ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 6.1 Clinical Studies ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of 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 SedationAdverse 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 hoursAdverse 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%0Atrial 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%0Chills2%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 StudiesAdverse 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%Agitation2%3%Hyperpyrexia2%3%Pain2%2%Hyperglycemia2%2%Acidosis2%2%Pleural Effusion2%1%Oliguria2%<1%Thirst2%<1%In 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 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 EventDexmedetomidine (N 244)Midazolam (N 122)Hypotension156%56%Hypotension Requiring Intervention28%27%Bradycardia242%19%Bradycardia Requiring Intervention5%1%Systolic Hypertension328%42%Tachycardia425%44%Tachycardia Requiring Intervention10%10%Diastolic Hypertension312%15%Hypertension311%15%Hypertension Requiring Intervention+19%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 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 Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Precedex GroupAverage maintenance dose over the entire study drug administrationPrecedex mcg/kg/hrAdverse Event<=0.7 (N 95)>0.7 to <=1.1 (N 78)>1.1 (N 71)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 SedationAdverse 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 PopulationAdverse 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.Hypotension154%30%Respiratory Depression237%32%Bradycardia314%4%Hypertension413%24%Tachycardia55%17%Nausea3%2%Dry Mouth3%1%Hypoxia62%3%Bradypnea2%4%6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post approval use of Precedex. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 PrecedexSystem Organ ClassPreferred TermBlood and Lymphatic System DisordersAnemiaCardiac DisordersArrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardiaEye DisordersPhotopsia, visual impairmentGastrointestinal DisordersAbdominal pain, diarrhea, nausea, vomitingGeneral Disorders and Administration Site ConditionsChills, hyperpyrexia, pain, pyrexia, thirstHepatobiliary DisordersHepatic function abnormal, hyperbilirubinemiaInvestigationsAlanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram wave inversion, gammaglutamyltransferase increased, electrocardiogram QT prolongedMetabolism and Nutrition DisordersAcidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremiaNervous System DisordersConvulsion, dizziness, headache, neuralgia, neuritis, speech disorderPsychiatric DisordersAgitation, confusional state, delirium, hallucination, illusionRenal and Urinary DisordersOliguria, polyuriaRespiratory, Thoracic and Mediastinal DisordersApnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosisSkin and Subcutaneous Tissue DisordersHyperhidrosis, pruritus, rash, urticariaSurgical and Medical ProceduresLight anesthesiaVascular DisordersBlood pressure fluctuation, hemorrhage, hypertension, hypotension. 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 greater than 2%) are hypotension, bradycardia, and dry mouth. (6.1 Adverse reactions associated with infusions greater than 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.. The most common adverse reactions (incidence greater than 2%) are hypotension, bradycardia, and dry mouth. (6.1 . Adverse reactions associated with infusions greater than 24 hours in duration include ARDS, respiratory failure, and agitation. (6.1).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of ActionPrecedex is relatively selective alpha2-adrenergic agonist with sedative properties. Alpha2 selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both alpha1 and alpha2 activity is observed following slow intravenous infusion of high doses (>=1000 mcg/kg) or with rapid intravenous administration.12.2 PharmacodynamicsIn study in healthy volunteers (N 10), respiratory rate and oxygen saturation remained within normal limits and there was no evidence of respiratory depression when Precedex was administered by intravenous infusion at doses within the recommended dose range (0.2-0.7 mcg/kg/hr).12.3 PharmacokineticsFollowing intravenous administration, dexmedetomidine exhibits the following pharmacokinetic parameters: rapid distribution phase with distribution half-life (t1/2) of approximately minutes; terminal elimination half-life (t1/2) of approximately hours; and steady-state volume of distribution (Vss) of approximately 118 liters. Clearance is estimated to