94
`
`0 One patient experienced a myocardial infarction said to have unlikely causality.
`
`PHASE III ‘37:- __-IES
`
`Deaths:
`None
`
`_
`
`Serious Adverse Events:
`9
`Patient experienced hypotension probably related to study drug; dyspnea/chest pain
`and pneumothorax with no stated relationship to study drug.
`Patient experienced cardiac arrest with a claimed possible relationship to study drug.
`Patient experienced diarrhea, tissue discharge, necrotic area on buttock, ischemic
`colitis, and vaginal fistula with claimed no relationship tostudy drug. Both the
`diarrhea and necrotic area on buttock were judged to be mild while the tissue
`discharge, ischemic colitis, and vaginal fistula were judged to be moderate.’
`
`0
`0
`
`SECTION 8.7
`
`LABORATORY FINDINGS
`
`SECTION 8.7.1
`
`SERUM CHEMISTRY PARAMETERS
`
`A summary of mean change from baseline to the last post baseline time point in
`hematology and chemistry parameters for patients in Phase II/III continuous infusion
`studies is presented in Table 41. Sponsor states the mEan changes from baseline in
`hematology and chemistry values appear consistent with what would be expected in this
`post-surgical population. Statistically significant differences were noted between the
`randomized Dexmedetomidine treated patients and placebo treated patients for mean
`changes from baseline hematocrit, hemoglobin, and red blood cells. These changes are
`claimed by the sponsor to be small and not clinically importantfl'his reviewer agrees that
`these hematology changes are small and not clinically insignificant.
`
`'
`
`Adverse events of hyperglycemia were reported by 2% of the patients in both the
`randornized_l_)_exm§detomidine and placebo treatment groups but the mean change from
`baseline to the' last post baseline time point in glucose values were statistically
`significantly higher in the randomized Dexmedetomidine patients than in the placebo
`patients. The changes were 1.5 mmol/L increase for randomized Dexmedetomidine
`patients and 1.0 mmol/L increase for placebo patients. [Reviewer Note: Normalfasting
`glucose is 4.2-6.4 mmoI/L or 75-115 mg/dL.] Urine glucose was not collected in the
`Dexmedetomidine studies.
`
`The mean changes from baseline to the last post baseline time point in liver chemistry
`parameters were similar between randomized Dexmedetomidine and placebo patients.
`
`

`

`
`
`95
`
`Mean Change From Baseline to the Last Post Baseline Time Point in
`Hematology And Chemistry Parameters: All Treated Patients in Phase
`II/HI Continuous Infusion Studies.
`All Treated Dexmedelomidine
`Randomized Dexmedelomidine
`
`
`Placebo
`
`mmol/L)
`
`mmol/L)
`
`22.10
`
`2 3.54
`
`22.55
`
`23.55
`
`22.12
`
`2 3.56
`
`12.47
`
`2360
`
`"Ian-mm
`
`20.72
`
`2 3.28
`
`2‘ 2.58
`
`2 3.55
`
`10.74
`
`23.79
`
`2 2.59
`
`2 3.63 '
`
`226.81
`
`Table 41
`
`
`
`
`-
`
`emaloloev Parameter
`
`Base
`:51)
`
`ematocrit. m 0.4
`1.0)
`20.07
`emoglobin -
`121.5
`.
`2 22.23
`
`x 10 vm
`
`.
`x109/L)
`hemmrv Parameter
`
`292.94
`
`20.72
`
`23.56
`
`Mean
`Change
`25D
`
`0.0
`20.07
`~16.l
`2 22.37
`
`3 58.36
`
`2 0.72
`
`2 3.94
`
`Base
`:51) "
`
`0.4
`20.07
`123.2
`: 22.04
`
`g 92.69
`
`20.74
`
`23.33
`
`58.83
`
`20.75
`
`'
`
`23.57
`
`Mean
`Change
`:51)
`
`Bue
`+50
`
`Change
`250
`
`0.0
`0.4
`.01.
`20.07
`20.07
`2 0.07
`.166
`121.3 '
`~17.6'
`673
`223.13 -- 2 23.87
`
`2 90.20
`
`260.63
`
`
`
`
`
`
`
`.. --------n
`
`
`We:
`
`
`
`
`
`
`
`
`
`
`
`mum-“Iain
`
`
`“mm“
`
`
`
`
`--------m
`
`
`—---—-m-—
`
`
`“Ian-“mum
`
`
`M‘2/L)
`212.68
`213.3
`
`
`
`Modified Sponsor’s Table 33 188 Vol 8/ 10-239-83
`
`umol/Ll
`
`mmol/L)
`
`(Ll/L)
`
`mmol/L)
`
`(U/L)
`
`UIL)
`
`umol/L)
`
`20.60
`
`261.30
`
`274.93
`
`2 0.46
`
`2 43.70
`
`2 37.52
`
`210.17
`
`227.75
`
`22.70
`
`235.l7
`
`24.52
`
`227.19
`
`22.62
`
`234.89
`
`24.25
`
`229.53
`
`22.78
`
`23.42
`
`2135.52
`
`2197.27
`
`213 5.52
`
`2197.27
`
`2150.82
`
`2177.44
`
`20.46
`
`2 3|.62
`
`2 36.02
`
`210.39
`
`$58.88
`
`278.06
`
`17.92
`
`+1105
`
`212.40
`
`20.45
`
`2 82.47
`
`2 46.89
`
`211.48
`
`20.57
`
`2 77.32
`
`2 43.58
`
`212.65
`
`N = number of patients; base = baseline; SD = standard deviation; RBC = red blood cells;
`WBC = white blood cells;-
`BUN = blood greanitrogen; LDH: lactate dehydrogenase; SGOT/ASAT = serum
`glutamic oxaloacetic transaminase/aspartate transaminase; SGPT/ALAT = serum
`glutamic-pyruvic transaminase/alaninetransaminase
`
`* Statistically significant difference (Shaded Areas) between randomized
`dexmedetomidine patients and placebo patients, p S 0.05.
`
`SECTION 8.7.2
`
`VITAL SIGNS AND ELECTOCARDIOGRAMS
`
`Phase I Studies
`
`

