M19212!
`
`This was a phase 1, single center, open-label study. After stable anesthesia was
`achieved using alfentanil and propofol, rocuronium administration began at an initial infusion rate
`of 200 ug/kg/hour (note: recommended initial infusion rate for continuous infiision is 600 to 720
`ug/kg/hour).
`It was then adjusted to maintain a stable Tul at 50% of the baseline value After
`stabilization of neuromuscular block, dexmedetomidinéwas administered to achieve a steady
`concentration of 0.6 ng/mL using a computer controlled infusion pump After 45 minutes of
`dexrnedetomidine infusion, all infusions were stopped
`
`Results and Discussion
`
`Statistical analysis was done to compare rocurohium concentrations prior to and
`'15, 30, and 45 minutes afier initiation of dexmedetomidine infiision by a paired t-test. No
`statistically significant difference was found between the rocuronium concentrations immediately
`before the start of dexrnedetomidine infusion and concentrations 15 and 30‘minutes later.
`
`the comparison of pre-dexmedetomidine
`there was a significant difference for
`However,
`rocuronium concentrations and those 45 minutes later. It should be noted that the elapsed time
`from last change in rocuronium infusion rate until dexmedetomidine infiision began ranged from
`10-24 minutes meaning that rocuronium with a terminal half-life of 71 minutes will not achieve
`new steady state concentrations within the 45 minutesof dexmedetomidine infusion. This is
`reflected" in
`the
`small
`rise
`in
`rocuronium concentrations during the 45 minutes of
`dexmedetomidine
`infusion.
`The
`small but
`statistically significant
`difi‘erence between
`concentrations of rocuronium prior to dexmedetomidine infusion as compared to 45 minutes afier
`the start of dexmedetomidine may be due to rocuronium not having achieved steady-state (1.66
`versus 1. 79 ng/mL).
`The changesin neuromuscular block before and after dexmedetomidine infusion
`were small (6. 6%1n T1%), clinically undetectabletand considered clinically unimportant by the
`investigator.
`
`Table 1. Mean dexmedetomidine and rocuronium concentrations.
`
`Dexmedetomidine
`
`0.002 t 0.005 -.
`
`1.03 :1: 0.15
`
`1.66 :t 0.29
`
`1.73 :t 0.37
`
`
`
` Rocuronium
`Time After Start of
`
`Dexmedetomidine
`Concentrations
`Concentrations
`
`
`
`Administration
`
`
`
`
`(nymL)
`(ng/mL)
`
`
`
`
`
`
`
`
`0.96 :1: 0.15
`
`
`0.94 i 0.14
`
`
`1.78 i 0.43
`
`1.79 i 0.41
`
`
`
`
`Note: Lack of analytical assay validation data precludes the use of rocuronium pharmacokinetic
`information1n the package1nsert.
`
`NDA 21-038, a,‘
`
`62 I
`
`

`

`
`
`IN VITRO NIETABOLISM
`
`Study Type: In Vitro Metabolism and inhibition.
`
`NDA: 21-038
`
`Submission Date: 12/18/98 Volume: 1.49
`
`Protocol: R&Dl97/757
`
`4
`Obiective: '
`the metabolism of
`in
`involved
`cytochrome P450 proteins
`To identify the hepatic
`[3H]dexmedetomidine in human liver microsomes and human B-lymphoblastoid; micosomes
`containing cDNA expressed cytochrome P450 proteins.
`.w
`
`_
`Conclusions: -
`Based on the results from this study, it was concluded that the hydroxylation of dexmedetomidine
`to 3-hydoxy dexmedetomidine and H-3 is largely mediated by CYP2A6, although other CYP
`forms may also play an ancillary role. Evidence for the involvement of CYP2A6 included: 1) 8-
`methoxypsoralen, a CYP2A6-selective inhibitor, inhibited (41-59%) the hydroxylation to both
`products; 2) couman'n, a CYP2A6-selective substrate, inhibited (34%) the hydroxylation to 3-
`hydroxy dexmedetomidine; 3) hydroxylation was also observed with human B-lymphoblastoid
`microsomes containing cDNA-expressed CYP2A6; and 4) the hydroxylation of dexmedetomidine
`was inhibited (33%) by a CYP2A6 antibody. Inhibition by CYP2A6 selective inhibitors, including
`antibodies, was incomplete and may indicate the involvement of one or more other CYP isozymes
`in human liver microsomes. Furthermore, minimal inhibition (<20%) by selective inhibitors of
`CYPs other than CYP2A6, lend credence to speculation that more than one other CYP isozyme
`might me involved. Several other cDNA expressed C¥Ps were also capable of catalyzing the
`metabolism of dexmedetomidine to one or both major products indicating that other CYP
`isofonns (e.g., CYP1A2, CYP2E1, CYP2D6 and CYP2C19) may play a role in the hydroxylation
`of dexmedetomidine.
`
`The dexmedetomidine ICso values for inhibition of the various isoforms ranged from 0.2-3.3 uM
`for the inhibition of 1A] (2.7 uM), 1A2 (2.0 uM), 2A6 (70 uM), 2Cl9 (3.3 uM), 2D6 (1.3 uM'),
`2E1 (2.2 HM), and 3A4 (0.65 M). Since the plasma concentrations of dexmedetomidine at
`clinically relevant doses are very low (510 ng/mL; $0.04 M compared to the in vitro
`determined 1C” values,
`the possibility of an inhibitory effect of dexmedetomidine on the
`metabolism of coadministered drugs in vivo in humans appears to be unlikely.
`In a clinical
`interaction study, dexmedetomidine did not have any efi‘ect on the phannacokinetics of
`midazolam, a CYP3A substrate. The lack of inhibitory effect is possibly due to very low plasma
`levels of dexmedetomidine (0.2-0.4 ng/mL) observed in this study, which are several fold lower
`than the in vitro determined [Cso values for CYP3A4 inhibition (0.65 M; 110 ng/mL).
`
`NDA 21-038,0 63 :~
`
`
`
`