be approximately 39 L/h. The mean body weight associated with this clearance estimate was 72 kg.Dexmedetomidine exhibits linear pharmacokinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered by intravenous infusion for up to 24 hours. TABLE shows the main pharmacokinetic parameters when Precedex was infused (after appropriate loading doses) at maintenance infusion rates of 0.17 mcg/kg/hr (target plasma concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33 mcg/kg/hr (target plasma concentration of 0.6 ng/mL) for 24 hours, and 0.70 mcg/kg/hr (target plasma concentration of 1.25 ng/mL) for 24 hours.Table 8: Mean +- SD Pharmacokinetic Parameters Presented as harmonic mean and pseudo standard deviation. Mean Css Average steady-state concentration of Dexmedetomidine. The mean Css was calculated based on post-dose sampling from 2.5 to hours samples for 12 hour infusion and post-dose sampling from 2.5 to 18 hours for 24 hour infusions.ParameterLoading Infusion (min)/Total Infusion Duration (hrs)10 min/12 hrs10 min/24 hrs10 min/24 hrs35 min/24 hrsDexmedetomidine Target Plasma Concentration (ng/mL) and Dose (mcg/kg/hr)0.3/0.170.3/0.170.6/0.331.25/0.70t1/2, hour1.78 +- 0.302.22 +- 0.592.23 +- 0.212.50 +- 0.61CL, liter/hour46.3 +- 8.343.1 +- 6.535.3 +- 6.836.5 +- 7.5Vss, liter88.7 +- 22.9102.4 +- 20.393.6 +- 17.099.6 +- 17.8Avg Css, ng/mL0.27 +- 0.050.27 +- 0.050.67 +- 0.101.37 +- 0.20The loading doses for each of the above indicated groups were 0.5, 0.5, and 2.2 mcg/kg, respectively.Dexmedetomidine pharmacokinetic parameters after Precedex maintenance doses of 0.2 to 1.4 mcg/kg/hr for >24 hours were similar to the PK parameters after Precedex maintenance dosing for 24 hours in other studies. The values for clearance (CL), volume of distribution (V), and t1/2 were 39.4 L/hr, 152 L, and 2.67 hours, respectively.DistributionThe steady-state volume of distribution (Vss) of dexmedetomidine was approximately 118 liters. Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and female subjects. The average protein binding was 94% and was constant across the different plasma concentrations tested. Protein binding was similar in males and females. The fraction of Precedex that was bound to plasma proteins was significantly decreased in subjects with hepatic impairment compared to healthy subjects.The potential for protein binding displacement of dexmedetomidine by fentanyl, ketorolac, theophylline, digoxin and lidocaine was explored in vitro, and negligible changes in the plasma protein binding of Precedex were observed. The potential for protein binding displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline and digoxin by Precedex was explored in vitro and none of these compounds appeared to be significantly displaced by Precedex.MetabolismDexmedetomidine undergoes almost complete biotransformation with very little unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6 with minor role of CYP1A2, CYP2E1, CYP2D6 and CYP2C19) of dexmedetomidine to generate 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxy-dexmedetomidine; and N-methylation of dexmedetomidine to generate 3-hydroxy N-methyl-dexmedetomidine, 3-carboxy N-methyl-dexmedetomidine, and dexmedetomidine-N-methyl O-glucuronide.EliminationThe terminal elimination half-life (t1/2) of dexmedetomidine is approximately hours and clearance is estimated to be approximately 39 L/h. mass balance study demonstrated that after nine days an average of 95% of the radioactivity, following intravenous administration of radiolabeled dexmedetomidine, was recovered in the urine and 4% in the feces. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the radioactivity recovered in the urine was excreted within 24 hours after the infusion. Fractionation of the radioactivity excreted in urine demonstrated that products of N-glucuronidation accounted for approximately 34% of the cumulative urinary excretion. In addition, aliphatic hydroxylation of parent drug to form 3-hydroxy-dexmedetomidine, the glucuronide of 3-hydroxy-dexmedetomidine, and 3-carboxylic acid-dexmedetomidine together represented approximately 14% of the dose in urine. N-methylation of dexmedetomidine to form 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide dexmedetomidine accounted for approximately 18% of the dose in urine. The N-Methyl metabolite itself was minor circulating component and was undetected in urine. Approximately 28% of the urinary metabolites have not been identified.GenderThere was no observed difference in Precedex pharmacokinetics due to gender.GeriatricsThe pharmacokinetic profile of