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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) ] 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 . 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 2: Adverse Reactions with an Incidence >2%-Adult Intensive Care Unit Sedation Population <24 hours 26 subjects in the all PRECEDEX group and 10 subjects in the randomized PRECEDEX group had exposure for greater than 24 hours. Adverse Event All PRECEDEX (N = 1007) (%) Randomized PRECEDEX (N = 798) (%) Placebo (N = 400) (%) Propofol (N = 188) (%) 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 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 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 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 Event Dexmedetomidine (N = 244) Midazolam (N = 122) Hypotension 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. 56% 56% Hypotension Requiring Intervention 28% 27% Bradycardia Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value. 42% 19% Bradycardia Requiring Intervention 5% 1% Systolic Hypertension 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. 28% 42% Tachycardia Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value. 25% 44% Tachycardia Requiring Intervention 10% 10% Diastolic Hypertension 12% 15% Hypertension 11% 15% Hypertension Requiring Intervention Includes any type of hypertension. 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 PRECEDEX (mcg/kg/hr) Adverse Event ≤0.7 Average maintenance dose over the entire study drug administration. (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% 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 6: Adverse Reactions with an Incidence >2%—Adult Procedural Sedation Population Adverse Event PRECEDEX (N = 318) (%) Placebo (N = 113) (%) Hypotension 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. 54% 30% Respiratory Depression Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or >25% decrease from baseline. 37% 32% Bradycardia 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)] . Subjects in Study 2 were pretreated with glycopyrrolate 0.1 mg intravenously before receiving study drug [see Clinical Studies (14.2)] . 14% 4% Hypertension 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. 13% 24% Tachycardia Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value. 5% 17% Nausea 3% 2% Dry Mouth 3% 1% Hypoxia Hypoxia was defined in absolute and relative terms as SpO 2 <90% or 10% decrease from baseline. 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