`

`96
`
`One of the Phase I studies was designed to determine the highest safe plasma
`concentrations of Dexmedetomidine. Continuous monitoring of subjects EKGs was
`performed. The Dexmedetomidine plasma concentrations achieved were greater than
`those expected based on PK parameters in use. A total of 7 subjects in the study had
`significant abnormalities on post-baseline EKGs; all had received Dexmedetornidine. 5
`subjects had sinus bradycardia; one also had nonsustained junctional rhythm One subject
`had Mobitz Type I second degree heart block which resolved spontaneously one minute
`after onset. Another subject had intermittent premature atrial contractions with variable
`first degree AV block.
`-
`
`The EKG disorders occurredprimarily at the plasma concentrations > 1.2 ng/ml. Sponsor
`speculates the probable mechanism of action was enhanced vagal nerve reflex activity
`without opposing sympathetic activity. Evaluation was confounded by use of
`phenylephrine which was used to determine baroreceptor sensitivity. Known adverse
`effects of phenylephrine administration include bradycardia and heart block. In this study
`involving EKGs, subjects were able to tolerate Dexmedetomidine plasma concentrations
`exceeding the anticipated therapeutic range by as much as 13 times.
`
`Phase II/III Studies
`
`Several of the perioperative studies collected vital sign data using a said novel monitoring
`system. Sponsor claims that as a result of validation concerns about the system and the
`inability to synchronize the data with an actual event or time of treatment, the data
`collected by this system could not be appropriately analyzed or interpreted. The vital sign
`data collected in the Phase II/III ICU sedation studies used traditional techniques to
`assure the reliability ofthe data. Because of the validation concerns, sponsor is only
`presenting vital sign data from the continuous infusion ICU sedation studies in the
`Integrated Summary of Safety.
`
`Analyses of vital signs in the continuous infusion ICU sedation studies included systolic
`and diastolic blood pressure, heart rate, central venous pressure, respiratory rate, oxygen
`saturation, and cardiac output.
`’
`
`Systolic Bloodl’rgssure (SBP):
`Mean baseline SBP was 126 mmI-Ig in the randomized Dexmedetomidine group and 126
`mmHg in the placebo group and was maintained within the normal range for both groups
`during the entire period of observation. After initial increases during the first 10 minutes,
`rapid moderate decreases (about 15 mmI-Ig) occurred within the next 10 minutesin the
`randomized Dexmedetomidine group after which decreases occurred more gradually until
`12-13 hours. After 15 hours, the time at which most patients completed study drug
`infusion, SBP slowly increased. In the placebo group, increases occurred during the first
`hour, after which there were decreases until 5 hours. Mean change from baseline in SBP
`during study drug infusion showed statistically significant differences between the
`treatment groups from 20 minutes through the 21 hour time point; variability between
`treatment and placebo groups was the same. After the 12-15 hour time point, SBP tended
`
`
`
`

`

`97
`
`to return to baseline with increases in the Dexmedetomidine group and decreases in the
`placebo group.
`
`Randomized Dexmedetomidine patients with hypotension showed a mean decrease in
`SBP of 20 to 25 mmHg during the first 20 minutes. SBP in the randomized
`Dexmedetomidine group with hypotension remained lower than the randomized
`Dexmedetomidine gréup without hypotension until 17-hours, after which they were
`similar.
`
`DiastolicBlood Pressure (DBP)
`
`Baseline DBP was 64 mml-lg in the placebo group and 65 in the randomized
`V
`Dexmedetomidine group. In the randomized Dexmedetomidine group, after initial
`increases the first 10 minutes, DBP returned to baseline followed by gradual decreases to
`12-13 hours and slight increases thereafter. In the placebo group, DBP remained
`increased for 2 hours before returning to baseline. At all times after the initial 10 minute
`evaluation, mean DBP was lower for the randomized Dexmedetomidine patients than for
`placebo patients. Analyses of mean change from baseline in DBP during study drug
`infusion showed statistically significant differences between the treatment groups at
`several time points. The most pronounced difference was at 12 hours after start of
`infusion with a difference of about 8 mran. Although statistically significant, the
`difference in variability between treated and placebo groups was clinically insignificant.
`Actual DBP was similar in the 2 groups by 24 to 27 hours.
`
`Heart Rate
`
`Baseline heart rate was 81 in the placebo group and 80 in the randomized
`Dexmedetomidine group. For the Dexmedetomidine treated group, heart rate detreased
`about 5 beats per minutes about 10 minutes after drug initiation. For both groups, mean
`rate remained within the normal range throughout the entire range of observation.
`
`Central Venous Pressure (CVP)
`
`Baseline CVP was 8 mmHg in the placebo group and 7 mmI-Ig in the randomized
`Dexmedetornidiner‘group. Mean change from baseline in CVP during study drug infusion
`showed small statistically significant differences between treatment groups from 1-12
`hours, the differences were not clinically significant. Mean CVP for randomized
`Dexmedetomidine patients with hypotension was clinically insignificantly higher than in
`Dexmedetomidine patients without hypotension.
`‘
`-
`
`Respiratory Rate (RR)
`
`Respiratory Rate was similar between treatment groups.
`
`Oxygen Saturation
`
`

