`

`HFD-17O
`
`.
`
`)n #21'—038
`
`KL":
`N21033
`||||l|l||||| llilllllllllllli
`IllliilIllllllllilillilllllllllllllli
`
`DRUG NAME: Precedex (dexmedetomidine IICI injection)
`-
`fit-f7
`,
`APPLICANT: ABBOTT LABORATORIES
`R ~l%/€;.<'
`
`CHEMICAL & THERAPEUTIC CLASSHS
`
`
`
`Review C cles
`
`Review Cycle: I _
`Submission patezlz-l8-98
`Receipt Date:12-18-98
`Goal Datezl2-18-99
`Action:AP
`
`Review Cycleuz‘Z
`Submission Date:
`Receipt Date:
`Goal Date:
`Action:
`
`
`
`;
`
`_
`
`Review Cycle: 3
`Submission Date:
`Receipt Date:
`Goal Date:
`Action:
`
`Review Cycle: 4
`Submission Date:
`Receipt Date:
`Goal Date:
`Action;
`
`
` PROJECT MANAGER! CSO :Susmita Samanta
`
` Phone # & Office Room #:301-827-7410, 98—45
` MEDICALzPatricia Hartwell, M.D., M.B.A.
` CHEMISTRY:Michael Theodorakis, Ph.D.
`
`PHARM/TOX:Harry Geyer. Ph.D.
`
`
`BlOPHARMACEUTlCS:Suresh Doddapaneni, Ph.D.
`
`
`ABUSE LIABILITY: BeLinda A. Hayes. Ph.D.
`
`MlCROBlOLOGlST: Patricia Hughes, Ph.D.
`
`BlOMETRlCS: Z.Jonathan Ma, Ph.D.
`
`I -_. -
`
`Volume 4 Of 4
`
`Administrative volume #(s): 1
`Clinical volume #(s): 2
`CMC volume #(s): 3
`
`Phannacology/Toxicology volume #(s): 4
`
`.
`
`--
`
`

`

`ODE II ACTION PACKAGE TABLE or CONTENTS
`
`‘ Application 521-038
`
`-'
`
`Drug Name: Precedex (dexmedetomidine Hydrochloride injection). 2 mL ampule/2 mL vial, 100
`' mcg/mL
`
`Applicant: Abbott Laboratories
`
`_.
`
`Chem/Then Type: IS
`
`CSO/PM: Susmita Samanta
`
`Phone: 301-827-7410
`
`HFD-l70
`
`‘
`
`Original Application Date: December 18, 1998 Original Receipt Date: December 18, 1998
`
`
`CURRENT USER FEE GOAL DATE: December 18, 1999DateTableofContentsCompleted:9/13/99
`V
`H
`X (completed),
`Adminislmixelnmnnaflnn
`N/A <notapplicable>-
`or Comment
`
`- mm
`
`'
`
`Tab A-l
`
`Action Letter(s)
`
`Current Action:AP
`
`'- Tab A-2
`
`Phase 4 Commitments:
`
`Tab A-3
`
`.‘
`
`__
`
`_
`
`Tab A-4
`
`Tab A-5
`
`Tab A-6
`Tab A-7
`Tab A-8
`
`Tab A-9
`
`Tab A-lO
`
`Tab A-l 1
`
`a. Copy of applicants communication committing to Phase 4 .............
`
`b. Agency Correspondence requesting Phase 4 Commitments ................
`
`FDA revised Labels & Labeling and Reviews:
`
`a. Package Insert .......................................................................
`
`b. Immediate Container and Carton Labels .; .....................................
`
`Original Proposed Labeling ...............................................................
`
`Foreign Labeling:
`
`a. Foreign Marketing History........................................................
`
`b. Foreign Labeling and Review(s) ...........2-. ...................................
`
`1
`
`Labeling and Nomenclature Committee’s Tradename Review .....................
`Summary Memoranda (e.g., Division Director, Group Leader, Office) .........
`Copy of Patent Statement ..................................................................
`
`Exclusivity Checklist (and any requests for exclusivity) .............................
`
`Debannent Statements ......................................................................
`
`Correspondences, Faxes, & Telecons ...................................................
`
`Minutes 6f Meetings:
`
`(Separate each version/cycle with a colored sheet)
`
`a. End-of-Phase ll meeting ..................._. .......................................
`
`b. Pre-NDA meeting(s) .......................... ....................................
`
`_
`
`c. Filing meeting .......................................................................
`
`d. Other meetings ......................................................................
`
`Advisory Committee Meeting:
`
`a. Questions Considered by the committee .......................................
`
`b. List" of Attendees .............................'.......................................
`
`. c. 24 hour alert memorandum .............. '.........................................
`
`Project Management Administrative Information (optional).........................
`
`.
`
`Tab A-IZ
`
`