`

`Drugs
`
`Experimental
`
`Dexmcdetomidine was labeled with tritium. as shown irtthe figure below:
`
`CT3
`
`CH3
`
`
`
`[3H]Dexmedetomidine (Lot 55585-ST-108;‘66 Ci/mmol: hydrochloric acid saltl was
`
`dissolved in ethanol and stored at 310°C. The radiochemieal purity was greater than 97%.
`
`Unlabeled dexmedetomidine (Lot No. 031940-002) was combined with the labeled drug
`
`only for final incubations requiring concentrations greater than 0.05 M.
`
`Preparation of Liver Mierosomcs
`
`Transplant quality human liver tissue was obtained from W"
`
`
`M was receiveclat Abbott Laboratories within
`
`24 hours of removal from the donor. Based on studies with microsomes containing
`
`cDNA expressed CYPs and given the potential role of CYPZDé in the oxidative
`
`metabolism of dexmedetomidine. liver microsomes prepared from an extensive
`metaboliur (1D: l 21 1961: male subject) and a poor metabolizer (ID:4 15961; male subject)
`
`of CYP 206 substrates were used in this study.
`
`
`i'_
`i:
`
`
`
`subsequently homogenized with ? \-————————md the resultant homogenatc
`
`was centrifuged :Wé“ was carefully
`
`NDA 21-038,“
`‘
`
`64:,
`
`
`
`

`

`1311
`
`In Vitro Metabolism of [3H]Dcxmedetomidine
`
`Assay S ystem—
`
`In vitro incubations of [3mdcxmedetomidine with human hepatic microsomcs were:
`mffnrn'wrl at
`.._
`
`Involvement of the CV? system in the metabolism‘of both compounds was auscsscd by
`omission of the NADPH and by the use of several CYP isoform selective inhibitors.
`
`Identlficatlon of the Oxidative Metabolites of Dexmedetomidine Produced
`by Human Liver Microsomes
`
`In vitro incubations of [3H]dexmedetomidinc with human hepatic microsomes for the
`
`.'
`
`t.\\___—____Mr_w__ --...____.,-._ t.
`
`.
`
`i.
`
`...._~ ____ .
`
`NDA21-038,~
`
`65 i
`
`#4
`
`

`

`
`
`Table 3.
`
`ICso values for inhibition of dexmedetomidine against the different cytochrome
`P450 isoforms.
`
`3C ' ochrom P3503
`
`“Tom
`
`‘
`
`
`
`u’
`”I"'te
`
`
`Ethoxyresorufin O-deethylase
`Ethoxyresorufin O-deethylase
`Coumarin 7-hydroxylase
`S-mephenytoin 4-hydroxylase
`Chlorzoxazone 7-hydroxylase
`' Testosterone 65-hydroxylase
`Dextrometho . han O-demeth lase
`
`APPEARS THIS WAY
`0" ORIGINAL
`
`_-.—..—
`
`NDA 21-038,— 73 .'
`
`
`
`

`

`
`
`DIVISION OF ANESTHETIC, CRITICAL CARE
`AND
`
`ADDICTION DRUG PRODUCTS
`
`ABUSE LABILITY ASSESSMENT
`
`
`
`NDAzm
`
`_
`
`21-038
`
`spousonz
`
`'
`
`i
`
`'
`
`Abbott Laboratories
`
`DRUG:
`
`/~——'
`
`(Dexmedetomidine Hydrochloride)
`
`CHEMICAL NAME:
`
`(+)-4-|l-(2,3-dimethyl)phenyl)ethyll-lIl:imidazole
`
`DOSAGE FORM:
`
`lnjectable solution (2 mL Ampul/‘Z mL Vials)
`
`"-
`
`STRENGTHS:
`
`INDICATION:
`
`100 meg/ml.
`
`ICU Sedative
`
`DATE SUBMITTED:
`
`February 4, 1999
`
`DATE Rcd. BY REVIEWER:
`
`February 10, 1999
`
`REVIEWER:
`
`BeLinda A. Hayes, Ph.D.
`
`REVIEWER DATE:
`July 20 , I999
`:
`1
`
`
`BACKGROUND
`
`Abbot Laboratories has submitted NDA 2170348 forA dexmedetomidine hydrochloride) to Food Drug
`Administration Division of Anesthetic, Critical Care, and Addiction Drug Products. -—\ " is indicated for ICU
`sedation. Dexmedetomidine, (+)-4-(l~(2.3-dimethylphenyl)ethyl-lH-imidazole hydrochloride, is an a, adrenergic
`receptor agonist.
`it is the pharmacological active dextroisomer of medetomidine which is marketed in Scandinavian
`countries as a sedative/analgesic agent for veterinary use in dogs and cats under the tradename Dominator.
`it is an a,
`adrenergic receptor agonist with high potency and specificity.
`its primary activities include: sedation, anesthesia,
`anesthetic-sparing effects, analgesia and anxiolytic activities.
`In pharmacological activity is very similar to clonidine.
`
`Per 21 CFR 3 l4.50(5)(vii) when a NDA is submitted for new pharmaceutical product, which demonstrates similar
`pharmacological profile and/or structural similarity with a known drug of abuse or there are evidences of dependence
`producing potential, the sponsor must submit an abuse liability assessment package. This package must contain a
`description and analyses of studies or information related to abuse of the drug and a scheduling proposal for the drug
`product. \—~— 5 these criteria It has been demonstrated that dexmedetomidine‘s pharmacological action
`is very similar to that of clonidine.
`it has been documented that clonidine ha been abused in patients with a history of
`opiate and alcohol dependencies (Dy and Yates, 1996; Lauzon, I992; Shanna and Newton; 1995; Anderson. er (11..
`I997); henceforth, the potential of abusing dexmedetomidine does exist.
`Preclinical studies have shown that
`dexmedetomidine has dependence potential in rats and primates, and functions as a positive reinforcer in primates.
`ln
`
`
`
`

