Dexmedetomidine HCl
`Draft Labeling
`PRECEDEXTM
`DEXMEDETOMIDINE HYDROCHLORIDE Injection
`
`December 23, 1999
`1
`
`DESCRIPTION
`PRECEDEXTM (dexmedetomidine hydrochloride injection) is a sterile, nonpyrogenic solution
`suitable for intravenous infusion following dilution. Dexmedetomidine hydrochloride is the S-
`enantiomer of medetomidine and is chemically described as (+)-4-(S)-[1-(2,3-
`dimethylphenyl)ethyl]-1H-imidazole monohydrochloride. Dexmedetomidine has a molecular
`weight of 236.7. The empirical formula is C13H16N2 • HCl and the structural formula is:
`CH3
`CH3
`
`CH3
`
`• HCl
`
`H
`
`N N
`
`H
`
`Dexmedetomidine hydrochloride is a white or almost white powder that is freely soluble in
`water and has a pKa of 7.1. Its partition coefficient in-octanol:water at pH 7.4 is 2.89.
`PRECEDEX is supplied as a clear, colorless, isotonic solution with a pH of 4.5 to 7.0. Each 1
`mL of PRECEDEX contains 118 mcg of dexmedetomidine HCl (equivalent to 100 mcg
`dexmedetomidine base) and 9 mg of sodium chloride in water. The solution is preservative-free
`and contains no additives or chemical stabilizers.
`
`CLINICAL PHARMACOLOGY
`General
`Dexmedetomidine is a relatively selective alpha2-adrenoceptor agonist with sedative properties.
`Alpha2-selectivity was observed in animals following slow intravenous (IV) infusion of low and
`medium doses (10-300 mcg/kg). Both alpha1 and alpha2 activity was observed following slow
`IV infusion of high doses (‡ 1000 mcg/kg) or with rapid IV administration.
`
`In a 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 IV infusion at doses within the recommended dose range (0.2-0.7 mcg/kg).
`
`Pharmacokinetics
`Following intravenous administration, dexmedetomidine exhibits the following pharmacokinetic
`parameters: a rapid distribution phase with a distribution half-life (t1/2) of approximately
`6 minutes; a terminal elimination half-life (t1/2) of approximately 2 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 HCl
`December 23, 1999
`Draft Labeling
`2
`Dexmedetomidine exhibits linear kinetics in the dosage range of 0.2 to 0.7 m g/kg/hr when
`administered by IV infusion for up to 24 hours. Table 1 shows the main pharmacokinetic
`parameters when PRECEDEX was infused (after appropriate loading doses) at maintenance
`infusion rates of 0.17 m g/kg/hr (target concentration of 0.3 ng/mL) for 12 and 24 hours, 0.33
`m g/kg/hr (target concentration of 0.6 ng/mL) for 24 hours, and 0.70 m g/kg/hr (target
`concentration of 1.25 ng/mL) for 24 hours.
`
`Table 1: Mean ± SD Pharmacokinetic Parameters.
`Parameter
`Loading Infusion (min)/Total infusion duration (hrs)
`10 min/12 hrs
`10 min/24hrs
`10 min/24 hrs
`35 min/24 hrs
`Dexmedetomidine Target Concentration (ng/mL) /Dose (mcg/kg/hr)
`0.3/0.17
`0.3/0.17
`0.6/0.33
`1.25/0.70
`tl/2*, hour
`1.78 ± 0.30
`2.22 ± 0.59
`2.23 ± 0.21
`2.50 ± 0.61
`CL, liter/hour
`46.3 ± 8.3
`43.1 ± 6.5
`35.3 ± 6.8
`36.5 ± 7.5
`Vss, liter
`88.7 ± 22.9
`102.4 ± 20.3
`93.6 ± 17.0
`99.6 ± 17.8
`Avg Css#, ng/mL
`0.27 ± 0.05
`0.27 ± 0.05
`0.67 ± 0.10
`1.37 ± 0.20
`*Presented as harmonic mean and pseudo standard deviation.
`#Avg Css = Average steady-state concentration of dexmedetomidine. (2.5 - 9 hour samples for
`12 hour infusion and 2.5 - 18 hour samples for 24 hour infusions.).
`
`Distribution
`The steady-state volume of distribution (Vss) of dexmedetomidine is approximately 118 liters.
`Dexmedetomidine protein binding was assessed in the plasma of normal healthy male and
`female volunteers. The average protein binding was 94% and was constant across the different
`concentrations tested. Protein binding was similar in males and females. The fraction of
`dexmedetomidine that was bound to plasma proteins was statistically 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 dexmedetomidine were observed. The potential for protein binding
`displacement of phenytoin, warfarin, ibuprofen, propranolol, theophylline, and digoxin by
`dexmedetomidine was explored in vitro and none of these compounds appeared to be
`significantly displaced by dexmedetomidine.
`
`Metabolism
`Dexmedetomidine undergoes almost complete biotransoformation 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
`
`