`

`ODE H ACTION PACKAGE TABLE OF CONTENTS (continued)
`
`Application #21-038 Drug Name: Dexmedetomidine HCL
`
`Mani:
`
`.
`ClinmaLInmrmatinn
`
`X (completed).
`NA (not applicable).
`or Comment
`
`Tab 8-]
`
`Clinical Reviews and Memoranda .......................................................
`
`Safety Update Reviews .....................................................................
`Pediatric Page ..................................................1.3.1:.......................
`
`Summary of Safety (from the summary volume of the application) .....................
`
`Tab B-2
`Tab B-3
`
`Tab B-4
`
`Tab-B-S
`Tab B-6
`
`Tab B-7
`Tab B-8
`-. Tab B-9
`
`Statistical (Clinical) Review and Memoranda ..........................................
`
`' Biopharrnaceutics Review and Memoranda ............................................
`Abuse Liability Review ............................i:......................................
`
`DSI Audits ....................................................................J.:4..............
`Summary of Efficacy (from the summary volume of the'application) ..................
`
`Section Q;
`
`.
`
`1
`
`.
`
`g ,
`Inmrmatmn
`
`I
`
`‘
`
`1
`
`X (completed).
`N/A (not applicable),
`o, Commem
`
`Tab C-l
`
`CMC Reviews and Memoranda ......................... ...............................
`
`Tab C-2
`
`DMF Reviews ..............................................................................
`
`Tab C-3
`Tab C-4
`Tab 05
`
`'
`EA Reviews/FONS] .......................................................................
`Micro Review (validation of sterilization) .......~......................................
`Statistical Review ofdrug stability
`”
`....................
`
`Tab C-6
`
`Inspection of facilities => Decision:
`
`-
`
`Date:
`
`Tab C-7
`
`Methods Validation Information ........................................................
`
`
`
`NA
`
`
`_
`‘-
`
`
`
`X
`
`
`
`X (completed),
`Section 2; WWW N/A (not applicable),
`-.
`or Comment‘.
`
`Tab D-I
`
`Phannacology/‘I‘oxicology Reviews and Memoranda ...............................
`
`Tab D-2
`
`Carcinogenicity Review (statistical) ...........t.'........................................
`
`—
`
`Tab D-3
`
`CAC/Executive Committee Report .....................................................
`
`
`ADDITIONAL NOTES:
`
`
`
`

`

`
`
`“our,
`‘- .
`
`.v-
`
`in FDA CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DIVISION OF ANL‘STIIFJIC. CRITICAL CARE, AM) ADDICTION PM}? Pnomrcrs
`HFn-I‘m. Room 913-45. 5600 Fishers Lane.1{uckville MD 20857
`. Tcl:(30l)443-374l
`
`
`
`
`
`MEMORANDUM
`
`
`DATE:
`
`:
`
`November 30. 1999
`
`TO:
`
`FROM:
`RE:
`
`Dr. Cynthia McCormick
`
`\g‘
`A
`Dr. Lucy Jean _
`Team Leader’s SummaryuofNDA 21-038
`
`
`
`I_r1t_roduction: Dexmedetomidine I-ICl (DEX) is a potent (7x clonidine), and selective
`alphag-agonist ‘-—-—-——. The drug is to be marketed as a parenteral solution
`(Trade name) for intravenous infusion. The indication is for supplemental sedation and/or
`analgesia in ICU for up to 24 hours. The recommended doses are a loading dose of
`lug/kg over 10 minutes, followed by a maintenance infusion of 0.2 to 0.7 ug/kg/hr to the
`desired level of sedation and/or analgesia.
`
`Efficacv: In the CNS via (:2 -agonist activity, DEX produces sedation, analgesia and
`reduced anxiety. The sedative/hypnotic (10-30 ug/kg iv), analgesic (3-6 ug/kg iv) and
`anxiolytic (0.3-2 ug/kg iv) effects were shown in mice and rats; and in dogs the
`sedative/hypnotic effects as well. No anticonvulsant activity was shown. In rats (3 ug/kg
`i.v.) DEX reducedischemic brain damage.
`
`Safetv pharmacology: The a; - agonist inhibits the release of norepinephrine at neurons.
`Thus DEX, via its (12 -agonist activity in the CNS, inhibits sympathetic activityresulting
`in decreases of blood pressure and heart rate. The CV effects of dec BP & HR were
`observed in rats, dogs and monkeys. In dogs (1 pig/kg iv), decreases of the heart rate,
`myocardial contractility, CO, and oxygen demand by the heart (increased AV 02
`saturation) were observed. Similar to some of the imidazole-derivates of intravenous
`anesthetics, suppression of the HPA was observed only following prolonged infusion. Ir.
`dogs prolonged sc infusion (IO ug/kg/hr for 7 days) of DEX decreased the ACTH-
`stimulated cortisol level by 40%, but no effect was observed following single sc dose of
`
`