`

`98
`
`All patients received oxygen while being ventilated and remained in the normal range.
`After extubation oxygen saturation decreased slightly within both treatment groups but
`remained within the normal range. Oxygen saturation was similar between placebo and
`Dexmedetomidine treatment groups.
`
`Cardiac Output
`
`Few patients had cardiac output measurements collected during the‘study. Among those
`that did, the pattern of changes was similar between placebo and Dexmedetomidine
`treatment groups.
`
`SECTION 8.8
`' "
`
`ADVERSE EVENTS AND PR‘ECLINICAL
`STUDIES
`
`In 28 day repeated dosing nonclinical toxicology studies, the primary Dexmedetomidine
`related effects were sedation, slightly reduced body weight, exophthalrnos, piloerection,
`gait changes, muscle twitching, irregular respiration, glucosuria. [Discussion with
`pharmacology reviewer Dr. Geyer discloses no concomitant elevations of blood glucose
`in the animals with glucosuria. However other animals in other studies did show
`significant hyperglycemia although the urinefor glucose was not analyzed. ]Changes in
`hepatic weight, some hepatic serum enzymes, and pulmonary hemosiderin deposits were
`also observed at the highest doses studied. In the clinical studies, the most frequently
`reported adverse events were likely extensions of the pharmacological effects of alpha2
`agonists, including hypotension, hypertension, and bradycardia.
`
`A dose related increase in the incidence of corneal keratitis and opacities was also
`reported in the preclinical studies. Sponsor states these last ophthalrnological findings
`were due to the pharmacological effect of Dexmedetomidine decreasing lacrimal
`secretions and blinking during-sedation.--[¥hisneviewer agrees-wirh-this assessment. I A
`total of 8 patients in the Phase II/III continuous infusion. studies reported vision disorders,
`including 5 reports of abnormal vision, one report of conjunctivitis, one report of
`diplopia, and one report of photopsia. The abnormal vision reports were primarily
`described as blurred vision. The one report of conjunctivitis was related to a corneal
`abrasion. Each of these events resolved without intervention.
`A
`
`SECTION 8.9
`
`DOSE-RESPONSE DATA
`
`Sponsor states that one of the Phase I studies (Dexmedetomidine-95-OO7) demonstrated
`that subjects were able to tolerate Dexmedetomidine plasma concentrations exceeding the
`anticipated therapeutic range of 1.2 ng/ml; maximum individual Dexmedetomidine
`concentrations in this study ranged from 2.123 ng/ml to 16.100 ng/rnl. A summary of the
`
`
`
`

`

`99
`
`most commonly experienced treatment emergent adverse events in Phase I continuous
`infusion studies by target plasma concentration is presented in Table 42.
`
`Table 42
`
`Most Common3 Treatment Emergent Adverse Events By Target
`Dexmedetomidine Plasma Concentration:
`All Dexmedetomidine Treated Subjects
`Phase I Continuous Infusion Studies
`
`
`Tar-et Dexmedetomidine Plasma Concentration (n- ml.) —
`
`Increasing
`
`0.1-0.2
`0.4-0.5
`1.25
`Dex Conc
`
`
`(N=61)
`(N=25)
`(N=34)
`(N=12)
`.(N=22)
`Adverse Event”
`(N=59)
`
`Subjects with at least
`
`
`24(96%)
`27(79%)
`12( 100%)
`10(45‘7c)
`39(66%)
`
`
`
` 39(§§'%)
`
`one treatment-emergent
`
`adverse event
`
`
`
`
`
`
`9(75%)
`1(5%)
`5(20%)
`16(27%)
`9(26%)
`12(20%)
`Mouth dry '
`
`
`20(59%)
`17(68%)
`10( 17%)
`10(83%)
`0
`Somnolence
`8( 13%)
`
`
`
`
`
`
`
`
`2(8%))
`15 (25%)
`4(33%)
`2 (9%)
`Headache
`5(15%)
`ll(18%)
`
`
`
`
`
`
`
`Hypotension
`l4(56%)
`9( 15%)
`l6(47%)
`9( 15%)
`0
`1(5%)
`
`
`
`
`
`
`
`Nausea
`l(4%)
`9(15%)
`2(6%)
`2(3%)
`0
`5 (23%)
`
`
`
`
`
`
`
`0
`Hypoxia
`0
`1(2%)
`1(2%)
`0
`O
`
`
`
`
`
`
`
`_
`3 (5%)
`1(3%)
`Diainess
`3 (12%)
`1(2%)
`1(8%)
`2(9%)
`
`
`
`
`
`
`
`
`
`.
`0
`4(7%)
`408%)
`Bradycardia
`l(4%)
`3 (5%)
`1(8%)
`
`
`
`Muscle contractions
`
`
`
`involuntary
`5 (8%)
`0
`1(3%)
`0
`3 (5%)
`2(9%)
`
`
`
`
`
`
`
`. Pallor
`5(8%)
`0
`0
`0
`0
`804%)
`
`
`
`
`
`Apnea
`4(7%)
`0
`0
`0
`O
`4(7%)
`
`
`
`
`
`
`
`
`Stupor
`1(2%)
`1(8%)
`2(6%)
`1(4%)
`1(5%)
`3 (5%)
`
`
`
`
`
`
`
`
`Hyperkinesia
`5 (8%)
`0
`1(3%)
`0
`0
`3 (570)
`
`
`
`
`
`
`
`
`
`
`Pain
`2(3%)
`0
`1(3%)
`0
`1(5%)
`4(7%)
`
`
`
`
`Pharyngitis
`4(7%)
`0
`1(3%)
`4(7%)
`
`
`
`
`
`
`
`Paresthesia
`4(7%)
`1(8%)
`0
`0
`
`
`
`Xerophthalmia
`0
`0
`3 (9%)
`5 (8%)-
`
`
`
`
`
`Fatigue
`3 (5%)
`1(8%)
`3 (5%)
`
`
`
`
`Hallucination
`u 3 (5%)
`4 (33%)
`0
`
`
`
`Vomiting
`0
`0
`5(8%)
`
`
`
`
`Agitation
`0
`O
`4(12%)
`0
`
`
`
`
`
`
`Prun'tus
`1(2%)
`4(7%)
`1(3%)
`
`
`
`
`
`Rhinitis
`0
`1(8%)
`1(3%)
`2 (3%)
`
`
`
`
`
`Back pain
`0
`2 (3%)
`1(8%)
`
`
`
`
`
`
`Vision abnormal
`2 (3%)
`4(7%)
`0
`
`
`
`
`
`Abdominal pain—1:
`0
`1(2%)
`1(2%)
`0
`
`
`
`
`
`o
`
`
`Con'unctivitis
`3 (25%)
`0
`”2%)
`
`Sponsor’s Table 43, ISS Vol 8/10-239-135
`
`
`
`
`
`
`
`
`'
`
`g
`
`~-
`
`‘
`a: Experienced by22‘7c offal] dexmedetomidine-treated subjects in the Phase lstudies.
`b: Subjects may have been counted in more than one column if theyreceived treatment in more than one treatment
`period. but a subject was counted only once in a given column.
`’
`Dex : Dexmedetomidine Cones = concentrations
`
`In the Phase I continuous infusion studies, the incidence of dry mouth and somnolence
`was highest at the highest Dexmedetomidine plasma concentrations (75% and 83%
`respectively). However only 12 patients were closed in this group. Sponsor states the
`incidence of somnolence showed no clear trend when analyzed by target plasma
`
`
`
`