`

`
`
`‘ NDA 2l—O38
`
`compliance with the requirement of 2] CFR 314.50(5)(vii), Abbott Laboratories submitted with the NDA an abuse
`liability assessment package. Evaluation of the compound’s chemical. pharmacological (both preclinical and clinical),
`pharmacokinetics, and pharmacodynamic profiles of the compound, and the adverse effects associated with the
`compound are the basis of the abuse liability assessment and the recommendation for scheduling under the CSA.
`
`ABUSE LIABILITY INFORMATION PROVIDED IN THE SUBMISSION.
`
`The Sponsor’s’s abuse liability data submitted in the NDA included the following:
`
`0
`
`0.
`
`0
`
`0
`
`O
`
`Report by K. Ando entitled “Dependence study on dexmedetomidine in rhesus
`Preclinical Study.
`monkeys and rats." Osaka, Japan. Preclinical Research Laboratories, June 1997.
`‘
`'
`
`The sponsor did not conduct any studies to'specifically address the abuse liability
`Clinical _Studies.
`of dexmedetomidine. They submitted results from studies W97-028, W97-249, W97-245, and W97-246.
`These studies included assessment of pharrnacokinetics and physiological parameters and adverse events which
`the sponsor felt had clinical relevance in evaluation of the potential for development of dependence.
`
`Published literature that the sponsor felt was pertinent to the abuse potential of dexmedetomidine.
`
`lnforrnation on the treatment of dexmedetomidine overdose.
`
`.
`.
`.
`.
`w
`, _The sponsor‘ recommendation for scheduling dexmedetomidine under the Controlled Substances Act.
`
`ABUSE POTENTIAL OF DEXMEDETOMIDINE.
`
`The abuse potential of dexmedetomidine has been evaluated in primates
`Preclinical Abuse Liability Assessment .
`and rats. These studies were performed to determine if the clondine-like pharmacological activity: ( that is, it exerts
`hypertensive effecs, heart rate lowering effects, and analgesic effects) of dexmedetomidine also extends to dependence
`potential that clondineflias demonstrated in preclinical studies. Preclinical studies have demonstrated that clondine can
`function as a positive reinforcer in primates, produces physical dependence and suppresses morphine withdrawal signs.
`The sponsor performed two preclinical studies to specifically address the dependence-producing potential of
`dexmedetomidine and three studies to characterize the overt behavioral effects associated with the acute administration
`of dexmedetomidine in rats and primates. Dexmedetomidinegability to function as a positive reinforcer was assessed
`in rhesus monkeys. The ability of dexmedetomidine to produce physical dependence and to suppress morphine
`withdrawal signs were evaluated in rats.
`Y Lil-on“. an .l'i M'f‘ Unham WCSA'
`
`Study 1.
`
`Gross Behavior Observation of Acute Effects in Rhesus Monkeys.
`
`To characterize the acute central nervous system effects of dexmedetomidine in rhesus monkeys
`Objective.
`following intraygnous and subcutaneous administration; and to determine the appropriate doses to use for the primate
`self-administration study.
`
`Procedure.
`
`The overt behavioral effects associated with acute administration of dexmedetomidine were
`
`characterized in rhesus monkeys following intravenous and subcutaneous administration. Six rhesus monkeys, males
`and females weighing between 4.3 and 7.5 kg, were subjects fOr this study. The monkeys were randomly selected to
`
`__
`
`2
`
`

`

`NDA 21-038
`
`receive a particular dose of dexmedetomidine or saline. Each subject received seven doses of dexmedetomidine; each
`dose was separated by 6 days or more. Dexmedetomidine was evaluated at 041625, 0._2_5, 1.0, 4:0. and 8.0 ug/kg
`following intravenous administration; three subjects were tested at each dose. Following subcutaneous administration.
`dexmedetomidine was tested at 4.0, 8.0 and 16.0 ug/kg; three or four monkeys were tested at each dose. Saline served
`as the control; saline was tested at 025 kag. Six monkeys served as control following the intravenous route and five
`monkeys were tested with saline following the subcutaneous route.
`
`Obsefi'ation/Data Analysis.
`
`The following observations were examined during the study:
`
`a.
`
`Overt Behavioral Signs. Observation for signs of dexmedetomidine-related overt behavioral signs were
`performed under blind conditions prior to drug administration, immediately after drug treatment, and at 15 min,
`30 min, and l hour after dosing, and then once every 1 hr for Star 6 hrs after dosing.
`it was noted that
`behaviorabsigns were not measured immediately after subcutaneous administration. Scoring involved noting
`each occurrence of the following signs:
`_
`.
`
`SCORE POSTURE
`
`
`
`
`
`mm—m
`m——m
`
`
`
`
`
`-m-m
`
`
`—w
`
`_m——
`-m——
`
`
`
`
`
`
`
`
`
`
`2-level scale: assigned either a - or + score; 3-level scale: assigned a -, +, or H score;
`4-level score: assigned a —, +, H. or ++-+ score
`
`b.
`
`Food Consumption.
`(at 22 hrs after dosing).
`
`Food intake was recorded on a 4.level scale at 5.5 hrs after dosing and the next day
`
`mm ““8 WAY
`A on ORlGlNAL
`
`"
`
`—
`
`
`
`