`

`2
`
`80 pig/kg. Glucosuria and transient hyperglycemia in rats, gerbils or rabbits are
`considered drug-class effects, since clonidine also shows similar changes. The effects
`may be species specific, as the available clinical data did not show these adverse effects.
`
`Special Toxicology Studies: No hemolytic potential—was shown in an in vitro study.
`Levomedetomidine, the principal impurity in clinical drug product, was shown to have
`low order of toxicity in both rats and dogs following 4-wk of daily iv administration; the
`NOAELS were at 625 and 400 pig/kg, respectively. Presence of this impurity at 1% in the
`.drug product should not pose safety concern.
`
`ADME/Pharmacokinetics: Pharmacokinetics and excretion are similar in humans and
`animal species; but metabolism is significantly species specific. Absorption was rapid in
`rats and dogs following im or sc administration with Tmax less than an hour. Following
`iv, Tl/2 was approximately 2.5 hrs (humans), 1.5 hrs (rat & dog). The extent of plasma
`protein binding was high in human, rat and dog (94%, 88% and 93%, respectively). No
`_ significant displacement of other protein-bound drugs was observed. In rats, tissue
`distribution was rapid and the highest levels were in the adrenal, liver and kidneys. By 72
`hrs the tissue levels were low. DEX was extensively metabolized in both humans, rats
`and dogs. All species shared a common pathway of N-methylation at 3-methyl position.
`followed by hydroxylation (forming 3-hydroxy N-methyl), then oxidation (forming
`carboxy-N-methyl) or glucuronidation (N-methyl o-glucuronide). But significant species
`specific metabolism was present. In humans, direct N-glucuronidation of the imidazole-
`N was the major metabolic pathway. The two major metabolites formed, (the N-
`glucuronides of imidazole nitrogen and N-methyl-Oglucuronide) were not detected in
`rats or dogs.
`In animal species besides glucuonides, sulfate, mercapturate and glutathione
`conjugates of the 3-methyl hydroxyl were also detected.
`
`Toxicolog': Acute and 4-wk repeated-dose toxicity studies were carried out in rats and
`dogs following various routes of administration. The acute toxicity of rapid intravenous
`bolus injections was low in animals, as 1000 ug/kg was not lethal to mice, rats or dogs.
`The clinical signs at high doses included sedation, piloerection, exophthalmos, salivation,
`tachypnea and clonic convulsion. Four-week repeated-dose toxicity studies in rats and
`dogs were carried out following daily iv and im bolus administration. Significant drug-
`related target organ toxicities or adverse effects were as follows: (1) Liver: apparent only
`in dogs with elevated liver enzymes (ALT, GGT), eosinophilic intracytoplasmic
`inclusions, hepatic apoptotic bodies at 50-250 ug/kg/d. In rats and dogs, dose-related
`increased liver absolute and relative weights; but no enzyme elevation or
`—
`histopathological findings in rats; (2) Lungs (in rats only): dose-related increases in
`hemosiderin-laden macrophages, possible reflecting some pulmonary inflammation; (3)
`Adrenals (in rats only): hypertrophy of zona glomerulosa, reflecting increased
`mineralocorticoid secretion; (4) Eyes (in dogs and rats): corneal cloudiness or opacities
`(keratitis) caused by loss of blinking reflex and dryness (from a; —agonist related
`sedation/analgesia/decreased lacrimination);
`(5) Reduced organ weights: in high—dose
`rats only: testes, seminal vesicles. prostate, epididymis, uterus; and in rats and dogs
`
`
`
`

`

`thymus: dose related weight decreases with no histopathology; (6) Injection site
`irritations (in dogs and ’rats):
`intravascular and perivascular fibrosis (iv), hemorrhages
`(all routes), and granulation (irn, sc). The NOAELs in rats (20 ug/kg/day im and so and
`10 ug/kg/day iv) and in dogs (10 ug/kg/day im and iv) are less than the MRI-[ID on a
`mg/m2 basis. The LOAELs in rats (100 ug/kg im andsc‘and 40 ug/kg iv) and in dogs (50
`,ug/kgz'1m and iv) are approximatelyl4X (rat/iv) and 56X (dog/iv) the MRHID on a
`rr__1g/m2 basis.
`
`. Reproductive Effects: DEXIs not teratogenic inrats (200 mcg/kg/d sc rats—— 2X
`MRI-11D on a mg/m2 basis) and rabbits (96 mcg/kg/d1v= MRHID) Fetal toxicity, as
`evidenced by increased postimplantation losses and reducedthe number of live pups per
`litter, was observedin rats (200 mcg/kg/d sc rats= 2X MRHlD). The NOAEL was 20
`mcg/kg/d (less than MRI-11D). Prenatal and postnatal effects included reduced pup body
`weights during and after nursing (8-32 mcg/kg/d ) and delayed motor development (32
`mcg/kg/d); the NOAEL was 2 mcg/kg/day (less than MRI-11D). Placental transfer
`occurred in rats.
`
`Genotoxic Effects: DEX was not mutagenic in Ames mutation assay with S.
`typhimurium or E. coli and in mouse lymphoma assay. DEX was shown to be
`clastogenic in both the in vitro human lymphocytes chromosomal aberration assay in the
`presence of metabolic activation and in vivo mouse micronucleus assay.
`
`CONCLUSIONS and RECOMMENDATIONS: Taking the data together and
`
`considering the different duration (4-wk vs 24-hr) and mode of administration (bolus vs
`infusion) in animal testings vs human use, it can be‘concluded that the pharmacological
`and toxicological profiles generated in the laboratory animals support theefficacy and
`reasonable safety that DEX can be labeled for human use. It should be noted that
`human metabolizes the compound differently from the animal species, the available
`clinical data also support the labeled usage of DEX. The pertinent nonclinical sections
`of the package insert have been amended.
`'
`
`Nonclinical issues:
`
`(A) The pertinent nonclinical sections of the sponsor’s proposed package insert have
`been amended by the reviewer.
`-
`
`(B) Phase IV studies:
`
`(1) To mimic the human clinical infusion use, the sponsor has agreed to conduct two
`infusion studies in dogs. The first two-week study with a 2-week recovery phase is to
`evaluate the general toxicology and effect on HPA axis. The second study is to
`determine changes in drug metabolism following two weeks of infusion. The protocols
`
`