`

`December 23, 1999
`Dexmedetomidine HCl
`3
`Draft Labeling
`hydroxylation (mediated primarily by CYP2A6) 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 N-methyl O-glucuronide
`dexmedetomidine.
`
`Elimination
`The terminal elimination half-life (t1/2) of dexmedetomidine is approximately 2 hours and
`clearance is estimated to be approximately 39 L/h. A mass balance study demonstrated that
`after nine days an average of 95% of the radioactivity, following IV 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-glucoronidation 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 a minor circulating
`component and was undetected in urine. Approximately 28% of the urinary metabolites have
`not been identified.
`
`Gender
`There was no observed difference in dexmedetomidine pharmacokinetics due to gender.
`
`Geriatrics
`The pharmacokinetic profile of dexmedetomidine was not altered by age. There were no
`differences in the pharmacokinetics of dexmedetomidine in young (18-40 years),
`middle-age (41-65 years), and elderly (>65 years) subjects.
`
`Pediatrics
`The pharmacokinetic profile of dexmedetomidine has not been studied in pediatric patients.
`
`Renal Impairment
`Dexmedetomidine pharmacokinetics (Cmax, Tmax, AUC, t1/2, CL, and VSS) were not significantly
`different in subjects with severe renal impairment (creatinine clearance <30 mL/min) compared
`to healthy subjects. However, the pharmacokinetics of the metabolites of dexmedetomidine
`have not been evaluated in patients with impaired renal function. Since the majority of
`metabolites are excreted in the urine, it is possible that the metabolites may accumulate upon
`
`

`

`Dexmedetomidine HCl
`Draft Labeling
`long-term infusions in patients with impaired renal function (See PRECAUTIONS, Geriatrics,
`DOSAGE AND ADMINISTRATION).
`
`December 23, 1999
`4
`
`Hepatic Impairment
`In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C),
`clearance values for dexmedetomidine were lower than in healthy subjects. The mean clearance
`values for subjects 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
`patients with hepatic impairment (see PRECAUTIONS, Hepatic Impairment and DOSAGE
`AND ADMINISTRATION).
`
`Clinical Trials
`The safety and efficacy of PRECEDEX has been evaluated in two randomized,
`double-blind, parallel-group, placebo-controlled multicenter clinical trials in 754 patients being
`treated in a surgical intensive care unit (ICU). All patients were initially intubated and received
`mechanical ventilation. These trials evaluated the sedative properties of dexmedetomidine by
`comparing the amount of rescue medication (midazolam in one trial and propofol in the second)
`required to achieve a specified level of sedation (using the standardized Ramsay sedation scale)
`between PRECEDEX and placebo from onset of treatment to extubation or to a total treatment
`duration of 24 hours. The Ramsay Level of Sedation Scale is displayed in Table 2.
`
`
`Table 2: Ramsay Level of Sedation Scale
`Clinical Score Level of Sedation Achieved
`6
`Asleep, no response
`5
`Asleep, sluggish response to light glabellar tap or loud auditory
`stimulus
`Asleep, but with brisk response to light glabellar tap or loud
`auditory stimulus
`Patient responds to commands
`Patient cooperative, oriented, and tranquil
`Patient anxious, agitated, or restless
`
`3
`2
`1
`
`4
`
`In the first study, 175 patients were randomized to receive placebo and 178 to receive
`dexmedetomidine by intravenous infusion at a 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 1 (one) mcg/kg over 10
`minutes. The study drug infusion rate was adjusted to maintain a 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
`
`

