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`Dexmedetomidine HCI
`Draft Labeling
`PRIiCI-ZDEXTM
`
`DEXMEDETOMIDINE HYDROCHLORIDE Injection
`
`[lPPlilWEl]
`
`DEC 1 7 1999
`
`.
`
`December 17, 1999
`l
`
`DESCRIPTION .
`PRECEDEXm (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 C,,H,6N2 o HC1 and the
`structural formula is:
`.
`s
`‘
`
`CH3
`
`° HCI
`
`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-octanolzwater 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 HCI (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 'alphaz-adrenoceptor agonist with sedative
`properties. Alphaz-selectivity was observed in animals following slow intravenous (IV)
`infusion of low and medium doses (10-300 meg/kg). Both alphal and alpha2 activity was
`observed following slow IV infusion of high doses (21000 meg/kg) or with rapid 1V
`adminisrration.
`*
`
`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 meg/kg).
`"
`
`Pharmacokinetics
`
`Following intravenous administration, dexmedetomidine exhibits the following
`pharmacokinetic parameters: a rapid distribution phase with a distribution half-life (tm) of
`approximately 6 minutes; a terminal elimination half-life (tin) of approximately 2 hours;
`and steady-state volume of distribution (V55) of approximately 118 liters. Clearance is
`
`
`
`
`
`Dexmedetomidine HCl
`Draft Labeling
`estimated to be approximately 39 L/h. The mean body weight associated with this
`clearance estimate was 72 kg.
`
`December 17, 1999
`‘7
`.
`
`Dexmedetomidine exhibits linear kinetics in the dosage range of 0.2 to 0.7 ug/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. 1 7 ug/kg/hr (target concentration of 0.3 ng/mL) for 12
`and 24 hours, 0.33 ug/kg/hr (target concentration of 0.6 ng/mL) for 24 hours, and 0.70
`ug/kg/hr (target concentration of 1.25 ng/mL) for 24 hours.
`
`'
`
` Table 1:
`Parameter:
`
`
`
`
`Mean i SD Pharmacokinetic Parameters.
`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)
`
`
`
`
`
`_
`
`
`
` tn", hour
`2.23 i 0.21
`2.50 i 0.61
`2.22 t 0.59
`1.78 :h 0.30
`
`
`36.5 :t 7.5
`43.1 i 6.5
`46.3 t 8.3
`CL, liter/hour
`
`
`
`99.6 :1: 17.8
`102.4 :t 20.3
`88.7 :t 22.9
`V“, liter
`
`
`
`
`
`
`1.37 t 0.20
`0.27 :t 0.05
`0.27 t 0.05
`Avg Css#, ng/mL
`
`
`
`'*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 (V55) of dexmedetomidine is approximately 1 18
`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:.
`I
`
`The potential forll‘protein binding displacement of dexmedetomidine by fentanyl,
`ketorolacfth‘eopli'ylline, digoxin, and lidocaine was explored in virro, 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 biotransoforrnation with very little
`unchanged dexmedetomidine excreted in urine and feces. Biotransformation involves
`
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`»
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`‘
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`December 17, 1999
`Dexmedetomidine HCl
`3
`Draft Labeling
`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)
`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 (tm) 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 phannaeokinctic profile of dexmedetomidine was not altered by age. There were no
`differences in the pharmacokinetics of dexmedetomidine in young (18-40 years),
`middle-age.(4l;_v65 years), and elderly (>65 years) subjects.
`
`_
`
`Pediatrics
`
`‘
`
`—
`
`The pharmacokinetic profile of dexmedetomidine has not been studied in pediatric
`patients.
`
`Renal Impairment
`Dexmedetomidine pharmacokinetics (Cm, Tm, AUC, tm, CL, and V55) were not
`significantly different in subjects with severe renal impairment (creatinine clearance <30
`mL/min) compared to healthy subjects. However, the phannacokinetics of the
`
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`
`Dexmedetomidine HCl
`Draft Labeling
`
`December I7, 1999
`4
`
`metabolites ofdexmedetomidine have not been evaluated in patients with impaired renal
`function. Since the majority ofmetabolites are excreted in the urine, it is possible that the
`metabolites may accumulate upon long-term infusions in patients with impaired renal
`function (See PRECAUTIONS, Geriatrics, DOSAGE AND ADMINISTRATION).