`

`100
`
`concentration probably because some investigators considered sonmolence an expected
`effect of the drug and did not report it as an adverse event.
`
`A summary of the most commonly experienced treatment emergent adverse events in
`Phase II/III continuous infusion studies by total Dexmedetomidine dose is presented in
`Table 43.
`
`Table 43
`"
`'
`
`
`
`Most Common3 Treatment Emergent Adverse Events by Total Dose of
`Dexmedetomidine: All Treated patients in Phase II/III Continuous
`Infusion Studies
`otal Dexmedetomidine Dosefmc- )
`
`>7- 10
`>10
`.>5-7
`0-1
`>3—5
`
`
`(N=1 731
`(N=92)
`(N=226)
`(N=455)
`(N=88)
`(N=300)
`‘dverse Event
`
`
`
`I04(60%)
`147(65%)
`255 (56%)
`66(75%)
`Patients with at least
`133 (61%)
`56(61‘7c)
`
`
`-
`une treatment-emergent
`—
`
`
`dverse event
`
`
`
`Hypotension
`l45(32%)
`92(3l%)
`65(29%)
`36(21%)
`25 (27%)
`29(33%)
`
`
`
`
`
`
`
`
`Hypertension
`47( 10%)
`'39( 13%)
`450096)
`28( 16%)
`12( 13%)
`5(6%)
`
`
`
`
`
`
`
`
`
`Nausea
`53 (12%)
`38(13%)
`28(12%)
`14(8%)
`5 (5%)
`24(27%)
`
`
`
`
`
`
`
`
`Brndycardia
`8(9%)
`28(6%)
`21(7%)
`12(5%)
`15(9%)
`10(11%)
`
`
`
`
`
`
`
`
`Tachycardia
`4(5%)
`25 (5%)
`12(4%)
`14(6%)
`4(2%)
`5 (5%)
`
`
`
`
`
`
`
`
`Fever
`3 (3%)
`20(4%)
`15(5%)
`9(4%)
`10(6%)
`4(4%)
`
`
`
`
`
`
`
`
`
`
`Hypoxia
`l9(22%)
`l4(3%)
`9(3%)
`8(4%)
`4(2%)
`4(4%)
`
`
`
`
`
`
`
`Anemia
`1 (1%)
`15(3%)
`l7(6%)
`14(6%)
`4(2%)
`1 (1%)
`
`
`
`
`
`
`
`.Vomiting
`2(2%)
`14(3%)
`12(4%)
`“(5%)
`6(3%)
`3 (3%)
`
`
`
`
`
`
`
`
`Hemorrhage NOS
`2(2%)
`13 (3%)
`9(3%)
`4(2%)
`5 (3%)
`3 (3%)
`
`
`
`
`
`
`
`
`Pain
`5 (6%)
`10(2%)
`7(2%)
`7(3%)
`4(2%)
`1 (1%)
`
`
`
`
`
`
`
`
`
`Rigors
`13 (3%)
`8(3%)
`5(2%)
`4(2%)
`3 (3%)
`
`
`
`
`
`9(3%)
`Atrial fibrillation
`100%)
`6(3%)
`6(3%)
`2(2%)
`
`
`
`
`
`
`
`
`
`
`6(7%)
`4(1%)
`Mouth dry
`3 (<l%)
`60%)
`1 1(6%)
`
`
`
`
`
`
`9(3%
`Agitation
`_
`9(2%)
`3 (1%)
`4(2%)
`4(4‘7c)
`
`
`
`
`
`
`
`Sponsor‘s Table 44 188 Vol 8/10-239-137
`NOS = not otherwise specified
`a: Experienced by 22% of all Dexmedetomidine treated patients in Phase II/111 continuous infusion studies
`
`'
`
`_
`
`In the Phase II/III continuous infusion studies, evaluation of adverse events by total dose
`of Dexmedetomidine showed no obvious dose response relationship. The most common
`adverse event at all doses was hypotension. Hypertension was the next most commonly
`occurring adverse-Event although there was no apparent dose response relationship. Dry
`mouth did appear to demonstrate a dose-response relationship above the lower doses.
`Sponsor states the relatively high incidence of hypoxia (22%) in the 0-1 meg/kg group
`can be attributed to'the results of one study (Dexmedetomidine-96012) where hypoxia
`was reported byz 75% of patients in all treatment groups including patients receiving
`placebo. With reSpect to laboratory evaluations, examination of the mean change from
`baseline in hematology and chemistry parameters by total dose of Dexmedetomidine did
`not show any apparent dose-response relationship.
`'
`
`SECTION 8.10 DRUG-DRUG INTERACTIONS
`
`
`
`