`

`Dexmedetomidine HCl
`Draft Labeling
`to maintain sedation as specified while intubated. Patients randomized to placebo received
`significantly more midazolam than patients randomized to dexmedetomidine (see Table 3).
`
`December 23, 1999
`5
`
`A second prospective primary analysis assessed the sedative effects of dexmedetomidine by
`comparing the percentage of patients who achieved a Ramsay sedation score of ‡ 3 during
`intubation without the use of additional rescue medication. A significantly greater percentage of
`patients in the dexmedetomidine group maintained a Ramsay sedation score of ‡ 3 without
`receiving any midazolam rescue compared to the placebo group (see Table 3).
`Table 3: Midazolam Use As Rescue Medication During Intubation (ITT)*
`Study One
`Placebo
`
`p-value
`
`Dexmedetomidine
`N=178
`
`N=175
`19 mg
`
`5 mg
`
`0.0011**
`
`Mean total dose of
`midazolam
` Standard deviation
`Categorized midazolam use
`
`
`
`53 mg
`
` 19 mg
`
`108 (61%)
`43(25%)
`0mg
`36(20%)
`34 (19%)
`0-4 mg
`34 (19%)
`98 (56%)
`>4 mg
`*ITT (intent-to-treat) population includes all randomized patients.
`**ANOVA model with treatment and Center ***Chi-Square
`
`
`
`<0.001***
`
`A prospective secondary analysis assessed the dose of morphine sulfate administered to
`patients in the dexmedetomidine and placebo groups. On average, dexmedetomidine-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 dexmedetomidine patients received no
`morphine sulfate for pain versus 19% (33 of 175 patients) in the placebo group.
`
`In a second study, 198 patients were randomized to receive placebo and 203 to receive
`dexmedetomidine by intravenous infusion at a 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 1 (one) mcg/kg IV over
`10 minutes. The study drug infusion was adjusted to maintain a 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 dexmedetomidine (see Table 4).
`
`

`

`Dexmedetomidine HCl
`Draft Labeling
`A significantly greater percentage of patients in the dexmedetomidine group compared to the
`placebo group maintained a Ramsay sedation score of ‡ 3 without receiving any propofol rescue
`(see Table 4).
`
`
`December 23, 1999
`6
`
`Table 4: Propofol Use As Rescue Medication During Intubation (ITT)
`Study Two
`Placebo
`
`Dexmedetomidine
`
`N=198
`
`513 mg
`
`p-value
`
`N=203
`
`72 mg
`
`<0.0001*
`
`Mean total dose (mg) of propofol
`Standard deviation
`
` 782 mg
`
` 249 mg
`
`Categorized propofol use
`122 (60%)
`47(24%)
`0mg
`43 (21%)
`30 (15%)
`0-50 mg
`38 (19%)
`121 (61%)
`>50 mg
`*ANOVA model with treatment and center **Chi-square
`
`
`
`<0.001**
`
`A prospective secondary analysis assessed the dose of morphine sulfate administered to
`patients in the dexmedetomidine and placebo groups. On average, dexmedetomidine-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 dexmedetomidine patients received no
`morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo group.
`
`INDICATIONS AND USAGE
`PRECEDEX is indicated for sedation of initially intubated and mechanically ventilated patients
`during treatment in an intensive care setting. PRECEDEX should be administered by continuous
`infusion not to exceed 24 hours.
`
`WARNINGS
`PRECEDEX should be administered only by persons skilled in the management of patients in
`the intensive care setting. Due to the known pharmacological effects of PRECEDEX, patients
`should be continuously monitored while receiving PRECEDEX.
`
`Clinically significant episodes of bradycardia and sinus arrest have been associated with
`PRECEDEX administration in young, healthy volunteers with high vagal tone or with different
`routes of administration, including rapid intravenous or bolus administration.
`
`