`Hepatic Impairment
`In subjects with varying degrees ofhepatic 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% ofthose 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.
`I
`'
`
`Although PRECEDEX is closed to effect, it may be necessary to consider dose reduction
`in patients with hepatic impairment (see PRECAUTIONS, l-lepatic 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 ofrescue 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.
`
`Asleep, but with brisk response to light glabellar tap or loud
`
`
`
`Ramsay Level of Sedation Scale
`Table 2:
`
`Level of Sedation Achieved
`
`
`“ Asleep, no response
`5
`Asleep, sluggish response to light glabellar tap or loud auditory
`
`
`--——
`
`
`“—
`— Patient cooperative, oriented. and tranquil
`
`
`Patient anxious. agitated, or restless
`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 meg/kg/hr) following an initial loading infusion of 1
`(one) meg/kg over IO minutes. The study drug infiision rate was adjusted to maintain a
`Ramsay sedationscore of 23. Patients were allowed to receive “rescue” midazolam as
`
`
`
`
`
`Dexmedetomidine HCI
`Draft Labeling
`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 dexmedetomidine (see'T'a‘ble 3).
`
`December 17, 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 23
`during intubatioun without the use of additional‘rescue medication. A significantly greater
`percentage of patients in the dexmedetomidine group maintained a Ramsay sedation
`score of 23 without receiving any midazolam rescue compared to the placebo group (see
`Table 3): ,.
`«—
`
`
`
`-
`Table 3: Midazolam Use As Rescue Medication During Intubatio
`
`
`Study One
`Placebo
`
`n (ITT)"
`
`
`
`
`
`
`Dexmedetomidine
`
` N=l 78
`
`
`5 mg
`
`
`19mg “
`‘
`53 mg
`Standard deviation
`
`
`
`Mean total dose of
`midazolam
`
`19 mg
`
`Categorized midazolam use
`
`‘
`
`
`
`
`<0.001"*
`108(61%)
`-m- 43(25%)
`36(20%) —
`34(19%)
`34(19%) -
`98(56%> ‘
`*ITT (intent-to-treat) population includes all randomized patients.
`* *ANOVA model with treatment and Center *"Chi-Square
`
`
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`
`.
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`
`
`A prospective secondary analysis assessed the dose of morphine sulfate administered to
`patients in the dexmedetomidinc and placebo groups. On average, dexmedetomidine-
`treated patientsnreceived less morphine sulfate for pain than placebo-treated patients (0.47
`versus 0.83 Trig/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.
`‘ ‘:
`h
`
`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 lkg/hr) following an initial loading infusion of 1
`(one) meg/kg IV over 10 minutes. The study drug infusion was adjusted to maintain a
`Ramsay sedation score of 23. 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 ofyrescue medication (propofol) needed to maintain sedation as specified
`
`
`
`
`
`Dexmedetomidine HCl
`‘
`Draft Labeling
`while intubated. Patients randomized to placebo received significantly more propofol
`than patients randomized to dexmedetornidine (see Table 4).
`
`December 17, I999
`6
`
`A significantly greater percentage of patients in the dexmedetornidine group compared to
`the placebo group maintained a Ramsay sedation score ‘of .>.3 without receiving any
`propofol rescue (see Table 4).
`
`' Table 4:
`
`
`
`513 mg
`
`72 mg
`
`‘ <0.0001‘
`
`
`, _Propofol Use As Rescue Medication During Intubation (ITT).
`‘
`Study Two
`"
`
`
`Placebo
`Dexmedetomidine -
`
`
`
`
`
`
`N=198
`N=203
`
`
`Mean total dose (mg) of
`propofol
`'
`249 mg
`782 mg
`Standard deviation
`
`_—_—
`“__-
`
`__——
`_———
`
`
`‘ANOVA model with treatment and center
`"Chi-square
`
`p-value
`
`
`
`
`
`
`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 dexmedetornidine patients
`received no morphine sulfate for pain versus 15% (30 of 198 patients) in the placebo
`group.
