`
`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
` NDA: 21-038
`_
`Code: 18
`
`Name:
`..._~.___
`.7” (Dexmedetomidine HCL) for Infusion
`
`Sponsor: Abbott Laboratories, 200 Abbott Park, Abbott Park IL 60064
`Submission Type: Original NDA
`Submission Date: December 18, 1998
`
`Reviewer: Suresh Doddapaneni, PhD.
`
`
`
`
`
`SYNOPSIS
`
`Dexmedetomidine is intended for alpha; sedation and analgesia in an intensive care
`setting (IC) and is claimed to produce titratable, predictable sedation, from whichpatients are
`easily arousable and cooperative.
`’
`
`'Chiral inversion of dexmedetomidine to the inactive Ievo isomer is likely to be
`,
`insignificant. Recovery of the radiolabel in the mass balance study was complete and quantitative.
`The excretion of the radioactivity was rapid with about 85% recovered in the urine within 24
`hours post dosing. Dexmedetomidine undergoes complete biotransforrnation in vivo with very
`little excreted unchanged in the urine or feces.
`Biotransformation involves both direct
`glucuronidation as well as cytOchrome P450 mediated metabolism. Direct N-glucuronidation to
`the inactive G-DEX—l and G-DEX-Z conjugates accounts for about 34% of its metabolism.
`Aliphatic hydroxylation of dexmedetomidine (mediated primarily by CYP2A6) to generate 3-
`hydroxy dexmedetomidine, glucuronide of 3-hydroxy dexmedetomidine,
`and 3-carboxy
`dexmedetomidine represents about 14% of the metabolism. N-methylation of dexmedetomidine to
`generate 3-hydroxy N-methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-
`methyl O-glucuronide dexmedetomidine
`accounted for about 18% of the metabolism.
`Approximately, 28% of the urinary metabolites have not been identified. The .average plasma
`protein binding of dexmedetomidine was 94%.
`The specific plasma protein to which
`dexmedetomidine binds is unknown.
`-
`
`Dexmedetomidine exhibits dose-independent pharmacokinetics in the dosage
`regimen (0.2 to 0.7 ug/kg/hr when infused up to 24 hours) proposed for the indication being
`sought. The main phannacokinetic parameter values were consistent across several studies with
`varied infusion regimens (10 minute infusion, two-stage regimens (loading dose + maintenance
`dose), three-stagé'regimens (two loading doses + maintenance dose), and virtually continuously
`changing infusion rate regimens) and are as follows; The clearance is about 39.0 liter/hr,
`the
`temiinal half-life_is about 2 hours, and the steady state volume of distribution'is about 1.3 liter/kg.
`
`Dexmedetomidine did not show gender and age differences in pharmacokinetics of
`adult subjects. Therefore, based on pharmacokinetic considerations no dosage adjustments are
`warranted in females or in the elderly.
`
`Dexmedetomidine pharmacokinetics were not afi‘ected in patients with severe renal
`impairment afier a single dose administration of dexmedetomidine. No dosage adjustments are
`warranted based on the results from this study. However, the metabolites are completely excreted
`
`
`
`

`

`
`
`in the urine and it is unknown if the metabolites accumulate. when dexmedetomidine is infused
`continuously.
`
`The pharmabokinetics of dexmedetomidine were afi'ected in hepatic impairment
`requiring dosage adjustments when dexmedetomidine is used in this patient population. The mean
`CL values for subjects with mild, moderate, and severe hepatic impairment were only 74%, 64%
`and 53%, respectively, of those observed in the normal healthy subjects.
`
`Based on in vitro metabolism studies, dexmedetomidine is not expected to inhibit
`the metabolism of drugs whose metabolism is mediated by CYP1A1, CYP1A2, 'CYP2A6,
`CYP2CI9, CYP2D6,‘CYP2E1, and CYP3A4 isoforms.
`In vivo interaction studies showed that
`the pharmacokinetics of dexmedetomidine were not affected by the concurrent administration of
`alfentanil, midazolam, propofol, and isoflurane.
`In vivo interaction studies also showed that the
`pharmacokinetics of propofol, midazolam, and rocuronium were not afi‘ected by the concurrent
`administration" of dexmedetomidine.
`
`_
`RECOMMENDATION
`NDA 21-038 can be approved from the viewpoint of Office of Clinical
`Pharmacology and Biopharmaceutics provided a mutually acceptable language can be worked out
`on the clinical pharmacology section of the package insert. Comments 1-2 on page 23 of this
`review'should be sent to the sponsor.
`\
`‘ f3 .
`
`/2—7/9~7
`
`~
`
`Suresh Doddapaneni, Ph.D.
`Clinical Pharmacologist
`DPE II/OCPB
`
`FT initialed by Ramana Uppoor, Ph.D.
`cc:
`
`.. /
`
`- m '
`
`5\
`Vi \ \
`
`‘
`
`\40 [Ci 0[
`
`-
`
`i
`
`NDA 21-038, RFD-170 (Division File, Samantha), RFD-850 (Lesko), RFD-870 (Doddapaneni,
`Mei-Ling Chen, Uppoor), Barbara Murphy (CDR).
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`‘
`
`‘
`
`NDA21-038,
`
`‘
`
`'
`
`:
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`2 -.
`
`