`

`
`
`were reviewed.
`
`(2) If, in the future the product willbe used for prolonged infusion1n ICU, the
`potential toxicity of human major metabolites which are absent1n rats and dogs should be
`addressed.
`:
`_ .3
`
`Because of species specific in metabolism, two human major metabolites (the N-
`glucuronides of imidazole nitrogen and N-methyl-O-glucuronide), absent in the rat and
`_ dog, were never studied in animals. If the drug product will be used in ICU for longer
`than 24 hrs of infusion, the potential toxicity of these human metabolites should be
`addressed1n Phase IV animal studies following long-term infusion. The studies can be
`conducted following either a successful search for a human-relevant animal species in
`terms of métabolism, or alternatively the toxicity of the human metabolites can be studied
`in animal species following direct administration of these metabolitesin an appropriate
`animal species.
`
`on 01119111111.
`
`
`
`

`

`REVIEW AND EVALUATION
`OF PHARMACOLOGY/TOXICOLOGY DATA
`
`NDA 21-038
`
`2
`
`INTRODUCTION
`
`PIIARMACOLOGY .
`
`‘
`
`.
`
`-. PHARMACOKINETICS/TOXICOKINETICS/ADME " '
`
`'
`
`TOXICOLOGY
`
`REPRODUCTIVE TOXICOLOGY
`
`GENETIC TOXICOLOGY
`
`SPECIAL TOXICOLOGY STUDIES
`
`1
`
`ANCILLARY STUDIES FROM THE LITERATURE .
`
`OVERALL SUMMARY AND EVALUATION
`
`CONCLUSIONS -'
`
`.
`
`RECOMMENDATIONS
`
`2
`
`"15'
`
`54
`
`106
`
`134
`
`149
`
`~. 163
`
`176
`
`181
`
`191
`
`_191
`
`
`
`

`

`
`
`REVIEWAND EVALUATION OF PHARMACOLOGY/1‘OXICOLOGY DATA
`
`am: Harry M. Geyer, 111 PhD.
`
`12mm: Division of Anesthetic, Critical Care ai'A'fidiction Drug Products
`HFD# 17o
`
`KW: September 20. 1999
`
`NDAnurnber: 21-038
`
`WWW: GOO/December 18, 1998/NDA original submission
`
`' _ ----__, -, 1999
`-July6, 1999
`
`NDA21-038 BZ
`
`5mm:
`
`Abbott Laboratories
`
`Abbott Park, IL, 60064
`
`W: Orion Corporation: Espoo, Finland
`
`12mg: 7
`
`Code Name: MPV-1440
`
`Generic Name: dexmedetomidine HCl
`
`.
`.
`
`Trade Name:
`
`_
`
`"'
`
`Chemical Name: (+)-4-[2,3-dimethylphenyl)ethyl]- lH-imidazole hydrochloride
`CAS Registry Number: 113775-47-6 (base)
`CAS Registry Number: 145108-58-3 (hydrochloride salt)
`Molecular Formula/ Molecular Weight: CBH. 6 N2.HC1/ m.w. 236. 7
`
`Structure:
`
`CH3
`
`ev
`
`‘
`
`-
`
`_
`
`dexmedetcmndme
`
`\H
`.
`_
`dexrnedetomrdme
`
`.
`
`
`
`CH3 -
`
`CH3
`
`.HC —
`.
`
`DEXMEDETOMIDINE
`HYDROCHLORIDE
`ABBOTT 85499.1
`
`DEELCIASS alpha2 adrenoreceptor agonist
`
`mum: sedative with analgesic properties for use. in intensive care
`
`
`
`

`

`NDA 21-038
`
`ClinicaLfomulgtign: clear isotonic solution pH 4.5 to 7.0, each milliliter contains 118 mcg of
`dexmedetomidine hydrochloride (100 mcg base) and 9 mgsodium chloride in water. The
`recommended dilution, for both loading dose and infusion, is 2 ml ofdexmedetomidine solution
`into 48 m1 of 0.9% saline. The infusion concentration is 4 meg/ml.
`
`Wrintravenous infusion. Suggested loading dose = 1.0 ug/kg over 10
`minutes and followed by 0.2 to 0.7 ug/kg/hr for as long as 24 hours.
`
`
`
`Disclaimer -- The sponsor’s material was occasionally copied unchanged to avoid transcription
`errors.
`_
`
`Introduction
`
`Dexmedetomidine, a congener of clonidine, is a potent, selective alphaz-agonist, v ,,
`
`-\
`-
`1. It15 the dextro'isomer of the racemate medetomidine and15 about 7x the
`potency Of clonidine at the «2 receptor.
`
`Dexmedetomidine has low or no affinity for dopaminergic, muscarinc or nicotinic cholinergic
`receptors, serotonin, GABA, histaminic, opioid mu or delta, benzodiazepines or sodium,
`potassium or calcium ion channels. There is also no affinity for the noradrenergic, dopaminergic
`or serotonergic reuptake receptors on the brain. The activity appears to be confined to the a,
`receptors. The a, receptors are located in the central nervous system (CNS), in autonomic
`ganglia, peripheral neurons and end-organs with sympathetic innervation. The on, activation of
`sympathetic neurons inhibits the release of norepinephrine and the on; in the CNS leads to
`inhibition of sympathetic activity, decreasing blood pressure and heart rate. The CNS mediated
`effects of sedation, ataxia and reduced anxiety have also been attributed to a, activation. Sedation
`in the ICU is the primary clinical use of this product.
`
`1.
`1. WI].
`S
`Review NDA ’
`No.
`Study
`No.
`
`.1
`
`.
`
`.
`
`u
`
`1:
`
`Study
`
`’-
`
`Review
`Page
`
`_ NDA
`Vol / page
`
`[I]
`
`[2]
`
`103. ReceptogramTM of six compounds
`
`104. Dexmcdetomidine: affinity and activity on
`aZ-adrenoceptor subtypes.
`
`15
`
`17
`
`27/ 115
`
`27/ 272
`
`