`
`INDICATIONS AND USAGE
`
`PRECEDEstjndicated for sedation of initially intubated and mechanically ventilated
`patients during treatment in an intensive care setting. PRECEDEX should be
`administered byc’ontinuous infusion not to exceed 24 hours.
`
`WARNINGS
`
`"
`
`—
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`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.
`
`
`
`
`
`Dexmedetomidine HCl
`Draft Labeling
`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.
`
`December 17, I999
`7
`
`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 efficacy1n the
`absence of other clinical signs and symptoms.
`
`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
`effectivenessofdexmedetomidine have not been evaluatedin infusions over 24 hours.
`Dexmedetomidine15 not indicated for infusions lasting over 24 hours (see
`INDICATIONS-AND USAGE, DOSAGE AND ADMINISTRATION).
`
`\\ ithdra“ al
`
`Although not specifically studied, if PRECEDEXis 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 HCI
`Draft Labeling
`
`December 17, 1999
`3
`
`-
`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%.
`
`.
`Hepatic Impairment
`Since dexmedetomidine clearance decreases with severityjof hepatic impairment, dose
`reductionshourd 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/I-lvpnotics/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 isoflurahe, 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 condéiitration 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 Iyphimurium) 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.
`Dexmedetomidin'e was also clastogenic in the in vivo mouse micronucleus test.
`
`
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`
`
` Dexmedetomidine HCI
`
`
`
`December 17,1999
`9
`
`Draft Labeling
`Fertility1n male or female rats was not affected after daily subcutaneousinjections at
`doses up to 54 meg/kg (less than the maximum recommended human intravenous dose on
`a meg/m 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/kg1n rats from day 5 to day 16 of gestation and
`' intravenous doses up to 96_ meg/kg1n 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 meg/m basis. The exposure in rabbits15 approximately e'qual to thatin humans at the
`maximum recommendedintravenous dose based on plasma area-under-the--curve vaers.
`However fetal toxicity, as evidenced by increased postimplantation losses and reduced
`live pups, was observed in rats at a subcutaneous dose of 200 meg/kg. The no-effect dose
`was 20 meg/kg (less than the maximum recommended human intravenous dose on a
`‘ meg/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 meg/kg as well as fetal and embryocidal toxicity of
`second generation offspring at a dose of 32 meg/kg (less than the maximum
`1 recommended human intravenous dose on a meg/m basis). Dexmedetomidine also
`produced delayed motor development1n pups at a dose of 32 meg/kg (less than the
`maximum recommended human intravenous dose on a mcg/m basis). No such effects
`vsere observed at a dose of 2 mcg/kg (less than the maximum recommendedintravenous
`dose on a meg/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
`f":— ‘.5.
`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
`It15 not known whether PRECEDEX1s excreted1n 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.
`
`
`
`
`
`Dexmedetomidine HCl
`Draft Labeling
`Pediatrics
`
`December 17. 1999
`10
`
`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.
`
`Geriatrics
`
`A total of 531 subjects in the clinical studies were 65 years of age and over. A total of
`'129 subjects1n 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 ,
`considered1n 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 bypotension hypertension nausea, bradycardia, fever, vomiting hypoxia,
`tachycardia and anemia (see Table 5).
`
`
`
`
`
`Table 5:
`Treatment--Emergent Adverse E\ents Occurring1n >l% of All
`
`Continuous Infusion ICU Sedation Studies
`
`Dexmedetomidine-Treated Patients1n the Randomized Placebo-controlled
`
`
`
` Hypotension
`
`Nausea-3.
`1 1%
`__
`10%
`
`Bradycardia
`8%
`4%
`
`
`Atrial Fibrillation
`7%
`6%
`Hypoxia”
`6%
`4%
`
`
`Anemia
`3%
`2%
`
`
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`
`
`
`
`
`
`
`
`
`
`
`Pain
`
`Pleural Effusion
`
`Infection
`
`1
`
`Leukocytosis
`Oliguria
`Pulmonary Edema
`Thirst
`'
`
`'
`
`3%
`
`3%
`
`2%
`
`2%
`2%
`
`‘
`
`2%.