`

`
`
`101
`
`Potential drug interactions were assessed in six Phase I studies which evaluated the use of
`Dexmedetomidine with esmolol, alfentanil, isoflurane, midazolam, propofol and
`rocuronium. Adverse events were analyzed for patients who received midazolam or
`propofol in the Phase II/III sedation studies.
`
`Phase I Studies
`
`;
`
`_
`
`Esmolol
`
`One Phase I continuous infusion study evaluated Dexmedetomidine and esmolol and
`' placebo and esmolol. The most commonly reported treatment emergent adverse event in
`this study was headache, with similar numbers of subjects reporting this event in the two
`dose groups. Nojgther safety concerns were identified.
`
`Alfentanil
`
`One Phase 1 continuous infusion study evaluated Dexmedetomidine with alfentanil
`(N=10) compared to placebo with alfentanil (N=9). Subjects who received
`Dexmedetomidine and alfentanil had more reports of dry mouth (100% vs 56%), apnea
`(60 vs 11%), xerophthalmia (50% vs 11%), bradycardia (40% vs 0), and hypotension
`(40% vs 0). Apnea lasting less than 1 minute was reported in 6 Dexmedetomidine
`subjects vs 1 alfentanil-placebo subject.
`‘
`
`Isoflurane
`
`One Phase I continuous infusion study evaluated Dexmedetomidinedsoflurane (N=10)
`and placebo-isoflurane (N=9). Subjects who received Dexmedetomidine-isoflur‘ane had
`more reports of hypotension (50% vs 0) and involuntary muscle contractions (50% vs 0)
`than the placebo-isoflurane group. Sponsor does not speculate on the etiology of the
`involuntary muscle contractions in the Dexmedetomidine-isoflurane group and claims the
`overall incidence of involuntary muscle contractions among all Dexmedetomidine treated
`patients in the Phase II/III continuous infusion studies was <l%.
`
`Midazolam u: -
`
`One Phase I continuous infusion study evaluated Dexmedetomidine~midazolam (N=19)
`and placebo-midazd‘lam (N=18). Somnolence (100% vs 11%), hypotension (95% vs
`22%), and dry mouth (42% vs 0) were more commOn among the Dexmedetomidine-
`mjdazolam group than the placebo-midazolam group. No obvious safety concerns were
`identified when the Dexmedetomidine-propofol (N=10) group was compared to the
`placebo-propofol (N=9) patients.
`'
`
`Rocuronium
`
`
`
`

`

`-
`
`102
`
`Noadverse events were reported for subjects who received rocuronium and
`Dexmedetomidine (N=lO).
`
`mm
`
`The investigation of potential interactions of Dexmedetomidine with midazolam or
`propofol was evaluated in Phase II/III continuous infusion ICU studies as presented in
`Table 44.
`
`‘ Table 44-
`‘
`
`—
`Most Common Treatment Adverse Events by Drug Interaction in
`Phase II/III Continuous Infusion ICU Sedation Studies Experienced by
`22% of Dexmedetomidine Treated Patients
`
`
`Randomized Dexmedetomidine
`Placebo
`Dexmedetomidine
`Dexmdetomidinc
`Dexmedetomidine
`Placebo Only
`Only
`_And Midazolam
`And propofol
`N=7l
`
`' N=l$8
`N=I04
`N=IE
`Modified Sponsor’s Table 48 158 Vol 8/10-239-143
`
`.,
`
`Placebo And .
`Midazolarn
`’ '
`N=I50
`
`-
`
`
`Placebo And
`Propofol
`
`
`
`N=l5
`'
`
`The proportion of patients experiencing hypertension or hypotension was higher in any
`group that included Dexmedetomidine as compared to any of the placebo groups. The
`proportion of patients who experienced bradycardia was higher among patients in the
`group who received Dexmedetomidine-propofol compared with patients in the groups
`who received Dexmedetomidine alone, Dexmedetomidine-midazolam, and
`placebo-propofol. Sponsor states that as propofol is known to produce bradycardia,
`Dexmedetomidine may have had an additive effect. Tests of significance were not noted
`in the comparisons of Drug Interactions in the Phase II/III Continuous Infusion Sedation
`Studies.
`
`SECTION 8.11 DRUG-DEMOGRAPHIC INTERACTIONS
`
`Adverse events for the Phase II/III continuous infusion and the Phase II/III continuous
`infusion ICU sedation studies were analyzed to assess the potential effects of
`demographic characteristics including age and gender. The majority of the patients
`enrolled in these studies were Caucasian, precluding meaningful comparisons by ethnic
`origin.
`-
`
`AGE
`
`”
`
`“:7.
`
`Randomized Dexmedetomidine treated patients in the 36 to 55 year old age group had a
`higher number of reports of hypotension compared to placebo treated patients in this age
`group. Randomized Dexmedetomidine exposed patients in the 56 to 65 year old age
`group had a higher number of reports of hypotension and bradycardia compared to
`placebo treated patients in this age group. Randomized Dexmedetomidine treated patients
`in the >65 year old age group had a higher number of reports of hypotension and
`bradycardia compared to placebo treated patients, Mean changes from baseline to the last
`post baseline time point for hematology and chemistry values were analyzed by age
`
`
`
`
`
`