`

`I.
`
`INTRODUCTION
`
`TABLE OF CONTENTS
`
`
`4
`
`INDICATIONS AND DOSAGE AND ADMINISTRATION AS STATED IN THE PROPOSED
`II.
`
`PACKAGE INSERT
`
`4
`
`
`III. PHYSICOCI-[EMICAL PROPERTIES 8: FORMULATION '
`
`4
`
`t _
`
`-
`
`IV. DEXMEDETOMIDINE METABOLISM
`
`
`
`5
`
`I. "
`
`PROPOSED METABOLICPATHWAYS
`
`_ II:
`III.
`
`.......................................................................... 7
`MAss BALANCE......'..-......................................................~
`METABOLIC INVERSION .......................................................................................................................................... 8
`
`VI. PHARMAGOKINETICS AND DOSE-PROPORTIONALITY
`
`
`I -
`
`8
`
`_
`
`VII.
`
`SPECIAL POPULATIONS
`
`
`
`12
`
`I.
`u.
`III.
`IV.
`v.
`VI.
`
`HEPATIC FAILURE .....................................................‘................................. ............................................................ l 2-
`RENAL FAILURE ..................................................................................................................................................... 13
`GENDER & ELDERLY ............................................................................................................................................. 14
`PEDIATRICS............................................................................................................................................................ 15
`MATERNAIJFETAL RATIO ..................................................................................................................................... 15
`DRUG-DRUG INTERACHONs ................................................................................................................................. l5
`
`Isafluraue ............................................................................’............................................................................ 1 5
`' a)
`b) Midazolam ....................................................................................................................................................... )6
`c)
`Propofal........................................................................................................................................................... I 6
`d)
`Rocurom'um .................................................................................................................................................... l 7
`e)
`Ay'eutanil...........‘.............................................................................................................................................. 18
`
`VIII.
`
`ANALYTICAL METHODOLOGYW18
`
`IX. CONCLUSIONS
`
`
`
`I9
`
`X.
`
`
`PROPOSED PACKAGE INSERT
`
`20
`
`XI. COMMENTS
`
`
`
`23
`
`XII. APPENDWWN
`MASS BALANCE .......................................................................................................................................................... 25
`
`1
`
`HEPATIC IMPAIRMENT ............................................................................................................................................. 34
`RENAL IMPAIRMENT.............................................................. 38
`EFFECT OF AGE AND GENDER ............................................................................................................................... 42
`DOSE-RANGING ................................................................................................................................................... 4S
`
`DEMDETOMIDINE-ALFENTANIL INTERACTION .......................................................................................... 52
`DEXMEDETOMIDINE-MJDAZOLAM INTERACTION .......................................................................................... 54
`DEMDETOWINE-PROPOFOL INTERACTION .............................................................................................. 59
`DEMDETOINAIDINE-ROCURONIUM INTERACTION .......................................................................................61
`IN VITRO METABOLISM ............................................................................................................................................. 63
`
`
`74
`
`XII].
`
`PROPOSED PACKAGE INSERT
`
`
`
`NDA 21-038,
`
`-
`
`3
`
`—————_
`
`