Precedex was not altered by age. There were no differences in the pharmacokinetics of Precedex in young (18-40 years), middle age (41-65 years), and elderly (>65 years) subjects.Hepatic ImpairmentIn subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values for Precedex were lower than in healthy subjects. The mean clearance values for patients with mild, moderate, and severe hepatic impairment were 74%, 64% and 53% of those observed in the normal healthy subjects, respectively. Mean clearances for free drug were 59%, 51% and 32% of those observed in the normal healthy subjects, respectively.Although Precedex is dosed to effect, it may be necessary to consider dose reduction in subjects with hepatic impairment [see DOSAGE AND ADMINISTRATION (2.2), WARNINGS AND PRECAUTIONS (5.7)].Renal ImpairmentDexmedetomidine pharmacokinetics (Cmax, Tmax, AUC, t1/2, CL, and Vss) were not significantly different in patients with severe renal impairment (creatinine clearance: <30 mL/min) compared to healthy subjects.Drug InteractionsIn vitro studies: In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450 mediated drug interactions that are likely to be of clinical relevance.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The safety and efficacy of Precedex has been evaluated in four randomized, double-blind, placebo-controlled multicenter clinical trials in 1185 adult patients.14.1 Intensive Care Unit SedationTwo randomized, double-blind, parallel-group, placebo-controlled multicenter clinical trials included 754 adult patients being treated in surgical intensive care unit. All patients were initially intubated and received mechanical ventilation. These trials evaluated the sedative properties of Precedex by comparing the amount of rescue medication (midazolam in one trial and propofol in the second) required to achieve specified level of sedation (using the standardized Ramsay Sedation Scale) between Precedex and placebo from onset of treatment to extubation or to total treatment duration of 24 hours. The Ramsay Level of Sedation Scale is displayed in TABLE 9.A second prospective primary analysis assessed the sedative effects of Precedex by comparing the percentage of patients who achieved Ramsay sedation score of >=3 during intubation without the use of additional rescue medication. significantly greater percentage of patients in the Precedex group maintained Ramsay sedation score of >=3 without receiving any midazolam rescue compared to the placebo group (see TABLE 10).In the first study, 175 adult patients were randomized to receive placebo and 178 to receive Precedex by intravenous infusion at dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion rate was adjusted to maintain Ramsay sedation score of >=3. Patients were allowed to receive rescue midazolam as needed to augment the study drug infusion. In addition, morphine sulfate was administered for pain as needed. The primary outcome measure for this study was the total amount of rescue medication (midazolam) needed to maintain sedation as specified while intubated. Patients randomized to placebo received significantly more midazolam than patients randomized to Precedex (see TABLE 10).A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-treated patients received less morphine sulfate for pain than placebo-treated patients (0.47 versus 0.83 mg/h). In addition, 44% (79 of 178 patients) of Precedex patients received no morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group.In second study, 198 adult patients were randomized to receive placebo and 203 to receive Precedex by intravenous infusion at dose of 0.4 mcg/kg/hr (with allowed adjustment between 0.2 and 0.7 mcg/kg/hr) following an initial loading infusion of one mcg/kg intravenous over 10 minutes. The study drug infusion was adjusted to maintain Ramsay sedation score of >=3. Patients were allowed to receive rescue propofol as needed to augment the study drug infusion. In addition, morphine sulfate was administered as needed for pain. The primary outcome measure for this study was the total amount of rescue medication (propofol) needed to maintain sedation as specified while intubated.Patients randomized to placebo received significantly more propofol than patients randomized to Precedex (see TABLE 11).A significantly greater percentage of patients in the Precedex group compared to the placebo group maintained Ramsay sedation score of >=3 without receiving any propofol rescue (see TABLE 11).A prospective secondary analysis assessed the dose of morphine sulfate administered to patients in the Precedex and