`

`NDA 21-038
`
`RESULTS:
`
`' Overt behavioral effects were observed in rhesus monkeys following the acute intravenous and subcutaneous
`administration of dexmedetomidine. Dexmedetomidine-induced behavioral effects were dose-dependent. The no effect
`doses following intravenous administration were 0.0625 ug/k and 1.0 pig/kg.
`lncreased aggression (2 out of 3
`monkeys), and hypoactivity (“1 out of 3 monkeys) were noted after 0T25"iig/kg dexmedetomidine. Hypoactivity, eye-
`closing, and crouching posture were observed in all three monkeys tested with 4.0 ug/kg and 8.0 ug/kg intravenous
`dexmedetomidine administration. Slowed motion, ataxia, hyporeactivity to observer, decreased aggression to observer
`and salivation were also observed in 2 of the 3 monkeys
`following both the 4.0 ug/kg and 8.0 ugfkg doses‘ of
`dexmedetomidine. These overt behavioral effects were also observed in some of the monkeys after being dosed with
`8.0' ug/kg of dexmedetomidine: lying down, decreased grimacing at observer, decreased aggression to observer, and
`salivation. Most of these behaviors were observed within 15 minutes after dosing and had disappeared within 3 hours
`after the 4.0 ug/kg dose and within 5 hours after the 8.0 ug/kg dose of dexmedetomidine.
`
`Similar results were observed when dexmedetomidine (4.0, 8.0 and 16.0 ug/kg) was administered subcutaneously.
`Following the administration of 4 .0 ug/kg dexmedetomidine, eye closing and crouching posture were observedIn 2 of
`the 3 monkeys tested Eye-closing were observedIn all three monkeys dosed with 8.0 ug/kg dexmedetomidine. Two
`of the three monkeys displayed hypoactivity and less grimacing at observer following this dose of dexmedetomidine.
`In addition to these behavioral changes, hyporeactivity to the observer. slowed motion, ataxia, and decreased continual
`movement were observed in one monkey. Following l6.0 ug/kg dexmedetomidine, eye-closing, hyporeactivity to
`observer, ataxia, and slowed motion were observed in all four monkeys. One monkey also showed decreased continual
`movement, decreased aggression to observer, and was lying down at this high dose of dexmedetomidine.
`
`Acute CNS effects were observed in rhesus-monkeys following intravenously and subcutaneously
`Conclusion.
`administered dexmedetomidine. Dexmedetomidine-induced behavioral effects included: eye-closing, hyporeactivity
`to the observer less grimacing at observer hypoactivity, slowed motion ataxia, and crouchinga.posture
`
`APPEARS rms wAv
`on ORIGINAL
`
`-._.-
`
`
`
`

`

`NDA 21-038
`
`Study 2.
`
`Tests of suppression of morphine withdrawal signs in rhesus monkeys.
`
`Objective.
`
`To determine whether or not dexmedetomidine possesses opioid type physical dependence as
`demonstrated by its ability to suppress morphirgeiwithdrawal signs in rhesus monkeys.
`
`METHODS.
`
`Six rhesus'monkeys (Macaca Mulalta), males and females, weighing between 4.7 to 5.4 kg and
`Subjects.
`between the age of 7 to 13 years served as subjects for the study. The monkeys were housed individually.
`
`Morphine wasadministered subcutaneously once 'a"day (around 9:30 a.m.) at a dose of 3.0
`Dosing Regimen,‘
`mg/kg for Zuweeksj During weeks} and 4 of the study, morphine (3.0 mg/kg) dosing was increased to twice daily
`(around 9:30 am. and 4:00 pm). The dose of morphine was increaed to 6.0 mg/kg for the next 8 weeks or more.
`
`After the development and maintenance of physical dependence, the
`Substitution and Withdrawal Phase.
`monkeys were withdrawn from morphine for about 22.0 to 22:5 hours. During this withdrawal phase. the signs of
`withdrawal were graded. Monkeys displaying intefi'nediate or severe withdrawal signs were used for the suppression
`(i.e., substitution) tests. During each suppression test, one monkey received 0.25 or 0. 5 ml/kg (s.c.) of saline. The
`other five monkeys received dexmedetomidine (8_.9 or lgfl ug/kg. s.c.) or codeine (1&0 or 21.0 pig/kg). The monkeys
`were observed for signs of withdrawal prior to the substitution test, at 15 min, 30 min. 1 hr. 2 hrs., and 3 hrs after dosing.
`
`Signs of withdrawal were scored during the substitution and withdrawal phase of the study. Using
`Data Analysis.
`a 2-level (-,+), 3-level (-.+, ++), or 4-level (-, +, 4+, +4-r) rating scale. each monkey‘s sign of withdrawal was scored
`and asigned a score. The score in each behavioral observation (See Table on page 8) was converted from the recorded
`levels of -, +, ++, +++, to values of 0, I, 2, and 3, respectively. The value was than multiplied by a factor of 0-60
`depending on the item. The total number of pains was calculated by adding each of~the weighed values and the grade
`of the withdrawal signs was classified as mild. intermediate or seven: depending on the total scores. The degree of
`morphine withdrawal signs were classified as following:
`
`CRITERIA FOR GRADING MORPHINE WITHDRAWAL SIGNS
`
`
`__
`—_
`Interm'ediate or severe depending on the
`signs observed'
`
`
`
`a: if at least one severe sign was observed, the morphine withdrawal was graded as “severe"
`
`
`
`
`
`