`

`Dexmedetomidine HCl
`Draft Labeling
`PRECAUTIONS
`General
`Some patients receiving PRECEDEX have been observed to be arousable and alert when
`stimulated. This alone should not be considered an evidence of lack of efficacy in the absence
`of other clinical signs and symptoms.
`
`December 23, 1999
`7
`
`Reports of hypotension and bradycardia have been associated with PRECEDEX infusion. If
`medical intervention is required, treatment may include decreasing or stopping the infusion of
`PRECEDEX, increasing the rate of IV 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 (eg, atropine) should be considered to modify vagal
`tone. In clinical trials, atropine or glycopyrrolate 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.
`
`Transient 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.
`
`PRECEDEX infusion should not be coadministered through the same IV catheter with blood or
`plasma since physical compatibility has not been established. Safety and effectiveness of
`dexmedetomidine have not been evaluated in infusions over 24 hours. Dexmedetomidine is not
`indicated for infusions lasting over 24 hours (see INDICATIONS AND USAGE, DOSAGE
`AND ADMINISTRATION).
`
`Withdrawal
`Although not specifically studied, if PRECEDEX is administered chronically and stopped
`abruptly, withdrawal symptoms similar to those reported for another alpha-2-adrenergic agent,
`clonidine, may result. These symptoms may include nervousness, agitation, and headaches,
`accompanied or followed by a rapid rise in blood pressure and elevated catecholamine
`concentrations in the plasma. PRECEDEX should not be administered for greater than 24 hours
`(see INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION).
`
`

`

`Dexmedetomidine HCl
`Draft Labeling
`Adrenal Insufficiency
`Dexmedetomidine had no effect on ACTH-stimulated cortisol release in dogs after a single
`dose; however, after the subcutaneous infusion of dexmedetomidine for one week, the cortisol
`response to ACTH was diminished by approximately 40%.
`
`December 23, 1999
`8
`
`Hepatic Impairment
`Since dexmedetomidine clearance decreases with severity of hepatic impairment, dose
`reduction should be considered in patients with impaired hepatic function (see CLINICAL
`PHARMACOLOGY, Pharmacokinetics, DOSAGE AND ADMINISTRATION).
`
`Drug Interactions
`General
`In vitro studies in human liver microsomes demonstrated no evidence of cytochrome P450-
`mediated drug interactions that are likely to be of clinical relevance.
`
`Anesthetics/Sedatives/Hypnotics/Opioids
`Co-administration of PRECEDEX with anesthetics, sedatives, hypnotics, and opioids is likely to
`lead to an enhancement of effects. Specific studies have confirmed these effects with
`sevoflurane, isoflurane, propofol, alfentanil, and midazolam. No pharmacokinetic interactions
`between dexmedetomidine and isoflurane, propofol, alfentanil, and midazolam have been
`demonstrated. However, due to possible pharmacodynamic interactions, when co-administered
`with PRECEDEX, a reduction in dosage of PRECEDEX on the concomitant anesthetic,
`sedative, hypnotic or opioid may be required.
`
`Neuromuscular Blockers
`In one study of 10 healthy volunteers, administration of PRECEDEX for 45 minutes at a plasma
`concentration of 1 (one) ng/mL resulted in no clinically meaningful increases in the magnitude or
`neuromuscular blockade associated with rocuronium administration.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`Animal carcinogenicity studies have not been performed with dexmedetomidine.
`
`Dexmedetomidine was not mutagenic in vitro, in either the bacterial reverse mutation assay (E.
`coli and Salmonella typhimurium) or the mammalian cell forward mutation assay (mouse
`lymphoma). Dexmedetomidine was clastogenic in the in vitro human lymphocyte chromosome
`aberration test with, but not without, metabolic activation. Dexmedetomidine was also
`clastogenic in the in vivo mouse micronucleus test.
`
`Fertility in male or female rats was not affected after daily subcutaneous injections at doses up
`to 54 mcg/kg (less than the maximum recommended human intravenous dose on a mcg/m2
`
`