`

`
`
`
`
`103
`
`group. While there were some statistically significant differences between some age
`groups, there does not appear to be any clinically meaningful trends in the analyses.
`
`Table 45
`
`Summary of Most Common3 Treatment Emergent Adverse Events By Age
`Randomized Patients in Phase II/III Continuous Infusion Studies
`_— Randomwexmedexommne
`> 65 years
`18 - 35 years
`36 - 55 years
`56 - 65 years
`
`(N=458)
`(N=43)
`(N=297)
`(N=350)
`Adverse Event
`
`atients with at least one treatment-emergent
`24(56%)
`187(63%)
`l96(56%)
`289(630/6)
`
`dvetse event
`I
`
`‘ ypotension
`I ypertension
`
`"
`
`12(28%)
`3(7%)
`604%)
`30%)
`604%)
`1 (2%)
`502%)
`10%)
`10%)
`10%)
`10%)
`
`82 (28%)‘
`44(15%)
`5007%) ‘
`130%) “
`210%) '
`230%)
`220%)
`14(5%)
`90%)
`70%)
`3 0%)-
`4 0%)*
`40%)
`5(2%)
`014%)
`
`109131 %)~
`41(12%)‘
`3701%)
`22 (6%)’
`17(5%)
`12 (3%)'
`120%)
`110%)
`80%)
`80%)
`110%)
`60%)
`8(2%)
`3 (<1%)
`60%)
`
`‘ dverse Event
`Patients with at least one treatment-emergent
`adverse event
`
`l8 - 35 years
`(N=34)
`22(65%)
`
`36-55 years
`(N=l96)
`112(57%)
`
`56 - 65 years,
`(N=212)
`126(59%)
`
`Placebo
`
`-
`
`140(31%)‘
`. 67(15‘7c)
`5302%)
`41 (9%).
`16(3%)
`200%)
`15 (3%)
`180%)
`230%)
`15 (3%)
`100%)
`200%)
`15 (3%)
`90%)
`110%)
`
`‘
`
`> 65 Years
`(N=375)
`217(58%)
`
`I ypotension
`I )pertension
`'
`
`.
`
`,-
`
`
`
`4(l2%)
`4(12%)
`9(26%)
`2(6%)
`2(6%)
`3(9%)
`2(6%)
`l(3%)
`3(9%)
`2(6%)
`H3927)
`
`‘
`
`49 (13%)
`40(l9%)
`38(l9%)
`64(17%)
`39(l8%)
`28(14%)
`48(13%)
`26( 12%)
`22(1 1%)
`14(4%)
`5 (2%)
`4(2%)
`l9(5%)
`17(8%)
`24'( 12%)
`8(2%)
`19(9%)
`12(6%)
`l4(4%)
`8(4%)
`12(6%)
`8 (2%)
`9(4%)
`6(3%)
`21 (6%)
`11 (5%)
`8(4%)
`11 (3%)
`4(2%)
`5 (3%)
`7(2%)
`4(2%)
`7(4%)
`10(3%)
`8(4%)
`9(5%)
`15(4%)
`4(2%)
`0
`_ 3 (< 1%)
`1 (<1%)
`0
`'
`3(2%)
`8(4%)
`16(4%)
`
`
`'
`
`trial fibrillation
`10th dry
`Agitation
`Sponsor’s Table 49 188 8/10-239-145
`
`‘
`
`NOS = not otherwise specified
`a: Experienced by 22% of all dexmedetomidine-treated patients in Phase II/Il] continuous
`infusion studies
`
`* Statistically significant difference between randomized dexmedetomidine patients and
`placebo patients.
`
`

