5.6.3
`
`Other Safety Issues
`
`Significant insights into exposure response and PK/PD relating to safety were gleaned from several
`phase I trials. Originally the reviewer was told not to review these studies (i.e. early phase I studies,
`studies of development formulations, and the QT study) and the reviewer had to agree in writing, however
`the reviewer included the provision that if any information pointed to the need to examine these studies in
`more detail then this reviewer would do so.
`
`Review of the PET studies indicated dose and time dependent hepatotoxicity had been seen with high
`oral doses. However review of the original data was not pursued by this reviewer, rather the medical
`officer was informed. Then on April 10, 2008 while checking the history of the formulation for the
`executive summary of the review (i.e. §2.2.3 Pertinent Clinical Pharmacology and Biopharmaceutic
`Questions) this reviewer sereptitiously came across descriptions of serious cardiotoxicity in the early
`phase I studies. Since a potential myocardial infarction was identified in the paroxetine drug-drug
`interaction study (25525) that was dismissed as musculoskeletal in origin, this reviewer examined these
`cases more closely prior to communication with the medical officer. It was then noted that some of these
`serious cardiac toxicities were noted in the QT study but that they hadn’t been highlighted and had been
`explained largely as vasovagal in origin, While looking into the cardiotoxicity issue additional pertinent
`information on hepatotoxicity came to light.
`
`Upon further examination of the various study designs it was noted that virtually all studies used low
`doses of short duration and tended to avoid subjects who might be at increased risk of hepatotoxicity. In
`addition in those studies where the risk might be apparent, i.e. the QT study and the adolescent study
`laboratory and other data were not reported so that a safety assessment could not be performed. In
`addition, the medical team leader requested a review of the adolescent study on Friday April 11, 2008
`immediately prior to the DFS due date (April 14, 2008) when a quick review was likely to overlook this
`important safety information, (see §6.6 April 11‘, 2008 Consult Request from Medical Team Leader).
`
`Vtfith regards to cardiotoxicity there appears to be a high incidence of AV block with junctional rhythms.
`Thus the vaso—vagal explanation for the large number of subjects fainting is suspect. Generally this is not
`a great concern clinically however, in the elderly and in the presence of certain other drugs this could be
`quite important. This asw well as the risk of agranulocytosis may explain why the sponsor did not include
`data in elderly subjects in this submission.
`
`A synopsis of a PK study in the elderly was accidentally found in the 120 day safety report several levels
`down under a folder for an efficacy study. This study synopsis was only identifiable by a study report code
`without a title and was only looked at because the study code did not match the study code for higher
`level folder. As with the adolescent study only mean PK data was provided without any safety information
`or laboratory values.
`
`Abbreviated information on these serious AEs follow:
`
`NDA 22-117 - Asenapine — Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 415 of 520
`
`

`

`5. 6.3. 1
`
`Hepatotoxicity
`
`5.6.3.1.1
`
`Single Rising Dose Oral Study 85029
`
`The clinical study report for study 85029 was dated November 1989. However based on the study title,
`(A Phase I, double-blind, placebo controlled, single rising oral dose study with Org 5222 in healthy male
`volunteers to assess tolerance and safety), it appears to be the first in human study. In the background
`information for this study, dose and time dependent hepatotoxicity in dogs were noted as shown in
`Figure 197.
`
`Figure 197 Background Information on Preclinical Safety for First in Man Study - Study 85029
`
`.31,» 1.3 week oral taxicologiml study in dogs has been
`
`amylamfiw
`
`image used were 1.2a, 1.5 and: 20 figflcgfdagpn
`
`Interim analysis was performed after one month because in
`
`preview; studies the. times: dram {2p mgjkgffiéay} still causati-
`
`hepatatexiflity.
`
`me.
`
`interim anatysiza am not
`
`show any
`
`ahwmatity of some himtmmiaa;
`
`(in. particular platens. liver
`
`enzyme concentrations} and haematological parameters in the
`
`LIE amt ”1.5 mgfkggday grmps,
`
`In the 213 mgfkgfdfiy group a
`
`flight
`
`increase.
`
`in plasma livaz‘ enzyme mncautx‘a‘tiohs was
`
`Eli—sited; although the, values observed were still within
`
`normal limits.
`
`The final analysis of this study indicated
`
`signs ef hegetetoxicity in some {but not: all} dogs treated
`
`with 5&5 and at} ngxkgfday; Ha imitations of newsstand-zigzag;
`tiara apparent
`in the 1.25 mgjkgjday {toga group; of dag-a.
`
`With“ reprodurzfive toxieM-agical.
`
`31:31:? antigenicity studies
`
`revealed any eimfztfl which preclude evaluation in: man,
`
`No significant adverse events were reported for this trial.
`
`NDA 22—117 — Asenapine - Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 416 of 520
`
`