`

`I.
`
`INTRODUCTION
`
`Dexmedetomidine is a potent and highly selective az-adrenoceptor agonist (aka.
`ratio of 1600:1).
`It is the f ~separated fi'om racernic medetornidine. Activation of
`alpha; receptors located in the sympathetic nerve endings inhibits the release of norepinephrine.
`Activation of postsynaptic receptors by alpha; agonists in the CNS leads to inhibition of
`sympathetic activity, decreases in blood pressure and heart rate, sedation, and relief of anxiety.
`Binding of agonists to alpha; adrenoceptors in the spinal cord produces analgesia.
`
`Dexmedetomidine is intended for alpha; sedation and analgesia in an intensive care
`.
`setting (IC) and is claimed to produce titratable, predictable sedation, from which patients are
`easily arousable and cooperative. It is claimed to be relatively fi'ee of side effects: Most common
`adverse events associated with its use have been hypotensio'n, hypertension, and bradycardia
`which are expected extensions of its pharmacologic effect and have been easily managed. Similar
`proportions of patients have had therapy discontinued because of adverse events in the
`dexmedetomidine and placebo control groups (3%, 30/1148 dexmedetomidine; 3%, 24/817
`placebo). Currently, dexmedetomidine I-ICI is not approved for marketing in any country.
`‘-
`
`II.
`
`INDICATIONS AND DOSAGE AND ADMINISTRATION AS STATED IN THE
`PROPOSED PACKAGE INSERT
`
`Indications:
`" \ is an alpha; sedative with analgesic properties for use in an intensive care setting.”
`
`Dosage and Administration:
`"' r‘ . should be administered using a controlled infiision device.
`
`
`can be individualized and titrated to the desired clinical effect. For adult patients,
`.72? is initiated with a loading dose of 1.0 meg/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 and/or analgesia.
`In clinical studies, doses as low
`as 0.05 mcg/kg/hr have been used and infusions up to 24 hours have been studied.”
`
`In.
`
`PHYSICDCREMICAL PROPERTIES & FORMULATION -
`
`_Dexmedetomidine is a white or almost white, crystalline powder freely soluble in
`water with a pKa of 7.1. Dexmedetomidine HCl for Infiision (100 pig/ml. as dexmedetomidine
`base) is presented as a sterile, aqueous solution in ampoules and vials with a pH of 4.5 to 7.0.
`This solution is preservative free and contains no additive or chemical stabilizers. This solution is
`further diluted with normal saline prior to intravenous infusion.
`
`NDA 21-038,
`
`-
`
`:
`
`4 ‘
`
`

`

`IV.
`
`DEXMEDETOMIDINE METABOLISM
`
`i.
`
`Proposed metabolic pathway
`
`Dexmedetomidine undergoes almost complete biotransformation. No unchanged
`dexmedetomidine was excreted in urine. Very little (less than 1%) dexmedetomidine was excreted
`in feces. Biotransfonnation involves both direct glucuronidation as well as cytochrome P450
`mediated metabolism. Figure 1 shows the proposed metabolic pathway of dexmedetomidine.
`Direct N-glucuronidation to the inactive G-DEX-l and G-DEX-2 conjugates accounts for about
`34%---of
`its metabolism. Aliphatic hydroxylation (mediated primarily by CYP2A6) 'of
`dexmedetomidine to -3%hydroxy dexmedetomidinefollowed by glucuronidation. to 3-hydroxy
`dexmedetomidine glucuronide, and/or fiirther oxidation to 3-carboxylic acid dexmedetomidine
`represents about 14% of the metabolism. N-methylation of dexmedetomidine followed by
`aliphatic hydroxylation to 3-hydroxy N-methyl dexmedetomidine, followed further by oxidation to
`3-carboxy N-‘niethyl dexmedetomidine, and/or glucuronidation to N-methyl O-glucuronide
`dexmedetomidine accounts for about 18% of the metabolism. The N-Methyl metabolite itself was
`a minor circulating component and was undetected in urine. There may be additional
`uncharacterized metabolites (approximately, 28% of the urinary metabolites have not been
`identified).
`~
`
`In vitro metabolism studies (using liver microsomes, microsomes containing
`cDNA—expressed CYP isofonns, and selective, CYP2A6 monoclonal antibody) showed that
`CYP2A6 is
`the
`largest
`single
`contributor of
`the CYP mediated
`hydroxylation of
`dexmedetomidine. Other isoforrns such as CYP1A2, CYPZEl, CYP2D6, and CYP2C19 may
`also play a role in the hydroxylation of dexmedetomidine (Inhibition by CYP2A6 selective
`inhibitors was incomplete).
`In vitro metabolism studies also showed that the ICso values for
`inhibition potential of dexmedetomidine against
`the djfl‘erent cytochrome P450 isoforrns are
`relatively high compared to the expected therapeutic plasma concentrations of dexmedetomidine.
`The upper limit of the anticipated therapeutic concentration range is 1.2 ng/mL, which is 0.0096
`uM. Based on this, the sponsor is concluding that dexmedetomidine is not likely to inhibit the
`metabolism and alter the pharmacokinetics of coadministered drugs.
`
`Table l.
`
`ICso values for inhibition potential of dexmedetomidine against
`cytochrome P450 isoforms.
`
`the different
`
`“C toc'hrofiué':iiiaP4503i36f6riii
`
`Dextrometho uhan O-demeth lase
`
`Ethoxyresorufin O-deethylase
`Ethoxyresomfin O-deethylase
`Couman'n 7-hydroxylase
`S-mephenytoin 4-hydroxylase
`Chlorzoxazone 7-hydroxylase
`Testosterone 6B-hydroxylase
`
`NDA21-038, v4“
`
`5
`
`