placebo groups. On average, Precedex-treated patients received less morphine sulfate for pain than placebo-treated patients (0.43 versus 0.89 mg/h). In addition, 41% (83 of 203 patients) of Precedex patients received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.In controlled clinical trial, Precedex was compared to midazolam for ICU sedation exceeding 24 hours duration. Precedex was not shown to be superior to midazolam for the primary efficacy endpoint, the percent of time patients were adequately sedated (81% versus 81%). In addition, administration of Precedex for longer than 24 hours was associated with tolerance, tachyphylaxis, and dose-related increase in adverse events [see ADVERSE REACTIONS (6.1)].14.2 Procedural SedationThe safety and efficacy of Precedex for sedation of non-intubated patients prior to and/or during surgical and other procedures was evaluated in two randomized, double-blind, placebo-controlled multicenter clinical trials. Study evaluated the sedative properties of Precedex in patients having variety of elective surgeries/procedures performed under monitored anesthesia care. Study evaluated Precedex in patients undergoing awake fiberoptic intubation prior to surgical or diagnostic procedure.In Study 1, the sedative properties of Precedex were evaluated by comparing the percent of patients not requiring rescue midazolam to achieve specified level of sedation using the standardized Observers Assessment of Alertness/Sedation Scale (see TABLE 12).Patients were randomized to receive loading infusion of either Precedex mcg/kg, Precedex 0.5 mcg/kg, or placebo (normal saline) given over 10 minutes and followed by maintenance infusion started at 0.6 mcg/kg/hr. The maintenance infusion of study drug could be titrated from 0.2 mcg/kg/hr to mcg/kg/hr to achieve the targeted sedation score (Observers Assessment of Alertness/Sedation Scale <=4). Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain an Observers Assessment of Alertness/Sedation Scale <=4. After achieving the desired level of sedation, local or regional anesthetic block was performed. Demographic characteristics were similar between the Precedex and comparator groups. Efficacy results showed that Precedex was more effective than the comparator group when used to sedate non-intubated patients requiring monitored anesthesia care during surgical and other procedures (see TABLE 13).In Study 2, the sedative properties of Precedex were evaluated by comparing the percent of patients requiring rescue midazolam to achieve or maintain specified level of sedation using the Ramsay Sedation Scale score >=2 (see TABLE 9). Patients were randomized to receive loading infusion of Precedex mcg/kg or placebo (normal saline) given over 10 minutes and followed by fixed maintenance infusion of 0.7 mcg/kg/hr. After achieving the desired level of sedation, topicalization of the airway occurred. Patients were allowed to receive rescue midazolam as needed to achieve and/or maintain Ramsay Sedation Scale >=2. Demographic characteristics were similar between the Precedex and comparator groups. For efficacy results see TABLE 13.. Image1.jpg. Image2.jpg. Image3.jpg. Image4.jpg. Image5.jpg.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 2.1 Dosing GuidelinesPrecedex 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 controlled infusion device.2.2 Dosage InformationTable 1: Dosage InformationINDICATIONDOSAGE AND ADMINISTRATION Initiation of Intensive Care Unit SedationFor adult patients: 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 [see DOSAGE AND ADMINISTRATION (2.2)].For patients over 65 years of age: dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.5)].For adult patients with impaired hepatic-function: dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)].Maintenance of Intensive Care Unit SedationFor adult patients: maintenance infusion of 0.2 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: dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.5)].For adult patients with impaired hepatic function: dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)]Initiation of Procedural SedationFor adult patients: loading infusion of one mcg/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable.For awake fiberoptic intubation in adult patients: loading infusion of one mcg/kg over 10 minutes.For patients over 65 years of age: loading infusion of 0.5 mcg/kg over 10 minutes [see USE IN SPECIFIC POPULATIONS (8.5)].For adult patients with impaired hepatic function: dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)].Maintenance of Procedural