`

`
`
`
`
`NDA 21-038
`
`[3]
`
`[4]
`
`162. The effects of.dexmedetomidine N-glucuronides
`on alpha-2 adrenoceptors in vitro and in vivo.
`Study No. CN597122100010
`
`18
`
`30/ 001
`
`127. Dexmedetomidine does not inhibit the activity of rat
`brain monoamine oxidase in vitro.
`
`19
`
`28/ I97
`
`[5]:
`
`84. The metabolic effects of dexmedetomidine.
`
`[6]
`
`[7]
`
`[8]
`
`122. A general pharmacology study of dexmedetomidineW
`
`159. CNS general pharmacology profile in the mouse
`and the rat. Scientific Report Number R&D 96/500
`
`78. The anticonvulsant and anticholinergic effects of
`dexmedetomidine.‘
`
`[91 _,
`
`80. Effect of dexmedetomidine against amygdala-lcindled
`‘ seizures
`
`[10]
`
`96. Neuroprotection by dexmedetomidine in rat focal
`ischemia - a comparative study with AMPA and NMDA
`receptor antagonists.
`:
`
`[11]
`
`99. Neuroprotection by-dexmedetomidine in gerbils
`
`20
`
`22
`
`23
`
`25
`
`26
`
`27
`
`31
`
`32
`
`33
`
`26/ 220
`
`:28/ 082
`
`29/ 155
`
`26/ 166
`
`26/ 180
`
`27/ 063
`
`27/ 090
`
`24/ 159
`
`29/ 065
`
`18. Effects of dexmedetomidine on motor—coordination
`and skeletal muscle tone in mice.
`‘
`
`151. Treatment of ethanol withdrawal symptoms with
`subcutaneously administered dexmedetomidine,
`a selective alpha-Z-adrenoceptor agonist.
`
`[12]
`
`[13]
`
`[14]
`
`152. Treatment of ethanol withdrawal symptcims with
`dexmedetomidine, a selective alpha-Z-adrenoceptor agonist
`
`34
`
`29/ 095
`
`

`

`NDA 21-038
`
`[15]
`
`47. The effect of dexmedetomidine on myocardial
`blood flow, metabolism and mechanical performance during
`short coronary occlusion and reperfusion in the dog.
`In. The effect ofrdexmedetomidine on the circulation and the _
`nonnoxic and ischemic heart.
`
`35
`
`25/ 099
`
`[16]....
`
`49. Comparison of the systemic hemodynamic
`and coronary vascular effects of dexmedetomidine in three
`animal experimental models. In: The effect of dexmedetomidine
`on the circulation and the norrnoxic and ischemic heart."
`
`36
`
`25/ 125 1
`
`{17]
`
`61. Comparison of the hemodynamic and coronary vascular
`effects of dexmedetomidine and clo‘nidine in the anesthetized dog.
`In: The effect of dexmedetomidine on the circulation and the
`
`39
`
`26/ 001
`
`norrnoxic and ischernic heart.
`
`[18]
`
`i
`
`[19]
`
`65. Changes in cardiac firnction induced by dexmedetomidine,
`as determined by pressure-volume analysis.
`In; The effect of dexmedetomidine on the circulation and the
`' norrnoxic and ischemic heart.
`
`40
`
`26/ 054
`
`70. Comparison of hemodynarnic stabilizing effects of
`dexmedetomidine and esmolol.
`
`-43
`
`26/ 080
`
`[20]
`
`59. Effect of medetomidine either as the racemate mixture
`
`48
`
`25/ 204
`
`or as the individual stereo isomers on the heart rate of
`anesthetized rats.
`
`[21]
`
`[22]
`
`177. Effects of a2-adrenoceptor agonist dexmedetomidine
`on human platelet aggregation in vitro.
`
`49
`
`30/ 160
`
`#4. Effects of dexmedetomidine on uterine contractions in rat
`
`50
`
`NBA 21-038 82 7/6/99 V1/p67
`
`[23]
`
`#12. Effects of medetomidine and dexmedetomidine on
`
`50
`
`adrenocortical function in dogs. NDA 21-038 BZ 7/6/99 Vl/p239
`
`[24]
`
`186. Plasma Concentrations of Dexmedetomidine
`
`54
`
`30/ 258
`
`Following Subcutaneous Dosing in Rat. R&D/97/617
`
`[25]
`
`265. Pharmacokinetics of [3H]-dexmedetomidine
`
`IV and IMin the rat.
`
`55
`
`46/ 384
`
`