`

`Figurc 1. Proposed dexmedetomidine metabolic pathway.
`
`
`
`_
`
`'2 as
`
`$5
`
`..,c/
`
`‘
`Carboxy N-Mcuayl
`
`Drum
`
`..,
`
`°§ cu.
`
`5553......
`
`NzMelhyl O-Glucumm'de
`
`Calm-n!
`
`
`
`mum
`
`m,
`
`cu,
`
`.
`
`cam-son
`04, as
`
`_
`
`H
`
`a
`
`man-
`
`
`
`Cal-boxy Dex O-Glumnlde
`
`NDA21-038, \2 '
`
`6 '
`
`
`
`

`

`ii.
`
`Mass Balance
`
`In this study, five (5) healthy male subjects each received a single intravenous
`infiision of 2 ug/kg [3H]Dexmedetomidine (99% radiochemical purity) over a period of 10
`minutes (study DEX-96-018). The majority of radioactivity was excreted into the urine. Afier
`nine days, an average of 95% was recovered in the urine with only 4% in the feces. Most of the
`radioactivity was rapidly excreted since about 85% of the radioactivity recovered in the urine was
`excreted within 24 hours afier the infusion. No unchanged dexmedetomidine was found in the
`urine or feces.
`'
`'
`
`The majority of the plasma total AUCo.24 radioactivity was comprised by
`dexmedetomidine
`(14.7%), G-DEX—l
`and G-DEX-Z (42%), N-methyl
`'O-glucuronide
`dexmedetomidine (21%), and H—3, an uncharacterized metabolite (10.5%). Glucuronide of 3-
`hydroxy dexmedetomidine, 3-carboxylic acid dexmedetomidine, N—methyl dexmedetomidine, and
`H-2 (uncharacterized) occurred in small quantities ranging from 0.3% to 3.0%. About 6%
`remained unknown.
`'
`
`the fractionated cumulative urinary excretion profile of
`shows
`Table 2
`[BI-flDexmedetomidine. N-glucuronide metabolites of dexmedetomidine, G-DEX-l and G—DEX-
`2, accounted for about 34% of its cumulative urinary excretion.
`‘In addition, aliphatic
`hydroxylation of dexmedetomidine (3-hydroxy dexmedetomidine, glucuronide of 3-hydroxy
`dexmedetomidine, and 3-carboxy1ic acid dexmedetomidine) together represented about 14% of
`the dose in urine. The N-methyl metabolite itself was a minor plasma circulating component and
`was undetected in urine. However, N-methylation pathway of dexmedetomidine (3-hydroxy N-
`methyl dexmedetomidine, 3-carboxy N-methyl dexmedetomidine, and N-methyl O-glucuronide
`dexmedetomidine) accounted for about 18% of the [3H]dexmedetomidine dose in urine.
`Approximately, 28% of the urinary metabolites have notubeen identified.
`‘
`
`Table 2. Summary of the Distribution of metabolites in 0-72 hour human urine following a ten
`minute infusion of 2 jig/kg [3H]Dexmedetomidine in five healthy male volunteers.
`
`% Dose Excreted
`
`Dexmedetomidine-.s.
`G-Dexl (N-Glucuronide of dexmedetomidine)
`G-Dex2 (N-Glucurojtide of dexmedetomidine)
`01-1 (3-Hydro3cy dexmedetomidine)
`G-OH (Glucuronide of 3-hydroxy dexmedetomidine)
`COOH (3-carboxylic acid dexmedetomidine)
`H-1 (N-Methyl O-glucuronide dexmedetomidine)
`H—4 (N-Methylated carboxylic acid dexmedetomidine)
`Others
`
`(0.0)
`0.0
`19.6 (3.1)
`14.4 (2.5)
`1.1
`(0.3)
`7.7
`(0.6)
`4.8
`(1.0)
`14.5
`(1.5)
`3.8
`(0.7)
`28.0
`(4.8)
`
`NDA21-038,. />\
`7 :
`
`
`