SedationFor 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 to mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation.For awake fiberoptic intubation in adult patients: maintenance infusion of 0.7 mcg/kg/hour is recommended until the endotracheal tube is secured.For patients over 65 years of age: dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.5)].For adult patients with impaired hepatic function: dose reduction should be considered [see USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)].2.3 Dosage AdjustmentDue to possible pharmacodynamic interactions, 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 (5.7), USE IN SPECIFIC POPULATIONS (8.6), CLINICAL PHARMACOLOGY (12.3)].2.4 Preparation of SolutionStrict aseptic technique must always be maintained during handling of Precedex.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.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 mL of Precedex Injection, and add to 48 mL of 0.9% sodium chloride injection to total of 50 mL. Shake gently to mix well.Precedex in 0.9% Sodium Chloride Injection, 80 mcg/20 mL (4 mcg/mL), 200 mcg/50 mL (4 mcg/mL) and 400 mcg/100 mL (4 mcg/mL)Precedex in 0.9% Sodium Chloride Injection is supplied in glass containers containing premixed, ready to use dexmedetomidine hydrochloride solution in 0.9% sodium chloride in water. No further dilution of these preparations are necessary.2.5 Administration with Other FluidsPrecedex 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:o0.9% sodium chloride in watero5% dextrose in watero20% mannitoloLactated Ringers solutiono100 mg/mL magnesium sulfate solutiono0.3% potassium chloride solution2.6 Compatibility with Natural RubberCompatibility 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.. 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 controlled infusion device.. Individualize and titrate Precedex dosing to desired clinical effect. (2.1)Administer Precedex using 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-use vial, and 200 mcg/50mL and 400 mcg/100 mL single-use bottles, do not require further dilution prior to administration. (2.4)For Adult Intensive Care Unit Sedation: Generally initiate at one mcg/kg over 10 minutes, followed by maintenance infusion of 0.2 to 0.7 mcg/kg/hour. (2.2)For Adult Procedural Sedation: Generally initiate at one mcg/kg over 10 minutes, followed by maintenance infusion initiated at 0.6 mcg/kg/hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to mcg/kg/hour. (2.2)Alternative Doses: Recommended for patients over 65 years of age and awake fiberoptic intubation patients. (2.2). Individualize and titrate Precedex dosing to desired clinical effect. (2.1). Administer Precedex using 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-use vial, and 200 mcg/50mL and 400 mcg/100 mL single-use bottles, do not require further dilution prior to administration. (2.4).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS SECTION. 8.1 PregnancyPregnancy Category CThere are no adequate and well-controlled studies of Precedex use in pregnant women. In an in vitrohuman placenta study, placental transfer of dexmedetomidine occurred. In study in the pregnant rat, placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was administered subcutaneously. Thus, fetal exposure should be expected in humans, and Precedex should be used during pregnancy only if the potential benefits justify the potential risk to the fetus.Teratogenic effects were not observed in rats following subcutaneous administration of dexmedetomidine during the period of fetal organogenesis (from gestation day to 16) with doses up to 200 mcg/kg (representing dose approximately equal to the maximum recommended human intravenous dose based on body surface area) or in rabbits following intravenous administration of dexmedetomidine during the period of fetal organogenesis (from gestation day to 18) with doses up to 96 mcg/kg (representing approximately half the human exposure at the maximum recommended dose based on plasma area under the time-curve comparison). However, fetal toxicity, as evidenced by increased post-implantation losses and reduced live pups, was observed in rats at subcutaneous dose of 200 mcg/kg. The no-effect dose in rats was 20 mcg/kg (representing dose less than the maximum recommended human intravenous dose based on body surface area comparison). In another reproductive toxicity study when dexmedetomidine was administered subcutaneously to pregnant rats at and 32 mcg/kg (representing dose less than the maximum recommended human intravenous dose based