`
`1%
`
`1%
`
`<1 %
`1%
`
`
`
`
`
`Dexmedetomidine HCl
`Draft Labeling
`
`December 17, 1999
`l
`l
`
`The treatment-emergent adverse events in Table 6 were reported in s 1% of all
`dexmedetomidine-treated patients and are potentially clinically relevant.
`
`Body System
`'
`"
`‘
`'
`‘
`'Body 5 a Whole
`Cardiovascular Disorders. General
`
`
`
`Preferred Term
`Fever. Hyperpyrexia. Hypovolcmia Light Anesthesia Pain. Rigors
`Blood pressure fluctuation, Heart disorder, Aggravated
`hypertension
`Dizziness. Headache, Neu't‘algia. Neuritis. Speech disorder
`. '
`
`>
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`Table 6:
`Potentially Clinically Relevant Treatment-Emergent Adverse Events to
`Dexmedetomidine Reported in 51% Patients in the Continuous Infiision ICU Sedation
`
`
`Trials
`
`
`
`
`
`
`
`
`
`'
`
`
`
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`
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`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
`
`phosphatue. Thirst
`Agitation, Confusion, Delirium, Hallucination, Illusion,
`
`Somnolence
`
`Red Blood Cc“ Disorders _
`
`
`Respiratory System Disorders
`Apnea Bronchospasm, Dyspnea, Hypercapnia. Hypoventilation.
`
`Hypoxia Pulmonary congestion
`
`
`
`
`Central and Peripheral Nervous System
`Disorders
`
`Gastrointestina] System Disorders
`Heart Rate and Rhythm Disorders
`
`Liver and Biliary System Disorders
`Metabolic and Nutritional Disorders
`
`Psychiatric Disorders
`
`
`
`
`
`
`Skin and Appendagcs Disorders
`
`.
`
`Phowpsia. 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 pharrnacologic actions similar to those of clonidine, it is possible that
`PRECEDEX may produce a clonidine-Iike withdrawal syndrome upon abrupt
`discontinuati‘dn'fSee PRECAUTIONS, Withdrawal).
`
`OVERDQSAGE
`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 mcglkg/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
`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 meg/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 meg/kg
`loading dose over —10 minutes, experienced bradycardia and/or hypotension. One patient
`who received a loading bolus dose of undiluted PRECEDEX (19.4 meg/kg), had cardiac
`arrest from which he was successfully resuscitated.
`
`December 17, 1999
`12
`
`‘ 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,Thamacokinetics &
`PRECAUTIONS, Hepatic Impairment).
`
`Dilution Prior to Administration
`
`PRECEDEX must be diluted in 0.9% sodium chloride solution prior to
`administration.
`-
`
`Preparation'gfsolutions 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 m1... 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 l-lCl
`Draft Labeling
`
`December 17, 1999
`l3
`
`Lactated Ringers
`5% dextrose in water, 0.9% sodium chloride in water, 20% mannitol, thiopental sodium,
`etomidate,vecuror_1ium bromide, pancuronium bromide, succinylcholine, atracurium
`besylate, mivacurium chloride, glycopyrrolate bromide, phenylephrine HCl, atropine
`sulfate midazolam, morphine sulfate, fentanyl citrate, and a plasma-substitute.
`
`.MHandling Procedures
`Parenteral productsshould 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 closed 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-XXJOGXX)
`2 mL ampule (NDC XXXX-XXXX-XX)
`
`Store at controlled room temperature, 25°C (77° F) with excursions allowed from 15° to
`30°C (59°to 86°F).
`Manufactured and Distributed by.
`Abbott Laboratories
`
`North Chicago, IL 60064
`
`Licensed from:
`
`Orion Corporation
`Espoo, Finland
`
`RA05979-Rl-Rev. Dec., 1998.
`
`
`
`