`

`iii.
`
`Metabolic Inversion
`
`‘
`
`:tiomer
`fiflflhfif'
`
`
`
`v.
`
`PROTEIN BINDING
`
`Dexmedetomidine plasma protein binding was assessed in the concentration range
`of ”V L. (therapeutic concentrations are around 1 ng/mL). The average protein
`binding was 94% and showed concentration independence. The specific plasma protein to which
`the drug bounds is unknown.
`
`it slightly
`impairment but
`The protein binding did not change in‘ severe renal
`decreasedIn hepatic impairment (88% and 82% in mild and severe hepatic impairment groups
`compared to 90%In normal group). Binding displacement of dexmedetomidine by therapeutic
`concentrations of fentanyl, ketorolac, theophylline, digoxin, and lidocaine explored in vitro did
`not show any changes in the protein binding of dexmedetomidine. Similarly, dexmedetomidine did
`not show any changesIn the in vitro protein binding of therapeutic concentrations of phenytoin,
`warfarin, ibuprofen,propranolol, theophylline, and digoxin.
`
`VI.
`
`PHARMACOKINETICS AND DOSE-PROPORTIONALITY
`originally, dexmedetomidine was pursued as an anesthetic adjunct. Therefore,
`majority of the studies evaluated the pharmacokinetics of dexmedetomidine after short
`term
`infusions. DEX-97-028 is the only study that evaluated the pharmacokinetics of dexmedetomidine
`simulating the continuous infusion regimen that will be used for sedation in ICU setting. Table 3
`provides a summary of clearance values from some of these studies and fi’om study DEX-97-028.
`This list contains a variety of infusion regimens including 10~minute infiJsions, two-stage regimens
`(loading dose + maintenance dose),
`three-stage regimens (two loading doses + maintenance
`dose), and virtually continuously changing infusion rate regimens. A computer controlled infusion
`pump (CCIP) was used to achieve these varying dosing regimens. Overall, mean estimates of
`
`NDA21-03'8,;1—-—-'=—’ -
`
`s :
`
`
`
`

`

`. clearance across these difl'erent studies ranged from 35 to 43 liter/hour with a central estimate of
`about 39 liter/hour, irrespective of the nature of the infiision regimen.
`
`Table 3. Dexmedetomidine pharmacokinetic parameters obtained in several different studies.
`
`Renal‘ .
`a.
`DCX‘95-008
`Impairment
`‘
`DEX-95-009 Hepatic‘
`Impairment
`DEX-91028 -Eatients
`
`10-minute
`
`10-minute
`
`Loading + Maintenance
`infusion up to 24 hours
`
`F-DEX-CL-
`05 92-FIN
`
`CABG Patients
`
`Loading + maintenance
`
`
`
`DEX-96-013 Age & Gender'
`
`10-minute
`
`DEX-95-OO7
`
`Safety‘
`
`CCIP#
`
`DEX-95~Oll
`
`Interaction with CCIP#
`Alfentanil
`
`DEX-96-Ol9
`
`Interaction with CCIP#
`Pro -ofol
`
`.
`
`.
`
`.
`
`.
`
`-
`
`‘ Pharmacokinetic parameters from healthy subjects.
`# Computer controlled infusion pump
`
`Study Dex-97-028 evaluated the pharrnacokinetics of dexmedetomidine in the dose
`range of 0 17 to 0 7 ug/kg/hour afier continuous infusion for 24 hours supporting the dosage
`regimen for theICU sedation indication being sought. This trial was designed as a two-part,
`Phase 1, placebo-controlled, double-blinded dose-ranging trial in 72 subjects. In pan 1, five dose
`levels targeting 0 1, 0.3, 0.45, 0.6, 1.25 nymL pseudo-steady-state plasma concentrations were
`evaluated after 1.-hour infusions.
`In part 2, dose levels to achieve 0.3, 0.6, and 1.25 ng/mL target
`plasma concentrations were evaluated after 24 hour infusions. Table 4 shows the corresponding
`infusion rates for the targeted plasma concentrations used in this study (note: during the initial
`development process, the doses were given in terms of target plasma concentrations).
`
`NDA 21-038, fi- -
`
`9 ?
`
`
`
`