on body surface area comparison) from gestation day 16 through weaning, lower offspring weights were observed. Additionally, when offspring of the 32 mcg/kg group were allowed to mate, elevated fetal and embryocidal toxicity and delayed motor development was observed in second generation offspring.8.2 Labor and DeliveryThe safety of Precedex during labor and delivery has not been studied.8.3 Nursing MothersIt is not known whether Precedex is excreted in human milk. Radio-labeled dexmedetomidine administered subcutaneously to lactating female rats was excreted in milk. Because many drugs are excreted in human milk, caution should be exercised when Precedex is administered to nursing woman.8.4 Pediatric UseSafety and efficacy have not been established for Procedural or ICU Sedation in pediatric patients. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of Precedex for this patient population. The use of Precedex for procedural sedation in pediatric patients has not been evaluated.8.5 Geriatric UseIntensive Care Unit SedationA total of 729 patients in the clinical studies were 65 years of age and over. total of 200 patients were 75 years of age and over. In patients greater than 65 years of age, higher incidence of bradycardia and hypotension was observed following administration of Precedex [see WARNINGS AND PRECAUTIONS (5.2)]. Therefore dose reduction may be considered in patients over 65 years of age [see DOSAGE AND ADMINISTRATION (2.2) and CLINICAL PHARMACOLOGY (12.3)].Procedural SedationA total of 131 patients in the clinical studies were 65 years of age and over. total of 47 patients were 75 years of age and over. Hypotension occurred in higher incidence in Precedex-treated patients 65 years or older (72%) and 75 years or older (74%) as compared to patients <65 years (47%). reduced loading dose of 0.5 mcg/kg given over 10 minutes is recommended and reduction in the maintenance infusion should be considered for patients greater than 65 years of age.8.6 Hepatic ImpairmentSince Precedex clearance decreases with increasing severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [see DOSAGE AND ADMINISTRATION (2.2) and CLINICAL PHARMACOLOGY (12.3)].. Geriatric Patients: Dose reduction should be considered. (2.2, 2.3, 5.1, 8.5)Hepatic Impairment: Dose reduction should be considered. (2.1, 2.2, 2.3, 5.7, 8.6)Pregnancy: Based on animal data, may cause fetal harm. (8.1)Nursing Mothers: Caution should be exercised when administered to nursing woman. (8.3)See 17 for PATIENT COUNSELING INFORMATION.Revised: 4/2016. Geriatric Patients: Dose reduction should be considered. (2.2, 2.3, 5.1, 8.5). Hepatic Impairment: Dose reduction should be considered. (2.1, 2.2, 2.3, 5.7, 8.6). Pregnancy: Based on animal data, may cause fetal harm. (8.1). Nursing Mothers: Caution should be exercised when administered to nursing woman. (8.3).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 5.1 Drug AdministrationPrecedex 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 ArrestClinically 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 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 HypertensionTransient 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 ArousabilitySome 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 WithdrawalIntensive Care Unit SedationWith administration up to days, regardless of dose, 12 (5%) Precedex adult subjects experienced at least event related to withdrawal within the first 24 hours after discontinuing study drug and (3%) Precedex adult subjects experienced at least event 24 to 48 hours after end of study drug. The most common events were nausea, vomiting, and agitation.In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after discontinuation of Precedex supportive therapy is indicated.Procedural SedationIn adult subjects, withdrawal symptoms were not seen after discontinuation of short term infusions of Precedex (<6 hours).5.6 Tolerance and TachyphylaxisUse of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and dose-related increase in adverse reactions [see ADVERSE REACTIONS (6.1)].5.7 Hepatic ImpairmentSince 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)].. 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)Prolonged exposure to dexmedetomidine beyond 24 hours may be associated with tolerance and tachyphylaxis and dose-related increase in adverse events. (5.6). 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). Prolonged exposure to dexmedetomidine beyond 24 hours may be associated with tolerance and tachyphylaxis and dose-related increase in adverse events. (5.6).