`

`NDA 21-038
`
`30/ 301
`
`[26]
`
`[27]
`
`[28]
`
`187. Plasma Concentrations of Dexmedetomidine
`
`Following a Single IV or IM Dose in Dog. R&D/97/615
`
`Abbott-85499 Drug Metabolism Report No.49
`Effects of Age on the Plasma Concentrations of
`‘ Dexmedetomidine following Subcutaneous Dosing in Rat
`V98-829 ; Repon R&D 98/653
`
`‘
`
`Abbott-85499 Drug Metabolism Report No.49
`- -
`Effectsof Age on the Plasma Concentrations of
`Dexrriedetomidine following Intravenous Dosing in Dog
`
`V98-830 Report: R&D/99/002
`
`57
`
`58
`
`59
`
`[29]
`
`237 Abbott-85499 Drug Metabolism Report No.5 -
`Plasma concentrations of Abbott-85499(dexrnedetomidine)
`
`60
`
`42/ 237
`
`[30]
`
`188. Plasma Concentrations of Dexmedetomidine
`
`Following Intravenous Dosing in Rabbit. R&D/9:7/616
`
`238. Abbott-85499 Drug Metabolism Report No.6 -
`Metabolism and excretion of[3H-dexmedetomidine
`(Abbott-85499) in rats (Protocol V95-031).
`Report No. R&D196/233
`
`:
`
`247. Abbott-85499 Drug Metabolism Report No. 7 -
`Tissue distribution of radioactivity in rats following a
`single intravenous 0.02 mg/kg dose of
`[3H]dexmedetomidine.HCl (Abbott-854991).
`Report No; R&D/96/720
`
`62
`
`63
`
`31/001
`
`42/ 270
`
`66
`
`44/ 001
`
`
`
`[31]
`
`[32]
`
`[33]
`
`[34]
`
`- 261. Abbott-85499 Drug Metabolism Report No. 11 -
`Metabolism and excretion of [’H]dexrnedetomidine following
`intravenous or subcutaneous administration to chronically
`bile duct cannulated rats (Protocol V96-014)2~
`Report No. R&D196/443.
`
`69
`
`45/ 221
`
`250. Abbott-85499 Drug Metabolism Report No.28 -
`Metabolism of [’Pfldexmedetomidine, [3H]levomedetomidine and
`[3H]medetomidine by precision-cut rat liver slices.
`Report No. R&D/971504
`
`70
`
`44/ 245
`
`
`
`

`

`
`
`
`
`NDA 21-038
`
`[35]
`
`240. Abbott-85499 Drug Metabolism Report No.19 -
`Metabolism and disposition of [3H]Abbott-85499.1
`(dexmedetomidi-neHCI) following subcutaneous and
`intravenous administration to dogs
`(Protocol V96-020). Report No. R&D/97/29.
`
`[36]....
`
`i371
`
`251. Abbott-85499 Drug Metabolism Report No.25 -
`Metabolism of [3H]dexmedetornidine, [3 H] levomedetomidine
`and [3H]medetomidine by precision-cut dog liver slices;
`Report No. R&D/97/454
`" _
`
`241. Abbott-85499 Drug Metabolism Report No.26 -
`Phase 1 study of the metabolism and excretion of
`[3H]dexmedetomidine.HCl (Abbott-85499. l)
`in normal male subjects
`(Protocol Dex-96-018). Report No. R&D/97/457
`
`73
`
`42/367
`
`75
`
`'45/ 001
`
`77
`
`43/ 001
`
`[33.] -
`
`262. Pharmacokinetics and metabolic profiling of 3I-I-labeled
`dexmedetomidine in healthy in male volunteers. Biometrical
`report. Study BA-91-04 (PER-9 10208-4)
`
`80
`
`46/ 001
`
`[39]
`
`[401
`
`[41]
`
`252. Pharmacokinetics and metabolic profiling of 3H-labeled
`dexmedetomidine in healthy male volunteers.
`~..
`Metabolite profile of 3H-dexrnedetoniidine in human urine.
`Study BA-91-04 (PER-9102084), DNO JSAS9S05 1.
`
`253. Abbott-85499 Drug Metabolism Report No.23 -
`Metabolism of [3H]dexmedetomidine, [’lfllevomedetomidine
`and [’H]medetomidine by precision-cut human liver slices.
`Report No. R&D/97/389,
`
`81
`
`45/ 039
`
`82
`
`45/ 065
`
`254. Abbott-85499 Drug Metabolism Report No.36 -
`Identification of cytochrome P450 isoforrns involved in
`the oxidative metabolism of dexmedetomidine (Abbott-85499)
`and the effect of dexmedetomidine on cytochrome P450-mediated-
`monooxygenase activities. Report No. R&D/97/757
`
`86
`
`45/ 109 .
`
`[42]
`
`258. Abbott-85499 Drug Metabolism Report
`No.13 - The in vitro interaction of dexmedetomidine with
`human liver microsomal cytochrome P450 2D6 (CYP2D6).
`
`89
`
`45/ 179
`
`6"
`
`

