administration

Precedex mcg/kg/hr

Adverse Event

≤0.7*
(N = 95)

>0.7 to ≤1.1*
(N = 78)

>1.1*
(N = 71)

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%

Procedural Sedation

Adverse reaction information is derived from the two trials for procedural sedation [see Clinical Studies (14.2)] in which 318 adult patients received Precedex. The mean total dose was 1.6 mcg/kg (range: 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of infusion of 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93 years of age, ASA I-IV, 30% ≥65 years of age, 52% male and 61% Caucasian.

Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 6. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [see Warnings and Precautions (5.2)]. Pre-specified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. 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
Adverse EventPrecedex
(N = 318)
(%)
Placebo
(N = 113)
(%)
1   Hypotension was defined in absolute and relative terms as Systolic blood pressure of <80 mmHg or ≤30% lower than pre-study drug infusion value, or Diastolic blood pressure of <50 mmHg.
2   Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or > 25% decrease from baseline.
3   Bradycardia was defined in absolute and relative terms as <40 beats per minute or ≤30% lower than pre-study drug infusion value.
4   Hypertension was defined in absolute and relative terms as Systolic blood pressure >180 mmHg or ≥30% higher than pre-study drug infusion value or Diastolic blood pressure of >100 mmHg.
5   Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value.
6   Hypoxia was defined in absolute and relative terms as SpO2 <90% or 10% decrease from baseline.

Hypotension1

54%

30%

Respiratory Depression2

37%

32%

Bradycardia3

14%

4%

Hypertension4

13%

24%

Tachycardia5

5%

17%

Nausea

3%

2%

Dry Mouth

3%

1%

Hypoxia6

2%

3%

Bradypnea

2%

4%

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of Precedex. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypotension and bradycardia were the most common adverse reactions associated with the use of Precedex during post approval use of the drug.

Table 7: Adverse Reactions Experienced During Post-approval Use of Precedex

System Organ Class

Preferred Term

Blood and Lymphatic System Disorders

Anemia

Cardiac Disorders

Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia

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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