`

`Table 4.' Maintenance infusion rates and corresponding expected steady state plasma
`dexmedetomidine concentrations.
`
`:azrraretaistea
`
`-
`
`'-
`
` ,
`
`_ Figures 2 and 3 present the mean dexmedetomidihe concentrations vs. time profile
`and mean AUC vs. mean dose profile following 1 hour and 24 hour dexmedetomidine infusions,
`respectively. The mean dexmedetornidine pharmacokinetic parameters after the 24 hour infiisions
`are presented in table 5.
`In general, the pharmacokinetic parameter values were similar to those
`values obtained in previous studies. There were no statistically significant difi‘erences in clearance
`or half-lives across the different regimens evaluated in this study.
`It could be seen fi'om figure 3
`and table 5 that
`there is approximate dose-proportionality in dexmedetomidine therapeutic
`concentrations when continuously infused for up to 24 hours. The mean AUC versus mean dose
`plot showed linearity. The average pseudo-steady-state concentrations approximately doubled
`and the clearance was similar.
`
`the mean Ramsay sedation scores vs. dexmedetomidine
`Figure 4 shows
`concentrations plot. Visual inspection of Ramsay sedation plots indicated that the midrange of
`sedation (Ramsay score of 3.5) was achievable by dexrfiedetomidine concentratibns in the range
`of 0.3 ng/mL to 0.6 ng/mL and the maximum Ramsay sedation score achieved in the current study
`appears to be in the range of about 4.5 to 5. Eight individuals achieved a Ramsay score of 6 on at
`least one assessment.
`
`Table 5. Mean i SD Phannacokinetic Parameters, Part II.
`;.)
`
`Parameter
`Loadin Infusion min [Total infusion duration hrs
`
`
`
`
`
`
`
`
`
`35 min/24 hrs
`10 min/24 hrs
`10 min/24hrs
`10 min/12 hrs
`
`
`
`Dexmedetomidine Ta et Concentration n mL
`
`
`
`
`
`
`
`
`0.87 i 0.25
`1.05 :l: 0.17
`2T40 :e 0.59
`1.78 :l: 0.30
`2.22 i 0.59
`
`
`2.50 a: 0.61
`
`
`
`
`
`
`99.6 i 17.8
`88.7 i 22.9
`102.4 :E 20.3
`
`
`
`
`
`1.37 :l: 0.20
`Av_ Css#, n mL
`0.27 d: 0.05
`0.27 :l: 0.05
`
`“
`Presented as harmonic mean and pseudo standard deviation.
`#
`Avg Css = Average steady-state concentration of dexmedetomidine. (2.5 - 9 h samples for
`12 hour infusion and 2.5 - 18 h samples for 24 hour infusions).
`
`46.3 :1: 8.3
`
`43.1 i 6.5
`
`36.5 :h 7.5
`
`NDA21-038, m 105.
`
`
`
`

`

`Figure 2. Mean dexmedetomidine plasma concentration vs. tithe profiles afier the infixsion of
`dexmedetomidine for 1 hour and 24 hours.
`
`IO
`
`. ..... Inmsion‘Dmation/Target Conc.
`
`
`24h I 1.25
`
`
`DennedcmidincConcentration(ng/nn.)
`
`h IOJ
`lb /0.3'
`lb /0.45
`lh-l 0.6
`"I / 1.25
`l2h /0.3
`24h l0.3
`24h/0.6
`
`Ml
`
`OO Vv Dl 0o A 1
`
`Tune (h)
`
`Figure 3. Dexmedetomidine mean AUC vs
`
`. mean dose profile.
`
`n\
`
`
`
`AUC_(nyh/mL)
`
`'6’8
`
`5
`
`0.0
`
`0.3
`
`0.9
`_0.6
`Dose (mg)
`
`1.2
`
`.5
`
`
`
`
`
`NDA 21-038, w
`
`

`

`
`
`Figure 4. Mean Ramsay sedation scores vs. dexmedetomidine concentrations.
`
`MeanRarmny
`
`Score
`
`' For each Ramsay score. a dexmedetomidine plasma contain-Ida's (nymL) m linearly interpolated
`fimunwmmdmdemodcmidiunhuilmm Amanllunnyscuewurhen
`calculuedfcrudiOJ Winemamfdsmmidinc. Eachbeyiscaitaedmthemm of":
`dexmedaomidineinmwudwumemmymfaMWcmidhe
`cmcemuioonnge. Mambaabowachhrhununbcmth-vuymuednmm
`Wmummmmmma hamprlsinaoflmhndvuuum
`
`VII.
`
`SPECIAL POPULATIONS
`
`i.
`
`Hepatic Failure
`
`Ihiswas a Phase I, two-center, open-label, single-period, single-dose study in
`which eighteen (T8)"nonnal healthy subjects and six (6) mild impairment, seven (7) moderate
`impairment and six (6) severe hepatic impairment subjects received an intravenous infusion of 0.6
`rig/kg of dexmedetomidine hydrochloride over ten minutes (study DEX-9S-OO9).
`
`Mean dexmedetomidine clearance values were lower in subjects with hepatic
`than in
`healthy subjects, which is
`consistent with the knowledge
`that
`impairment
`dexmedetomidine is eliminated primarily by hepatic metabolism and is highly bound to plasma
`proteins (table 6). As a result of reduced serum albumin, the (fiction of dexmedetomidine that
`was bound to plasma proteins decreased statistically significantly in subjects with hepatic
`impairment compared to healthy subjects. The mean clearance values for subjects with mild,
`moderate, and severe-hepatic impairment were only 74%, 64% and 53%, respectively, of those
`observed in the normal healthy subjects. Compared‘to the subjects with normal hepatic fiinction
`
`NDA21-038,""\1\—~
`
`12 5.
`
`
`
`