`

`NDA 21-038
`
`[43]
`
`242. Abbott-85499 Drug Metabolism Report No.8 -
`In vitro protein binding of [3H]Abbott-85499 (dexmedetomidine)
`in mouse, rat, dog, monkey, and human plasma
`(Protocol V96-004)Report No. R&D/96/320
`
`‘
`
`91
`
`43/ 136
`
`[44]
`
`243.. Abbott-85499 Drug Metabolism Report No.20 -
`In vitro binding of [3H]Abbott-85499 (dexmedetomidine)
`to human serum albumin and (cg-acid glycoprotein)
`(Protocol V96-0 11). Report No. R&D/97/338,
`
`244. Abbott-85499 Drug Metabolism Report No.29 -
`Protein binding interactions between Abbott-85499-
`3H (dexmedetomidine) and selected other drugs in human
`plasma (Protocol V97-034). Report No. R&D1971525
`
`245. Abbott-85499 Drug Metabolism Report No.22 -
`Metabolism Report No.30 - Effect of Abbott-85499
`(dexmedetomidine) on the protein binding of selected other
`drugs in human plasma (Protocol V97-027).
`Report No. R&D/971526
`
`246. Abbott-85499 Drug Metabolism Report No.22 -
`In vitro determination of human red cell bindingof
`Abbott-85499-3H (dexmedetomidineXProtocol V97-026).
`Report No. R&D/97/37l
`
`92
`
`43/161 '-
`
`94
`
`43/ 182
`
`95
`
`43/ 201
`
`96
`
`43/ 221
`
`'[45]
`
`[46]
`
`[47]
`
`[48]
`
`[49]
`
`[50]
`
`256. Abbott-85499 Drug Metabolism Report No.27 -
`Conversion of [’H]dexmedetomidine to [’H]. levomedetornidine
`in male subjects following a 2 ug/kg infusion of
`[3H]dexmedetomidine.HC1 Report No. R&D/97/458
`
`97
`
`45/ 153
`
`212. Subacute_Toxicity Study of Dexmedetomidine
`(MPV-1440 x HCI) by Daily Intramuscular
`Administration to Rats for 28 Days.
`
`213. Subacute Toxicity Study of Dexmedetomidine
`(MIN-1440 x HCI) by Daily Intravenous Administation
`to Rats for 28 Days. TOX 89-020
`
`106
`
`33/ 001
`
`112
`
`34/ 001
`
`
`
`

`

`NDA 21-038
`
`[51]
`
`[52]
`
`mi
`
`:[54]
`
`[55]
`
`[56]
`
`[57]
`
`215. Dexmedetomidine Hydrochloride:
`Subacute Toxicity Study by Daily Intramuscular
`Administration to Male Dogs for Four Weeks. TOX 90-006
`
`216. Dexmedetomidine Hydrochloride:
`Subacute Toxicity Study by Daily Intramuscular
`Administration to Female Dogs for Four Weeks. TOX 90-013
`
`—
`
`222. Fourteen Day Intrathecal Toxicity Study of
`Dexmedetomidine in the Rat, TOX 94-019
`
`223. A 3Pilot Intrathecal Injection Study of Dexmedetoniidine
`Hydrochloride (Abbott- 84599 Hydrochloride) in the
`Beagle Dog. 1895-2 16, 1995.
`
`224. A 28-Day Intrathecal Injection Toxicity Study of
`Dexmedetomidine Chloride (Abbott -85499 Hydrochloride)
`in the Beagle Dog with a 14-Day Recovery Period.
`TB95-224, 1995.
`
`228. Fertility study (Segment I study) of Dexmedetomidine
`in Rats by Subcutaneous Administration.
`TOX 89-001, 1991.
`
`230. Pre- and Post-Natal Study (Segment III study)
`of Dexmedetomidine in Rats by Subcutaneous
`Administration. TOX 90-017, 1994.
`
`116
`
`35/ 190
`
`120
`
`36/ 001
`
`123
`
`37/ 001
`
`124
`
`37/ 112
`
`126
`
`37/ 187
`
`38/ 305
`
`134
`
`40/ 147
`
`138
`
`41/ 001
`
`[58]
`
`231. Examination of the Influence of MPV-1 440 He]
`
`141
`
`42/ 001
`
`on the Pregnant Rabbit and the Foctus by Intravenous
`Administration. 5193/89, 1991 .
`
`[59]
`
`248. Abbott-85499 Drug Metabolism Report No.31 -
`Lacteal excretion and fetal tissue distribution of
`
`143
`
`44/ 149
`
`radioactivity following a single subcutaneous. dose of
`[3H]de)unedetornidine.HC1 (Abbott-85499. 1) in the rat
`(Study No. Covance 6161-175). Report No. R&D/97/565
`
`[60]
`
`232. Dexmedetomidine Hydrochloride.
`Bacterial Mutation Assay - - r’\——.
`
`149
`
`42/ 082
`
`

`

`
`
`NDA 21-038
`
`[61]
`
`[62]
`
`233. Bacterial Reverse Mutation Assay of
`Dexmedetomidine Hydrochloride in Escherichia Coli.
`
`150
`
`42/ 107
`
`234. Dexmedetqmidine Hydrochloride.
`Mammalian Cell Mutation Assay FSG 19/931143,1994.
`
`151
`
`42/ 130
`
`[63] .1
`
`.235 Dexmedetomidine Hydrochloride Metaphase
`Chromosome Analysis of Human Lymphocytes Culturedin
`vitro. FSG 18/93 206
`‘
`
`153
`
`42/168 ~.
`
`[64]
`
`[65]
`
`[66].
`
`200. Dexmedetomidine: Preliminary Dose-Range Finding
`Study fOr Mouse Micronucleus Test. TOX 95-007/1
`
`156
`
`31/ 125
`
`199. Hypothermia Induces Micronuclei in Mouse
`Bone Marrow Cells. Mutation Res 1997;393:91-98.
`
`198. Erythroid Hypoplasia in Bone Marrow Induced
`by Hypothermia in Mice. TOX 95-007/2
`
`157 '-
`
`31/ 117
`
`158
`
`31/075
`
`[671'
`
`' 201. Micronucleus Test of Dexmedetomidine Hydrochloride
`in Mouse Bone Marrow. PT971 12100025
`
`160
`
`31/ 149
`
`[68]
`
`[69]
`
`[70]
`
`[71]
`
`[72]
`
`[73]
`
`217. Local intramuscular Irritation Study of MPV-1440
`(dexmedetomidine) in Rat. TOX 90-004/1
`
`163
`
`36/ 247
`
`218. Acute Anen'al Irritation Evaluation of ,
`Dexmedetomidine Hydrochloride in Rabbits. TE 95-284
`
`164
`
`36/ 276
`
`219. Hemolysis test on Eight Formulations of MPV- 1440
`
`220. Evaluation of Dexmedetomidine, Admim''istered as the
`Hydrochloride Salt, for Passive Cutaneous Anaphylaxis
`in Guinea Pigs.
`'I'F95-009, 1995.
`
`165
`
`166
`
`36/ 298
`
`36/ 343
`
`221 . Evaluation of Dexmedetomidine, Administered as the
`Hydrochloride Salt, for Delayed Contact Hypersensitivity
`in Guinea Pigs (Draize Method). TF95-0 II
`
`167
`
`36/ 381
`
`225. Subacute Toxicity Study of Levomedetomidine
`Hydrochloride by Daily Intravenous Administration to Female
`Rats for Two Weeks. TOX 91-032
`
`168
`
`38/ 306
`
`
`
`