`

`
`
`The degree of withdrawal signs suppression was calculated a the Percent'Suppression Score = 100 x (A-B)/A. “A“
`is the total number of points before'the administration of dexmedetomidine or codeine. “B" is the minimum total number
`of points after administration. The grades of suppression of withdrawal signs were classified as following: ’
`
`NDA 21-038
`
`WITHDRAWAL SIGNS
`
`
`
`
`
`
`
`_—
`
`_-
`
`
`
`
`APPEARS rms win
`on ORIGINAL
`
`
`
`

`

`Behaviors Obser'Ved During Withdrawal Phase
`
`
`
` BEHAVIORAL OBSERVATION
`
`
`
`NDA 21-038
`
`
`
`
`
`
`
`Dehydration
`
`fl.-
`
`.
`
`7
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` INTERMEDIATE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_II_
`—II-
`_lfl_
`—II_
`
`_II_
`
`__flfl
`_III
`
`—II_ '
`
`—II_
`
`
`—flI-_
`—II_ -
`
`_II_
`_II_
`—III
`
`_II_
`
`Mu--
`
`_II_
`
`_flflfl
`
`—IIu
`MI.-
`—II_
`—-II_
`_‘flfl_
`_III
`—II-
`
`—II--
`
`—II-
`
`
`VERY SEVERE
`
`
`
`
`
`
`—fl--
`
`
`_fl--
`c: Scored as “extreme restlessness";
`d: Scored as “marked spasticity"
`
`

`

`
`
`“NDA 21~038
`
`RESULTS.
`
`-
`
`_/
`
`_
`
`After dosing‘with morphine was terminated, only four (Monkeys Number: 1350 (9), 1377 (9), 1368 (d'), and 1409
`(d')) out of the six monkeys‘ morphine signs were graded as intermediate or severe. The remaining two monkeys“
`morphine withdrawal signs were graded as “mild”; these monkeys were not used in the substitution test. The withdrawal
`signs mainly associated with termination of morphine included: apprehension, chattering, twitching of the whole body,
`intention tremors restlessness, pilomotor activity, muscle twitching and rigidity, holding of the abdomen retching, and
`quarreling and fighting Marked spasticity, extreme restlessness and vomiting were observedIn some of the monkeys.
`flaw/v“
`'
`platl
`_,./Results from this study have shown that dexmedetomidine doespossess opioid-l-ike activity in rhesus monkeys) As,—
`depicted in Tables 1, 2, and 3, dexmedetomidine substituted for morphine during the withdrawal phase Prior to
`dexmedetomidine administration, both monkeys' withdrawal signs were graded as intermediate Following the
`administration of 8.0 rig/kg of dexmedetomidine the degree of suppression ofinorphine withdrawal signs was graded
`as mild (47.2%) and intermediate (50%)In monkey 1350 and monkey 1368', respectively. The 8.0- rig/kg dose of
`dexmedetomidine reduced the withdrawal score of some of the behavioral signs of morphine withdrawal. When monkey
`1350 received 80 ug/kg dexmedetomidine (Table 1), the withdrawal score for restlessness and twitching of the whole
`body was lowered at 0.25, 0.5, and 1.0 hr post-dosing; restlessness was also reduced at 3 hrs observation time point.
`Assumption of peculiar attitudes’ score was lowered at 1.0 and 3.0 hrs post-dosing (Table 1). This dose of
`dexmedetomidine enhanced the score assigned to pilomotor activity and retching at 2 and 3 hrs, and 3 hrs post-dosing,
`respectively.
`1-14m I, is
`The withdrawal score for pilomotor activity and retching was reduced at 0.5, 1.0, 2.0, and 3.9 and at 0.25, 0.5, and 3.0
`hrs after_dexmedetomidine, respectively in monkey 1368 (Table 2). Holding the abdomen was not observed at 0.5 hrs
`after dexmedetomidine administration but returned to pre-dosing level at 1 hr post-treatment and persisted throughout
`the observation period. The withdrawal score for chattering, twitching of the whole body, muscle twitching and rigidity,
`and erection and continual masturbation was increased in monkey 1368 after treatment with 8.0 ug/kg of
`dexmedetomidine.
`
`_
`
`The degree of suppression of morphine withdrawal signs was only slightly higher by increasing the dose of
`dexmedetomidine to 16. 0 ug/kg This dose of dexmedetomidine suppressed morphine withdrawal signs by 58%
`(intermediate) in monkey 1377 (Table 3) and by 26.1% (mild) iii—monkey 1350 (Table 1) However, it should be.
`pointed out that because of the study design, thatIs testing different monkeys with different doses and not all monkeys
`with both doses, characterization of the dose-effect relationship is difficult. The withdrawal score for apprehension,
`twitching o‘ the whole body. muscle twitching and rigidity, and retching was reduced in monkey 1377. Assumption
`of peculiar attitudes wa abolished by 16.0 rig/kg dexmedetomidine. The withdrawal score was decreased at 0.25, 0.5,
`1.0, and 2 hrs post-dosing in monkey 1350. The reduction in the total withdrawal score at these observation times was
`the result of the score for the following withdrawal signs being reduced: apprehension, chattering, and holding the
`abdomen. The withdrawal score at the 3 hr post-dosing observation time was higher because the score for muscle
`twitching and rigidity, and muscle spasticity was higher.
`
`The ability of codeine (16.0 and 24.0 mg/kg) to'suppress morphine withdrawal signs was assessed in monkeys 1350,
`1368, and 1409.
`in contrast to the suppressing effects of dexmedetomidine, codeine was more effective in suppressing
`morphine‘s withdrawal signs
`(Tables 4, 5, 6, and 7). Both doses of codeine effectively suppressed the withdrawal
`signs associated with morphine. Codeine, at a dose of 16.0 mg/kg, suppressed morphine withdrawal signs by 65.4%
`(intermediate suppression), and by 80.5% (marked suppression) in monkeys 1350 and 1409, respectively. Morphine
`withdrawal signs were suppressed by 78.3% (marked suppression), and 82.4% (marked suppression) by 24.0 mg/kg
`in monkeys 1368 and 1409, respectively.
`
`
`
`