`

`(mean tn of 2.5 hours), the mean terminal half-life for the subjects with mild, moderate or severe
`hepatic impairment were prolonged to 3.9 hours, 5.4 and 7.4 hours, respectively. Therefore, the
`dose of dexmedetomidine may need to be reduced in subjects with hepatic impairment depending
`on the degree of impairment.
`
`Table 6. The main mean :t standard deviation of dexmedetomidine pharmacokinetic parameters
`obtained in normal healthy subjects and subjects with various degrees of hepatic
`impairment.
`
`
`
`87.9 i 0.9
`
`3.3 i 1.6
`
`
`
`.
`.
`
`
`
`-... ~-
`-.
`--
`1239 i 489
`776 i 172
`"‘ Harmonic mean and pseudo-standard deviation
`
`247.9 1 85.5
`
`0.44 :t 0.17
`
`
` §6.5 :20
`~821:3.8
`T46¢22
`
`
`7.2 i 1.8 p
`
`0.34 :t 0.18
`0.25 :i: 0.03
`
`
`
`
`
`
`1.49 :t 0.44
`1.31 i 0.49
`
`
`
`741 :t 338
`1167 i 217
`
`
`
`211.7 i 140.6
`
`132.9 1: 34.6
`
`2.36 i 0.49
`
`ii.
`
`.
`
`' Renal Failure
`
`two-center, open-label, single-period, single dose study in
`This was a Phase 1,
`which six (6) normal healthy subjects and six (6) subjects with severe renal impairment received
`an intravenous infusion of 0.6 pig/kg of dexmedetomidine-BC] over ten minutes using a computer
`controlled infusion pump (study DEX-95-008).
`
`dexmedetomidine
`in
`difl‘erences
`significant
`statistically
`no
`There were
`pharmacokinetics between normal healthy subjects and subjects with severe renal
`impairment
`(Table
`7)
`consistent with the knowledge
`that dexmedetomidine undergoes
`complete
`biotransformation and is not excreted unchanged in the urine.
`In addition, no significant
`associations were observed between dexmedetomidine clearance and creatinine clearance values.
`Accordingly, for a given administration regimen the pharmacokinetic profile of dexmedetomidine
`is expected to beindcpendent of the patient's renal function. No data was provided addressing the
`accumulation of metabolites. It should be noted that since the metabolites of dexmedetomidine are
`excreted in the urine,.they may accumulate in renal impairment subjects (dexmedetomidine for
`lCU sedation is irtfiised continuously for several hours). The direct N-glucuronide metabolites,
`G-DEX-l and G-DEX-Z (accounting for 35% of urinary excretion) were found to be inactive in
`vivo in animal studies. However, the activity of other metabolites excreted in the urine and their
`potential accumulation when dexmedetomidine is infused continuously for several hours in renal
`impairment subjects is unknown.
`
`NDA21-038, ‘W 13 C
`
`
`
`

`

`. Table 7. The main mean :t standard deviation of dexmedetornidine pharmacokinetic parameters
`obtained in normal healthy subjects and subjects with severe renal impairment.
`
`
`
`ii
`
`0.900; 043
`2.22 :1: 0.39
`
`04'10 i 0.11
`
`1.3l:t0.26
`‘ “ Harmonic mean and pseudo-standard deviation.
`
`0.833 10.25
`2.02 :1: 0.25
`
`0.560 :k 0.25
`
`1.40:0.52
`
`iii.
`
`Gender & Elderly
`This was a Phase 1, single-center, open label parallel group study (DEX-96-013)
`stratified by three age groups with sufficient male and female subjectsin each age group to permit
`gender analysis, 18 to 40 years (9 male, 11 female), 41 to 65 years (14 male, 6 female), and older
`than 65 years of age (12 male, 8 female). Each subject received a single 10 minute intravenous
`infiision of 0.6 ug/kg dexmedetomidine-HCI.
`
`Dexmedetomidine phannacokinetics were not different between young, middle-age
`and elderly adult subjects (table 8). Therefore, the same dexmedetomidine infusion is expected to
`produce, the same dexmedetomidine concentrationprofile and the elimination characteristics are
`expected to be the same irrespective of age.
`
`Dexmedetomidine pharmacokinetics were not different between male and female
`subjects, when differences
`in body weight were accounted for. Therefore,
`the same
`dexmedetomidine infusion is expected to produce the same dexmedetomidine concentration
`profile and the elimination characteristics are expected to be the same‘for men and women.
`‘
`
`Table 8. The main mean i standard deviation of dexmedetomidine pharmacokinetic parameters
`obtained in subjects with different age groups.
`
`y
`
`1.48 i 0.28
`2.11 i 0.48
`38.1 $8.7
`1.191024
`"‘ Harmonic mean and pseudo-standard deviation
`
`”1.62 i 0.28
`2.18 :t 0.34
`412* 10.1
`1.13 21:0.17
`
`l
`
`1.5 i 0.29
`2.28 i 0.35
`38.7i9J
`1.29:0.23
`
`NDA 21-038, A'
`
`'
`
`14‘-
`
`
`
`