`

`
`
`NDA 21-038
`
`‘ [74]
`
`226. MPV- 1441 (Levomedetomidine Hydrochloride)
`Subacute Toxicity Study by Daily Subcutaneous
`Administration to Rats for Four Weeks. TOX 88-029
`
`170
`
`39/ 001
`
`[75]
`
`[76]
`
`[77]
`
`227. Subacute Toxicity Study ofMPV-l441
`(Levomedetomidine Hydrochloride) by Daily Intravenous
`Administration to Dogs for 28 Days. TOX 96-002
`
`'
`
`171
`
`39/ 249
`
`Porter, David E. and Ogidigben. Miller J.; Medetomidine-Induced
`Alterations of Intraocular Pressure and Contraction of the
`Nictitating Membrane. Invest Ophth and Vis Sci
`- —
`32(1):2799-2805, 1991 (#88)
`_
`
`176
`v
`
`‘
`
`'
`
`827/ 006
`,
`
`Viniainen J, MacDonald E, Uritti A, Rouhiainen H and Virtanen, R; 177
`Dexmedetomidine-Induced Ocular Hypotension in Rabbits With
`Normal or Elevated Intraocular Pressures Invest. Opthamol & Vis Sci
`33(6):2019-23(1992) (#37)
`
`27/ 001
`
`[78],
`
`r; Savola J-M, Virtanen R; Central az-adrenoreceptors are highly
`stereoselective for dexmedetomidine, the dextro enantiomer of
`medetomidine Eur J Pharmacol 195: 193-199 (1991) (#4)
`
`178
`
`24/ 019
`
`[79]
`
`Sabbe MB, Penn mg JP, Ozaki GT, Yaksh TL. “Spinal and
`Systemic action of the 0:2 Receptor Agonist Dexrhedetomidine
`in Dogs - Antinociception and Carbon Dioxide Response”
`Anesthesiology 80:1057-72 (1994)
`(#6)
`
`179
`
`t 24/ 033
`
`x
`
`Studies within this submission previously reviewedi
`
`NDA
`study
`
`__
`
`-
`
`Page
`number
`
`NDA
`Volume
`
`7. Viitamaa T. The anxiolytic effects of medetomidine and
`dexmedetomidine in a rat conflict test. Orion Pharm. Report;
`7 November 1983.
`
`8. Haapalinna A, MacDonald B, Virtamen R, et a1. Studies on
`the anxiolytic effects of racemic medetomidine and its
`stereoisomers in mice. Orion Pharm. Report; 7 November
`1988.
`
`24
`—
`
`49
`
`24
`
`66
`
`10‘~
`
`

`

`NDA 21-038
`
`37. Ruskoaho H. Effect of dexmedetomidine on coronary
`vascular tone, heart rate and contractile force in the isolated
`perfused rat heart. Orion Pharrn. Report; 7 November 1988.
`
`62. MacDonald E. Effect of atropine on the cardiovascular
`response of the anesthetized rat to acute administration of
`dexmedetomidine. Orion Pharrn. Report; 7 November 1988.
`
`90. VirtanenR. Effect of dexmedetomidine on intestinal
`motility. Study Report, Orion Pharma, Turku, Finland; 7
`November 1988.
`
`95. Virtanen R. Effect of dexmedetomidine on kidney
`function in rats. Study Report, Orion Pharrna, Turku, Finland;
`7 November 1988.
`
`106. Saano V. Affinities of medetomidine, MPV-l440 and
`MPV- 1248 on benzodiazepine, tryptamine, opiate, serotonin,
`and GABA-receptors in rat brain. University of Kuoplo
`Report. Department of Pharmacology and Toxicology,
`University of Kuopio, Kuopio, Finland; 3 January 1988.
`
`107. Savola I-M. Inhibition of 3H-prazosin and gH-clonidine
`binding by enantiomers of medetomidine in rat cerebrocortical
`membranes. Study Report,m
`Finland; 7 November 1988.
`
`113. Savola J-M. Cardiovascular effects of the enantiomers of
`medetomidine in anaesthetized rats and in pithed rats. Study
`Report, Farmos Group LTD, Turku, Finland; 7