`

`NDA 21-038
`
`Following the administration of 16.0 mg/kg of codeine, the score assigned to chattering, twitching of the whole body,
`intention tremor, restlessness, pilomotor activity, msumption of peculiar attitudes, muscle twitching and rigidity,
`quarreling and fighting, and muscle spasticity were reduced or not present at some of the observation times in monkey
`1409 (Table 6). Apprehension‘and holding the abdomen which was not evident before codeine (16.0 mg/kg)
`administration became evident at 0.25, 2, and 3 hrs post-dosing, respectively.
`
`Codeine, 16 mg/kg, abolished the withdrawal score for twitching (If-the whole body, restlessness, and holding the
`abdomen during the 0.25-l hr, 025 - 2 hr, and 0.5 - 2 hr observation period in monkey 1350, respectively (Table 4).
`Assumption of peculiar attitudes was not evident after codeine administration.
`
`When the dose of codeine was increased to 24.0 mg/kg, codeine markedly suppressed morphine withdrawal signs in
`monkey 1368 (Table 5); chattering,
`restlessness, holding the abdomen, and assumption of peculiar attitudes were
`suppressed 100%. Apprehension, twitching ofthe whole body, intention tremor and muscle twitching and rigidity were
`reduced at several observation time points. Codeine, 24.0 mg/kg, suppressed morphine withdrawal sign by 100% ore
`reduced the score in monkey 1409 (Table 7). Yawning. chattering, intention tremor assumption of peculiar attitudes,
`quarreling and fighting, and muscle spasticity were suppressed 100%. Pilomotor activity and muscle twitching and
`rigidity were reduced at some of the observation times.
`
`Results from this study have shown that both dexmedetomidine and codeine possess cross-dependence
`Conclusion.
`potential
`for morphine.
`Both drugs partially substituted for morphine in morphine-dependent primates.
`Dexmedetomidine and codeine were effective in abolishing or reducing the score of the morphine withdrawal signs.
`The degree of suppression of morphine withdrawal sign observed following dexmedetomidine ranged from mild to
`intermediate Codeine suppressed the withdrawal signs intermediately or markedly. canW tar-M *
`(it/i Vidar—rfi‘” W Vulcan) %ww.
`.U'prsvrpa can M-bw‘nnw
`>
`BEST POSSIBLE COPY
`
`'7
`
`AEPEARs ‘fms' IIIAY
`Oil 0RlGlNAL _
`
`1 .
`
`~
`
`

`

`
`
`‘
`
`a
`
`"
`
`l
`
`NDA 2l-038
`
`Results from the substitution of Dcxmcdctomidinc (8.0 pig/kg, s.c. ) in Monkey N°. l350-altcr withdrawal from morphine.
`Table I.
`
`
` SCORE 0F THEWITIIDRAWAL SIGN (POINT ASSIGNED T6 SCORE)
`DEXMEDETOMIDINE: [6.0 pgikg
`DEXMEDETOMIDINE: 8.0 pg/kg
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Time After Dosing (hr)
`
`.-
`
`Time After Dosing (hr)
`
`an 5" .,o
`
`'
`
`- ,
`
`--
`
`+
`
`A0‘v ‘iA0‘V
`
`+++
`
`AaV
`
`++
`
`Ait v
`
`++
`
`A8 v
`
`m-‘(0)
`a. m-
`+-w *0) mm)
`
`WITIIDRAWAL SIGN
`
`-
`
`~
`3:‘3.9: 3on S"0 >6’O.o.303 I++
`A0"V
`Assumption of peculiar attitudes
`
`Erection and Continual Masturbation m
`Quaneling and fighting “
`Marked Spasticity
`“
`
`- I
`
` m
`
`“
`I“
`
`m
`
`
`10
`
`

`

`Table 2.
`
`Results from the substitution ofSaline and Dcxmcdctomidinc (8.0 [lg/kg, s.c. ) in Monkey N°. l368 after withdrawal from morphine.
`
`NDA 2l-038
`
`WITIIDRAWAL SIGN
`
`
`
`SCORE 0F TllE-WITIIDRAWAL SIGN (POINT ASSIGNED T0 SEORE)
`
`Time After Dosing (hr)
`
`u.
`
`Time After Dosing (hr)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`HoldingthcAbdomcn
`
`“-(o)
`
`.(o)
`
`-(0) mun-m +0)
`
`+0)
`
`
`
`
`
`—mm
`
`
`Vomiting
`
`4
`
`11
`
`
`
`
` Wam-
`
`
`' m
`TOTAL POINTS
`GRADE 0F WITHDRAWAL SIGNS MILD
`
`
`
`
`
`
`
`
`
`