`

`December 23, 1999
`Dexmedetomidine HCl
`9
`Draft Labeling
`basis). Dexmedetomidine was dosed from 10 weeks prior to mating in males and 3 weeks prior
`to mating and during mating in females.
`
`Pregnancy: Teratogenic Effects. Pregnancy Category C
`Teratogenic effects were not observed following administration of dexmedetomidine at
`subcutaneous doses up to 200 mcg/kg in rats from day 5 to day 16 of gestation and intravenous
`doses up to 96 mcg/kg in rabbits from day 6 to day 18 of gestation. The dose in rats is
`approximately 2 times the maximum recommended human intravenous dose on a mcg/m2 basis.
` The exposure in rabbits is approximately equal to that in humans at the maximum recommended
`intravenous dose based on plasma area-under-the-curve values. However, fetal toxicity, as
`evidenced by increased postimplantation losses and reduced live pups, was observed in rats at
`a subcutaneous dose of 200 mcg/kg. The no-effect dose was 20 mcg/kg (less than the
`maximum recommended human intravenous dose on a mcg/m2 basis). In another reproductive
`study when dexmedetomidine was administered subcutaneously to pregnant rats from gestation
`day 16 through nursing, it caused lower pup weights at doses of 8 and 32 mcg/kg as well as
`fetal and embryocidal toxicity of second generation offspring at a dose of 32 mcg/kg (less than
`the maximum recommended human intravenous dose on a mcg/m2 basis). Dexmedetomidine
`also produced delayed motor development in pups at a dose of 32 mcg/kg (less than the
`maximum recommended human intravenous dose on a mcg/m2 basis). No such effects were
`observed at a dose of 2 mcg/kg (less than the maximum recommended intravenous dose on a
`mcg/m2 basis).
`
`Placental transfer of dexmedetomidine was observed when radiolabeled dexmedetomidine was
`administered subcutaneously to pregnant rats.
`
`There are no adequate and well-controlled studies in pregnant women.
`Dexmedetomidine should be used during pregnancy only if the potential benefits justify the
`potential risk to the fetus.
`
`Labor and Delivery
`The safety of PRECEDEX during labor and delivery has not been studied. Therefore,
`PRECEDEX is not recommended during labor and delivery, including cesarean section
`deliveries.
`
`Nursing Mothers
`It is not known whether PRECEDEX is excreted in human milk. Radiolabeled
`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 a nursing woman.
`
`Pediatrics
`
`

`

`Dexmedetomidine HCl
`Draft Labeling
`There have been no clinical studies to establish the safety and efficacy of PRECEDEX in
`pediatric patients below 18 years of age. Therefore, PRECEDEX is not recommended for use
`in this population.
`
`December 23, 1999
`10
`
`Geriatrics
`A total of 531 subjects in the clinical studies were 65 years of age and over. A total of 129
`subjects in the clinical studies were 75 years of age and over. In patients greater than 65 years
`of age, a higher incidence of bradycardia and hypotension was observed following
`administration of PRECEDEX. Therefore a dose reduction may be considered in patients
`over 65 years of age.
`
`Dexmedetomidine is known to be substantially excreted by the kidney, and the risk of adverse
`reactions to this drug may be greater in patients with impaired renal function. Because elderly
`patients are more likely to have decreased renal function, care should be taken in dose selection
`in elderly patients, and it may be useful to monitor renal function.
`
`ADVERSE REACTIONS
`Adverse event information is derived from the placebo-controlled, continuous infusion trials of
`dexmedetomidine for sedation in the ICU setting in which 387 patients received PRECEDEX.
`Overall, the most frequently observed treatment-emergent adverse events included hypotension,
`hypertension, nausea, bradycardia, fever, vomiting hypoxia, tachycardia and anemia (see Table
`5).
`
`Table 5: Treatment-Emergent Adverse Events Occurring in >1% of All
`Dexmedetomidine-Treated Patients in the Randomized Placebo-controlled
`Continuous Infusion ICU Sedation Studies
`Dexmedetomidine
`(N=387)
`30%
`11%
`8%
`7%
`6%
`3%
`3%
`3%
`2%
`2%
`2%
`2%
`2%
`
`Placebo
`(N=379)
`15%
`10%
`4%
`6%
`4%
`2%
`2%
`1%
`1%
`<1%
`1%
`<1%
`<1%
`
`Adverse Event
`
`Hypotension
`Nausea
`Bradycardia
`Atrial Fibrillation
`Hypoxia
`Anemia
`Pain
`Pleural Effusion
`Infection
`Leukocytosis
`Oliguria
`Pulmonary Edema
`Thirst
`
`

