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PRECEDEX (dexmedetomidine hydrochloride injection) Adverse Reactions

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

6.1 Clinical Trials Experience

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

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

Intensive Care Unit Sedation

Adverse reaction information is derived from the continuous infusion trials of Precedex for sedation in the Intensive Care Unit setting in which 1,007 adult patients received Precedex. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% ≥65 years of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions occurring at an 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.
Hypotension25%24%12%13%
Hypertension12%13%19%4%
Nausea9%9%9%11%
Bradycardia5%5%3%0
Atrial Fibrillation4%5%3%7%
Pyrexia4%4%4%4%
Dry Mouth4%3%1%1%
Vomiting3%3%5%3%
Hypovolemia3%3%2%5%
Atelectasis3%3%3%6%
Pleural Effusion2%2%1%6%
Agitation2%2%3%1%
Tachycardia2%2%4%1%
Anemia2%2%2%2%
Hyperthermia2%2%3%0
Chills2%2%3%2%
Hyperglycemia2%2%2%3%
Hypoxia2%2%2%3%
Post-procedural Hemorrhage2%2%3%4%
Pulmonary Edema1%1%1%3%
Hypocalcemia1%1%02%
Acidosis1%1%1%2%
Urine Output Decreased1%1%02%
Sinus Tachycardia1%1%1%2%
Ventricular Tachycardia<1%1%1%5%
Wheezing<1%1%02%
Edema Peripheral<1%01%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 EventRandomized Dexmedetomidine
(N = 387)
Placebo
(N = 379)
Hypotension28%13%
Hypertension16%18%
Nausea11%9%
Bradycardia7%3%
Fever5%4%
Vomiting4%6%
Atrial Fibrillation4%3%
Hypoxia4%4%
Tachycardia3%5%
Hemorrhage3%4%
Anemia3%2%
Dry Mouth3%1%
Rigors2%3%
Agitation 2%3%
Hyperpyrexia 2%3%
Pain2%2%
Hyperglycemia2%2%
Acidosis2%2%
Pleural Effusion2%1%
Oliguria2%<1%
Thirst2%<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
Adverse EventDexmedetomidine
(N = 244)
Midazolam
(N = 122)
*
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.
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 >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.
Includes any type of hypertension.
Hypotension*56%56%
Hypotension Requiring Intervention28%27%
Bradycardia42%19%
Bradycardia Requiring Intervention5%1%
Systolic Hypertension28%42%
Tachycardia§25%44%
Tachycardia Requiring Intervention10%10%
Diastolic Hypertension12%15%
Hypertension11%15%
Hypertension Requiring Intervention19%30%
Hypokalemia9%13%
Pyrexia7%2%
Agitation7%6%
Hyperglycemia7%2%
Constipation6%6%
Hypoglycemia5%6%
Respiratory Failure5%3%
Renal Failure Acute2%1%
Acute Respiratory Distress Syndrome2%1%
Generalized Edema2%6%
Hypomagnesemia1%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
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.
Constipation6%5%14%
Agitation5%8%14%
Anxiety5%5%9%
Edema Peripheral3%5%7%
Atrial Fibrillation2%4%9%
Respiratory Failure2%6%10%
Acute Respiratory Distress Syndrome1%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)
(%)
*
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.
§
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 Depression37%32%
Bradycardia14%4%
Hypertension§13%24%
Tachycardia5%17%
Nausea3%2%
Dry Mouth3%1%
Hypoxia#2%3%
Bradypnea2%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 ClassPreferred Term
Blood and Lymphatic System DisordersAnemia
Cardiac DisordersArrhythmia, 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 DisordersAbdominal pain, diarrhea, nausea, vomiting
General Disorders and Administration Site ConditionsChills, hyperpyrexia, pain, pyrexia, thirst
Hepatobiliary DisordersHepatic function abnormal, hyperbilirubinemia
InvestigationsAlanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolonged
Metabolism and Nutrition DisordersAcidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia
Nervous System DisordersConvulsion, dizziness, headache, neuralgia, neuritis, speech disorder
Psychiatric DisordersAgitation, confusional state, delirium, hallucination, illusion
Renal and Urinary DisordersOliguria, polyuria
Respiratory, Thoracic and Mediastinal DisordersApnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis
Skin and Subcutaneous Tissue DisordersHyperhidrosis, pruritus, rash, urticaria
Surgical and Medical ProceduresLight anesthesia
Vascular DisordersBlood pressure fluctuation, hemorrhage, hypertension, hypotension

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