`

`104
`
`GENDER
`
`Randomized Dexmedetomidine treated patients who were male had a higher number of
`reports of hypotension and bradycardia compared to placebo treated patients who were
`male. Randomized Dexmedetomidine treated patients who were female had a higher
`number of reports of hypotension compared to placebo treated patients who were female.
`
`Table 46
`
`
`
`
`
`Adverse Event
`Patients with at least one treatment-
`
`Summary of Most Common“ Treatment Emergent Adverse Events By
`- " Gender: Randomized Patients in Phase II/III Continuous Infusion Studies
`
`Randomiud Dexmedetomidine
`
`
`Male
`(N=790)
`
`486(62%)
`
`
`Female
`(N=358)
`209(58‘7c)
`
`.
`
`Male
`(N=555)
`
`318(57‘7c)
`
`Female
`(N=262)
`159(6l%)
`
`
`
`2
`
`-
`
`
`
`
`
`
`
`
`
`
`
`Hemorrhage NOS
`
`
`Pain
`
`
`Rigors
`
`Atrial fibrillation
`
`
`Mouth dry
`
`
`Agitation
`
`
`
`259 (33%).
`84 03%)'
`91(16%)
`40(15%)
`
`112(14%)
`43 (12%)
`90(16%)
`45(17%)
`
`
`
`700%)
`76(2|%)
`500%)
`55 (21%)
`
`
`
`63 (8%)'
`‘ 16(4%)
`200%)
`5 (2%)
`
`
`
`450%)
`15 (4%).
`390%)
`23 (9%)
`
`
`
`470%)
`90%)
`320%)
`10(4%)
`
`
`
`30(4%)
`240%)
`22(4%)
`140%)
`
`
`
`33 (4%)
`11(3%)
`15 (3%)
`90%)
`
`
`
`170%)
`240%)
`15 (3%)
`28(11%)
`
`
`
`21(3%)
`fi 170 (3%)
`16(3%)
`6(2%)
`
`
`
`21(3%)
`40%)
`110%)
`80%)
`
`
`
`270%)
`3 (<1%)
`240%)
`3 (1%)
`
`
`
`250%)
`2 (<1%)
`150%)
`I
`40%)
`
`
`
`
`
`120%)
`5 (1%)
`1 (<1%)
`3 (1 %)
`
`
`
`23 (3%)
`60%)
`5 (1%)
`21(4%)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`_
`
`Sponsor’s Table 50, lSS 8/10-239-147
`NOS = not otherwise specified
`a: Experienced_flby‘_g>.‘2% of all Dexmedetomidine treated patients in Phase II/III
`continuous infusion studies
`I
`* Statistically significant difference between randomized dexmedetomidine patients and
`placebo patients. ?
`
`DRUG-DISEASE INTERACTIONS:
`
`Renal/Hepatic Failure:
`
`Based on Phase I studies in renal and hepatic failure, sponsor makes the following
`statements:
`-
`
`

`

`105
`
`In renally impaired subjects, Dexmedetomidine pharmacokinetics were not different
`compared to healthy subjects. Administration of Dexmedetomidine was well tolerated in
`the renally impaired subjects participating in the trial. In hepatically impaired subjects,
`the mean half life for the subjects with mild, moderate, and severe hepatic impairment
`was prolonged to 3.9, 5.4, and 7.4 hours, respectively, compared to subjects with normal
`hepatic function (2.5 hours). Consequently the dose of Dexmedetornidine may need to be
`reduced in subjects with hepatic impairment. A higher incidence of treatment emergent
`adverse events were reported among hepatically impaired subjects, including dry mouth,
`hypotension, and headache, compared with healthy subjects.
`
`Surgical Procedures: ,-
`
`Adverse events for the Phase II/III continuous infusionlCU sedation studies were.
`analyzed to assess the potential effects of the surgical procedures performed.
`
`APPEARS THIS WAY '
`0N ORIGINAL
`
`is
`
`’1
`
`