`

`Dexmedetomidine HCl
`Draft Labeling
`
`December 23, 1999
`11
`
`The treatment-emergent adverse events in Table 6 were reported in (cid:152)1% of all
`dexmedetomidine-treated patients and are potentially clinically relevant.
`
`Table 6: Potentially Clinically Relevant Treatment-Emergent Adverse Events to
`Dexmedetomidine Reported in £ 1% Patients in the Continuous Infusion ICU Sedation Trials
`Body System
`Preferred Term
`Body as a Whole
`Fever, Hyperpyrexia, Hypovolemia, Light Anesthesia, Pain,
`Rigors
`Blood pressure fluctuation, Heart disorder, Aggravated
`hypertension
`Dizziness, Headache, Neuralgia, Neuritis, Speech disorder
`
`Cardiovascular Disorders, General
`
`Central and Peripheral Nervous System
`Disorders
`Gastrointestinal System Disorders
`Heart Rate and Rhythm Disorders
`
`Liver and Biliary System Disorders
`Metabolic and Nutritional Disorders
`
`Psychiatric Disorders
`
`Red Blood Cell Disorders
`Respiratory System Disorders
`
`Skin and Appendages Disorders
`Vision Disorders
`
`Abdominal pain, Diarrhea, Vomiting,
`Arrhythmia, Ventricular arrhythmia, AV block, Cardiac arrest,
`Extrasystoles, Atrial fibrillation, Heart block, T wave
`inversion, Tachycardia, Supraventricular tachycardia,
`Ventricular tachycardia
`Increased GGT, Increased SGOT, Increased SGPT,
`Acidosis, Respiratory acidosis, Hyperkalemia, Increased
`alkaline phosphatase, Thirst
`Agitation, Confusion, Delirium, Hallucination, Illusion,
`Somnolence
`Anemia
`Apnea, Bronchospasm, Dyspnea, Hypercapnia,
`Hypoventilation, Hypoxia, Pulmonary congestion
`Increased sweating
`Photopsia, Abnormal vision
`
`DRUG ABUSE AND DEPENDENCE
`PRECEDEX (dexmedetomidine hydrochloride) is not a controlled substance.
`
`The dependence potential of dexmedetomidine has not been studied in humans. However,
`since studies in rodents and primates have demonstrated that dexmedetomidine exhibits
`pharmacologic actions similar to those of clonidine, it is possible that PRECEDEX may produce
`a clonidine-like withdrawal syndrome upon abrupt discontinuation (See PRECAUTIONS,
`Withdrawal).
`
`OVERDOSAGE
`The tolerability of PRECEDEX was noted in one study in which healthy subjects were
`administered doses at and above the recommended dose of 0.2 to 0.7 mcg/kg/hr. The
`maximum blood concentration achieved in this study was approximately 13 times the upper
`boundary of the therapeutic range. The most notable effects observed in two subjects who
`achieved the highest doses were first degree AV block and second degree heart block. No
`hemodynamic compromise was noted with the AV block and the heart block resolved
`spontaneously within one minute.
`
`