`

`
`
`iv.
`
`Pediatrics
`
`The pharmacokinetics of dexmedetomidine have not been characterized in
`children. The sponsor is proposing the following statements in the package insert regarding this
`issue:
`
`“The phannacokinetic profile N's-\— ( has not been studied in children”.
`
`
`in children below 18 years of age have not been established".
`“Safety and'eflicacy of _
`Per this reviewer’s request on the sponsor's pediatric pharmacokinetic study plans, the sponsor
`through a fax dated 9/16/99 informed that pediatric pharmacokinetic data will be obtained from
`the ongoing study W98-266. Final reports of this study may beavailable in mid-2000.
`
`v.
`
`Matemal/Fetal Ratio
`
`‘
`
`No adequate and well-controlled studies have been conducted in pregnant women
`or in labor and delivery.
`Therefore, no pharmacokinetic information is available in these
`populations. The sponsor is proposing the following statements in the package insert regarding
`these patient populations:
`
`“There are no adequate and well-controlled studies in pregnant women. '~ should be
`used during pregnancy only if the potential benefits justify the potential risk to the fetus.”
`
`
`
`in labor and delivery has not been studied and is, therefore, not
`“The safety _
`recommended for obstetrics, including cesarean section deliveries.”
`
`vi.
`
`Drug-Drug Interactions
`The ICso values for inhibition potential of dexmedetomidine against the different
`cytochrome P450 isoforrns are relatively high compared to the expected therapeutic plasma
`concentrations of dexmedetomidine-(see section IV.i, page-Er ofthis review). Based on this, the
`sponsor is concluding that dexmedetomidine is not likely to inhibit the metabolism and alter the
`pharrnacokinetics of coadministered drugs.
`In addition, pharmacokinetic data was obtained from
`several
`studies"'*‘co‘t‘rducted
`to examine the clinical
`effects when dexmedetomidine was
`coadrninistered with isoflurane (CYPZEI substrate), rocuronium, alfentanil (CYP 3A4 substrate),
`propofol, and midazglam (CYP3A4 substrate). However, it is possible that inducers/inhibitors of
`CYP2A6,
`the major isoforrn involved in the metabolism of dexmedetomidine, may affect
`dexmedetomidine metabolism. No formal drug-drug interactions were conducted examining the
`affect of CYP2A6 inducers or inhibitors on dexmedetomidine metabolism.
`
`3)
`
`Isoflurane
`
`This was a phase 1, single center, randomized, single blind, three-way crossover,
`controlled study to determine the effects of dexmedetomidine on isoflurane requirements in ten
`(10) healthy volunteers (study Dex-95-001). Subjects received infusions of placebo or pseudo-
`steady--state dexmedetomidine target concentrations of 0.3 ng/mL or 0.6 ng/mL for two hours
`prior to receiving isoflurane anesthesia.
`
`NDA21-038, M 15"
`
`
`

`

`the main
`any of
`in
`There were no statistically significant differences
`pharmacokinetic parameters of dexmedetomidine between the two target concentrations of 0.3
`ng/mL and 0.6 ng/mL (table 9) indicating that isoflurane did not affect the pharmacokinetics of
`dexmedetomidine.
`'
`
`Table 9. The main mean i standard deviation of dexmedetomidine pharmacokinetic parameters
`obtained after isoflurane administration.
`
`“
`
`0.352 t 0.46
`
`0.729 1 0.106
`
`
`
`
`
`
`0.52 i 0.06
`
`
`' 0.495 t 0.09
`
`
`.............
`1.47 :l: 0.46
`1.33 i 0.19
`
`
`
`
`
`" Harmomc mean and pseudo-standard deviation.
`# average of concentrations measured between 2 hours and end of infiision.
`
`1.86 i 0.39
`
`1.94 :1: 0.14
`
`_
`”
`"“
`b) Midazolam
`three-
`This was a single-centre, double-blind, randomized, placebo controlled,
`cross-over
`study
`in
`nineteen
`(19)
`healthy
`volunteers
`(study DEX-95-005).
`period,
`Dexmedetomidine or placebo was administered as a loading infusion given for 10 minutes
`followed by a maintenance infusion cf up to 12 hours, targeting dexmedetornidine steady-state
`plasma levels of 0.0 ng/mL, 0.2 ng/mL or 0.4 ng/mL. Midazolam was administered stepwise
`using a CCIP 2 hours after the start of