`

`
`
`106
`
`Table 47
`
`Most Common3 Treatment Emergent Adverse Events by Surgery Type:
`Randomized Patients in Phase II/III Continuous Infusion ICU Studies
`
`
`
`
`
`Other
`Laparotomy
`Cardiac
`Head and Neck
`
`(N=63)
`(N=95)
`(N=202)
`(N=27)
`
`
`
`
`Patients with at least one treatment-emergent
`
`
`144019?)
`[7(63‘7c)
`adverse event
`56(59%)
`42079:)
`
`
`
`
`
`
`
`
`5 (1970‘
`58 (29%)‘
`23 04%)'
`22 05%)‘
`Hypotension
`
`
`
`
`
`
`
`Hypenension
`800%)
`'31~(15%)
`004%)
`”(17%)
`
`
`
`
`
`Nausea
`”4%)
`“(15%)
`80%)
`209?)
`
`
`
`
`
`
`
`
`
`Bradycardia
`3 01%?
`”(50%)
`30%)
`10 06%)‘
`
`
`
`
`
`
`Mouth dry
`”4%)
`”(5%)
`l (1%)
`0
`
`
`
`Fever
`405%)
`2 (<I%)
`4(4%)
`803%)
`
`
`
`
`
`
`
`Vomiting
`“4%)
`11 (5%)
`401%)
`0
`
`
`
`Atrial fibrillation
`[(4%)
`”(6%)
`I (1%)
`1(2‘7r)
`
`
`
`
`
`
`
`
`. Hypoxia
`”4%)
`12(696)
`l (19:)
`20%)
`
`
`
`
`
`
`Anemia
`20%)
`30%)
`4(4%)
`20%)
`
`
`
`
`
`Pain
`0
`70%)
`o
`20%)
`
`
`
`
`
`Tachycardia
`20%)
`30%) -"'
`30%)
`4(6%)
`
`
`
`
`
`
`Hemorrhage not otherwise specified (NOS)
`0
`901%)
`20%)
`10%)
`, -
`
`
`
`Pleural effusion
`0
`60%)
`20%)
`O
`
`
`
`
`
`Hypovolemia
`[(4%)
`2 (<l%)
`l (1%)
`10%)
`
`
`
`
`
`
`
`Thirst
`0
`5 (2%)
`0
`3 (5%)
`
`
`
`
`
`
`Rigors
`2(796)
`I (<l9e)‘
`“4%)
`10%)
`
`
`
`
`
`Hyperpyrexia
`0
`1 (<1%)
`5 (5%)
`10%)
`
`
`
`
`Agitation
`20%)
`2 (<1%)
`107:)
`30%)
`
`
`
`
`Somnolence
`0
`10%)
`30%)
`0
`
`
`
`
`
`
`
`Atelectasis
`20%)
`2 (<1%)
`(1%)
`
`40%)
`Olizuria
`20%)
`
`
`
`
`
`
`Other
`Lapamtomy
`Cardiac
`Head and Neck
`(N=52)
`(N=87)
`(N2206)
`tN=34)
`
`
`
`
`
`
`Patients with at least one treatment-emergent
`
`adverse event
`
`34(65‘7c)
`44019:)
`143(69%)
`”(50%)
`
`
`
`
`
`Hypotension
`10%)
`3607*)
`5(6%)
`6( l 2%)
`
`
`
`Hypertension
`701%)
`32067:)
`18(21%)
`1 101%)
`
`
`
`
`
`
`24027:)
`8(9‘7c)
`40%)
`Nausea
`
`
`
`
`Bradycardia
`100%)
`0
`0
`
`
`
`
`Mouth dry
`40%)
`0
`0
`
`
`
`
`60%)
`Fever
`50%)
`2mm
`
`
`
`
`
`5(6%)
`Vomiting
`140%)
`0
`
`
`
`
`Atrial fibrillation
`13(6%)
`0
`
`
`
`Hypoxia
`100%)
`40%)
`
`
`
`
`Anemia
`60%)
`3(6‘7e)
`
`
`
`
`Pain
`70%)
`0
`
`
`
`
`Tachycardia
`70%)
`4(8%)
`
`
`Hemorrhage NOS
`12(6%)
`3(6‘7c)
`
`
`
`
`
`Pleural effusion
`2 (<1%)
`10%)
`
`
`
`Hypovolemia
`904%)
`0
`
`
`
`Thi:st
`1 (<15?)
`0
`
`
`
`
`5-
`”2..
`Rigors
`80%)
`107:)
`
`
`
`
`5 ' ‘
`Hyperpynexia
`50%)
`10%)
`
`Agitation
`60%)
`2(4%)
`
`
`
`
`-
`0
`Somnolence
`60%)
`
`
`
`
`0
`‘ , -
`20%)
`Atelectasis
`9(4%)
`
`
`
`
`
`0
`_—
`10%)
`‘V
`Olinuria
`2(<1%)
`
`
`
`»
`Sponsor’s Table 53 188 Vol 8/10-239-154
`‘
`a: Experienced by 2 2% of all dexmedetomidine-treated patients in Phase II/III
`continuous infusion ICU sedation studies
`
`‘
`
`
`
`
`
`
`
`*: Statistically significant difference between randomized dexmedetomidine patients and
`placebo patients.
`
`
`
`

`

`107
`
`Hypotension was significantly more common among all surgical groups receiving
`Dexmedetomidine as compared to placebo patients. Bradycardia was more common in
`the Head / Neck and Other surgical groups receiving Dexmedetomidine versus the
`placebo counterparts. The Dexmedetomidine patients in the Cardiac Surgery group had
`less rigors compared to the Cardiac Surgery patients receiving placebo.
`
`SECTION 8.12 ' LONG TERM ADVERSE EFFECTS
`
`Sponsor reports that no obvious long term adverse effects have been associated with
`Dexmedetomidine administration. For the Phase H/Il] continuous infusion ICU sedation
`trials from the Abbott sponsored studies (exclusive of Japan), the total listing of.all.
`Serious Adverse Events reported for subjects/patient includes events from the time
`informed consent—is signed to at least 30 days after participation in the Abbott sponsored
`trials. Long’t'erm administration studies of Dexmedetomidine have not been conducted.
`
`SECTION 8.13 WITHDRAWAL EFFECTS
`
`Sponsor reports no withdrawal effects have been noted during the conduct of the
`Dexmedetomidine clinical programs.
`
`SECTION 8.14
`
`120 SAFETY UPDATE
`
`Sponsor states studies whose databases were not locked or that were ongoing at-the time
`of the NDA submission and studies initiated after the submission are included in the 120
`Day Safety Update. 3 Phase I and 4 Phase II studies are included; there are no Phase III
`studies in the presentation. Since the submission of the NDA, 159 subjects/patients have
`been enrolled in clinical studies conducted in the United States, Canada, and Europe. The
`sponsor appears to have provided safety information on 87 patients/subjects exposed to
`Dexmedetomidine in the 120 Day Safety Update presentation. Because of the limited
`number of new-patients exposed to Dexmedetomidine since the NDA submission, the
`Sponsor did not integrate the new data with the data submitted in the NDA.
`
`The Phase I studies:had 3 premature discontinuations after exposure to
`Dexmedetomidine. The Phase II studies had no one discontinue prematurely but—2 deaths
`did occur. The deaths occurred in studies that remain blinded therefore treatment
`exposure is not clear. A request has been made to sponsor for Case Report Forms on the
`discontinuations.
`'
`
`The adverse events reported in the presentation are similar to that reported in the
`Integrated Summary of Safety: hypotension, hypertension, and bradycardia. Other
`adverse events reported were headache, nausea, and dry mouth. The occurrence of these
`
`
`
`

`

`
`
`
`
`_,
`
`108
`
`events appears Similar to placebo treated individuals although tests of significance were
`not performed.
`
`SECTION 8.15 .- SAFETY DISCUSSION»
`
`Sponsor claims the safety profile of Dexmedetomidine has been evaluated in more than
`3300 patients in clinical studies conduc