`

`Dexmedetomidine HCl
`Draft Labeling
`
`December 23, 1999
`12
`
`Five patients received an overdose of PRECEDEX in the ICU sedation studies. Two of these
`patients had no symptoms reported; one patient received a 2 mcg/kg loading dose over 10
`minutes (twice the recommended loading dose) and one patient received a maintenance infusion
`of 0.8 mcg/kg/hr. Two other patients who received a 2 mcg/kg loading dose over 10 minutes,
`experienced bradycardia and/or hypotension. One patient who received a loading bolus dose
`of undiluted PRECEDEX (19.4 mcg/kg), had cardiac arrest from which he was successfully
`resuscitated.
`
`DOSAGE AND ADMINISTRATION
`PRECEDEX should be administered using a controlled infusion device.
`
`PRECEDEX dosing should be individualized and titrated to the desired clinical effect. For adult
`patients, PRECEDEX is generally initiated with a loading infusion of 1 (one) mcg/kg over 10
`minutes, followed by a maintenance infusion of 0.2 to 0.7 mcg/kg/hr. The rate of the
`maintenance infusion should be adjusted to achieve the desired level of sedation.
`Dexmedetomidine is not indicated for infusions lasting longer than 24 hours.
`
`PRECEDEX has been continuously infused in mechanically ventilated patients prior to
`extubation, during extubation, and post-extubation. It is not necessary to discontinue
`PRECEDEX prior to extubation provided the infusion does not exceed 24 hours.
`
`Dosage Adjustment
`Dosage reductions may need to be considered for patients with renal or hepatic impairment (see
`CLINICAL PHARMACOLOGY, Pharmacokinetics & PRECAUTIONS, Hepatic
`Impairment).
`
`Dilution Prior to Administration
`PRECEDEX must be diluted in 0.9% sodium chloride solution prior to administration.
`
`Preparation of solutions is the same, whether for the loading dose or maintenance infusion.
`
`To prepare the infusion, withdraw 2 mL of PRECEDEX and add to 48 mL of 0.9% Sodium
`Chloride injection to a total of 50 mL. Shake gently to mix well.
`
`Administration With Other Fluids
`Compatibility of PRECEDEX with coadministration of blood, serum, or plasma has not been
`established. PRECEDEX has been shown to be compatible when administered with the
`following intravenous fluids and drugs:
`
`

`

`Dexmedetomidine HCl
`Draft Labeling
`
`December 23, 1999
`13
`
`Lactated Ringers
`5% dextrose in water, 0.9% sodium chloride in water, 20% mannitol, thiopental sodium,
`etomidate, vecuronium bromide, pancuronium bromide, succinylcholine, atracurium besylate,
`mivacurium chloride, glycopyrrolate bromide, phenylephrine HCl, atropine sulfate, midazolam,
`morphine sulfate, fentanyl citrate, and a plasma-substitute.
`
`Handling Procedures
`Parenteral products should be inspected visually for particulate matter and discoloration prior to
`administration. Strict aseptic technique must always be maintained during handling of
`PRECEDEX. Ampules and vials are intended for single use only.
`
`Compatibility studies have demonstrated the potential for adsorption of dexmedetomidine 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 must be diluted in 0.9% sodium chloride solution to achieve the required
`concentrations prior to administration. Preparation of solutions is the same, whether for the
`loading or maintenance infusion (see DOSAGE AND ADMINISTRATION).
`
`HOW SUPPLIED
`PRECEDEX (dexmedetomidine hydrochloride injection), 100 mcg/mL as the base is available
`in 2 mL clear glass vials and 2 mL clear glass ampules.
`
`2 mL vial (NDC XXXX-XXXX-XX)
`2 mL ampule (NDC XXXX-XXXX-XX)
`
`Store at controlled room temperature, 25oC (77o F) with excursions allowed from 15o to 30oC
`(59oto 86oF).
`Manufactured and Distributed by:
`Abbott Laboratories
`North Chicago, IL 60064
`
`Licensed from:
`Orion Corporation
`Espoo, Finland
`
`RAO5979-R1-Rev. Dec., 1998
`
`