`

`Results from the substitution oISaline and Dcxmcdclnmitlinc (l6.0 gig/kg, s.c. ) in Monkey N°. 1377 after withdrawal from morphine.
`
`NDA 2 [1038
`
`SCORE 0F TllE-WITIIDRAWAL SIGN (POINT ASSIGNED T0 SEORE)
`
`SALINE (0.25 ml/kg)
`
`‘
`
`Time After Dosing (hr)
`
`DEXMEDETOMIDINE: l6.0 pglkg
`
`Time After Dosing (hr
`
`+
`
`+
`
`A 3
`
`A .— v
`
`+
`
`A C
`
`+0)
`
`+(I)
`
`+(‘)
`
`II
`+'+aA N V
`‘A 5 '+'+'
`AAN.-vhi all+AAAN__VVv
`
`+(I)
`
`+0)
`
`H (2)
`
`+ (2)
`
`+(I)
`
`+(')
`
`+
`
`A :5
`
`++ (2) H (2)
`+
`A N V
`
`E.A N v
`
`+
`
`A C
`
`.4.
`
`AA_.—vV
`
`- (0)
`+
`
`AN v
`
`
`
`
`
`
`++ (2) H (2)
`+
`
`)
`
`N(
`
`++ N
`
`A
`
`AN v
`
`A¢5
`
`A
`
`+I
`
`+
`
`++ (2)
`
`IEE+I
`AANNvV
`
`+
`
`_.
`
`+ (2)
`
`+ (2)
`
`4.
`
`AN V
`
`+
`
`A N v
`
`- (0)
`
`+
`
`A NV
`
`.4.
`
`AN V
`
`+
`
`A N v
`
`+
`
`A N v
`
`Table 3.
`
`
`
`WITIIDRAWAL SIGN
`
`
`
`4.
`
`+
`
`A
`
`v
`
`A _ v
`
`A83
`
`A+
`
`
`
`
`
`
`
`
`
`
`
`
`Muscle Twitching and Rigidity
`
`+ (2)
`
`Holding the Abdomen
`
`H (4)
`
`,
`
`Assumption ofpccultar attitudes
`
`- (0)
`
`Erectton and Continual Masturbation
`
`v
`AN v
`
`I
`
`Aow
`
`A N V
`
`OV
`
`- (
`
`.(ov
`
`+
`
`AN v
`
`I
`
`ACv
`
`+ (2)
`+
`AN V
`
`+
`
`I
`
`A w v
`
`Aow
`
`H (4)
`+
`AN v
`
`.4.
`
`A m V
`
`' (0)
`+4.
`
`AA v
`
`+
`
`A H V
`
`+ (2)
`Ad V
`
`+
`
`A b; V
`
`A
`
`w
`
`A& V
`
`+.4.
`
`AA v
`
`l
`
`AOV
`
`Quanehng and fighting
`
`4.+4.
`
`Auv
`
`u v
`
`+++(3)
`
`+++(3)
`
`E
`
`A u v
`
`
`
`
`
`Marked Spastlcny
`
`Vomiting
`
`TOTA L POINTS
`
`l7
`
`
`
`
`
`Vv
`
`
`
`
`
`
`
`
`*
`cmnaorwnnnmwusucus mm- mmmm
`
`DEGREE OF SUPPRESSION
`100 x (l7-l3)/l7 = 23.5% “NONE" - [00 x (2440/24 = 58.3% ‘INTERMEDIATE“
`
`I
`
`'6
`
`ACv
`
`I
`
`I
`
`A
`
`v
`
`A
`
`v
`
`- (0)
`
`- (0)
`
`
`
`
`
`+++(3)
`I
`
`AO
`
`IIAAOovV
`
`I
`
`AOv
`
`I
`
`Aov
`AHv
`
`12
`
`.-4
`
`I
`
`AaV
`
`O-()
`
`
`
`
`
`
`

`

`
`
`Table 4.
`
`Results from the substitution oI’Saline and Codeine (I6.0 mg/kg, s.c. ) in Monkey N°. |350 after withdrawal from morphine.
`
`NDA 2l-038
`
`, .
`
`SCORE OF THE WITIIDRAWAL SIGN (POINT ASSIGNED TO'SCQRE)
`
`
`
`l‘l.
`
`to
`
`'
`
`'
`
`I
`
`1‘
`WWW}??? H (4’
`"
`'
`5:15:22"
`.
`a _. at«3% tat-ta.
`-“.'!;.
`'.i
`W
`Strum
`. ~
`WiiiiWia
`.4”
`.
`g.
`
`K
`
`.
`
`mi} «Wit
`..
`'-‘.
`
`\ I
`
`. v
`
`WITIIDRAWAL SIGN
`
`Apprehension
`
`E.
`
`';
`
`': %%
`
`I-.
`Twitching of the whole Body
`at}
`{’2'_ ,- W a
`.
`g? ,
`Intention Tremor
`:-
`64)
`
`vii\
`
`.'.
`
`;.vi.'I.-.~.<~.-I..
`
`t‘v
`{A
`It“
`g270“?
`HHW
`@125?
`(MM
`3:
`9a
`
`.oxo’
`
`.(x
`
`I’ilomotor Activity
`Muscle Twitrhing and Rigidity
`Holding the Abdomen
`
`Assumption of peculiar attitudes
`
`GRADE OF WITIIDRAWAL
`SIGNS
`
`

`

`Table 5.
`
`Results from the substitution ol'Snliue and Codeine (24.0 rug/kg, s.c. ) in Monkey N9; I368 after withdrawal from morphine.
`
`NDAZl-038
`
`.-
`
`.'
`
`CODEINE: 24.0 mglkg
`'
`
`Time After Dosing (hr)
`
`AlaV
`
`'l AA \—w
`II
`
`I
`
`AI.v
`
`I
`
`A0v-
`
`+
`
`A .— v
`
`I
`
`A3:!
`
`I+n’5’28vvv
`
`4.
`
`Q
`
`AN V
`
`A
`
`v
`
`
`
`
`
`
`
`
`
`
`
`
`- (0)
`
`a
`
`AOV
`
`ANv
`
`ANV
`
`+
`
`o
`
`I
`
`AOv
`
`A‘9-v
`
`4.
`
`A :3
`
`+
`
`ANV
`
`a
`
`AOv
`
`
`
`WITHDRAWAL SIGN
`
`
` y.
`
`.
`
`AN V
`
`ANv
`
`a
`
`Aov
`
`.
`
`A
`
`V
`
`
`
`
`
`
`
`II:.I.(I,
`.
`.
`
`1 i
`
` c
`
`V.
`
`l
`
`
`
`
`
`
`Assumption of peculiar attitudes
`
`Erection and Continual Masturbation
`.
`.
`Quarrcllng and fighting
`.
`_
`Markedswuwy
`
`DEGREE orsumuzssnon
`
`I
`
`AO
`V
`IA N- V
`+
`A N v
`
`I
`
`AOv
`
`.L6V
`n
`
`AOV
`I
`Alv
`
`+. A :3
`
`
`
` +
`
`
`
`WIN
`
`4 {Ed- ..
`'1'
`n
`
`I...
`.W
`12.
`
`i,"
`mil/XI
`\
`I
`55:
`
`”I
`Eight/M vI'g‘I‘I-R»
`-’>'
`mm
`
`
`. 9
`
`' ll
`”.321:
`I
`III
`I
`V
`
`-.-v
`if
`I
`.
`l"
`{n
`..
`N
`23:234.?
`.-
`fig'bw‘llfism" m
`3}.
`.-_ “up”;
`I 5}
`I
`.0.
`Kw;
`. " .
`,.
`y
`Mm
`
`
`"WEEK"
`”ifXR’M-W- WWW“-
`“1'3."
`...‘.
`I
`If_
`....
`)l‘nu .
`.
`'.
`II...
`.
`Wartimsmmllr
`
`
`n:.I;.-_
`I
`_k -
`
`
`TOTAL POINTS
`'
`
`
`
`GRADE OFWITIIDRAWAL
`3:5
`,.
`.-
`
`is”
`srcns
`12‘
`
`
`
`'
`‘
`.
`' - I00 x (23-51/23 378.3% “MARKED”
`
`
`

`

`I
`
`-‘
`
`NDA 2l-038
`
`SCORE 0F TIIE WI'I'IIDRAWAL SIGN (POINT ASSIGNED'T0;SCORE)
`
`’
`
`SALINE 0.5 mllkg
`
`.
`
`Time After Dosmg (hr)
`
`CODEINE: I6.0 mall‘s
`.
`Tlme'Afler Doslng (hr)
`
`.
`
`‘
`
`_
`
`Table 6.
`Results from the substitution olSaline and Codeine (“5.0 mg/kg. s.c. ) in Monkey N31 I409 alter withdrawal from morphine.
`
`
`
`WITIIDRAWAL SIGN
`
`
`
`I
`
`AOV
`
`A3
`
`::
`
`A“
`A _ V
`
`+
`
`AOv
`
`l
`
`I
`
`I
`
`AOv
`
`AHQ”‘1
`
`I
`
`AOv
`
`I
`
`AGv
`l
`Aav
`
`+
`
`A _. v
`
`++(4)
`I
`AOV
`
`I
`
`+++(9)
`I
`A0v
`
`+++(9)
`+
`A NV
`
`- (0)
`
`-+’8AV5’
`
`- (0)
`
`++
`
`AAw
`
`++(4)
`
`At;3S
`
`l
`
`AOv
`
`++(4)
`
`AOV
`
`'+'0''I'E'
`
`A
`
`+ +
`
`AN V
`
`+++
`
`A H v
`
`A I.» V
`
`MusclcTwitchingand Rigidity
`
`++(4)
`+
`++ (9)
`
`{4(4)
`+++(9)
`ACv
`
`AANNvv
`+‘+(4) - Hm ++(4) Hus)
`+++(9)i
`+++(9)
`+++(9)
`+++(9)
`
`4.+
`
`++
`
`A0V
`
`I
`
`
`
`
`
`
`II
`++~A+8:.
`II
`
`
`
`
`
` I
`
`AAso—vw
`A\DV
`A\OV
`A OV
`A\OV lA‘0V IAC v
`AAHIVv
`
`
`
`v
`
`A8‘
`
`I
`
`AOV
`
`AOv
`
`I
`
`-<0
`D
`
`A
`
`3—
`
`AO.v'
`
`(0)
`
`
`
`I
`
`AOv
`
`V
`
`A\OV
`
`(0)
`
`(0)
`
`AOV
`.4.4.
`
`A-Nv
`
`I
`
`+
`
`n
`
`AOV
`
`+++
`
`AH V
`
`A0v
`
`.4.
`
`AOV
`
`AOv
`
`SEVERE
`
`
`
`
`
`
`
`
`
`
`
`
`
`0'?V
`m w)
`Erection and Continual Masturbation
`- (0)
`+
`
`E.A U V
`
`IEE+AA_UvV
`
`Quaneling and fighting
`
`‘IEFr
`
`+
`
`A :3
`
`«0)
`
`+