`

`5.6.3.1.2
`
`PO MRD PK SIT Study 85136
`
`Although this clinical study report, (Feb 3, 1988), predates the previous study report. The title, (A Phase I,
`double-blind, placebo controlled, sub—chronic study with increasing doses of Org 5222 up to 30 mg daily
`in healthy male volunteers) and other indicators suggest that study 85136 was the second study in man.
`
`The sponsor’s conclusions that are shown in the following figures clearly indicate a close and time
`dependent direct hepatocellular hepatotoxicity (see Figure 198 to
`
`Figure 200), and that occurs sooner with higher doses and later with lower doses, (is. as soon as Day 2
`with 20 mg PO BID and no sooner than day 10 with 10 mg PO BID and below), (see Figure 201).
`Although transaminases declined with drug discontinuation in two of the nine subjects LFT increases
`were greater than 3 fold, (see Figure 202 and Figure 203).
`
`Figure 198 Sponsor’s Safety Conclusions Regarding Hepatotoxicity — Study 85136
`
`1"
`
`Confiirmiaa
`
`it DEG 3222 tweed mitéfi to moderate liver :egyma increases
`
`mommy mm to direct hsmmceituiar toxicity.
`
`Figure 199 Sponsor’s Safety Conclusions Regarding Hepatotoxicity (Continued A) — Study 85136
`
`In sfimmary, 9 out of 2!} subjects given active: medieafim developed
`
`chafigfifi
`
`in News;
`
`liver enzymes. during the sway.
`
`Three, of 5.53.
`
`Sfifikfim who received the highest dosage of ORG 5.222 experienced
`
`abandon of 3331* mash: AL? to gar-eater
`
`that; swim the anger rim:
`
`of normal.
`
`Cine of B ptsceho assigns her: an elevated alkatine
`
`phosphatase throughout
`
`the study 9.31:! had a singte mildiy eievawd
`
`MS? have} recorded.
`
`Figure 200 Sponsor’s Safety Conclusions Regarding Hepatotoxicity (Continued B) — Study 85136
`
`“affix: flatten: of smarts-e changes ~ cicadas: 13f
`
`transaminases with
`
`normaf alkaline: ghosphaitssa andé no fibsempanyieg rig»:
`
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`
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`
`toxicity rather than
`
`shalestaais as,
`
`the undertying machanixm. Enzyme induct-ion atom
`
`is waits-sly to have caused Staci: shangas in the plasma liver
`
`«enzymes,
`
`NDA 22—1 17 — Asenapine - Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 417 of 520
`
`

`

`
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`

`Figure 202 Plot of Significantly Elevated Liver Function Tests (> 3X ULN) vs. Time - Case 1 —
`Study 85136
`
`an M1! mu ”an” mu ml! an! Inga
`
`Study Bey
`I + amine m:
`
`Figure 203 Plot of Significantly Elevated Liver Function Tests (> 3X ULN) vs. Time - Case 2 —
`Study 85136
`
`inEFmFfihetinn Tests
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`
`NDA 22—1 17 — Asenapine — Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 419 of 520
`
`

`

` 5.6.3.1.3 Pivotal BE_Study ___ ;
`
`
`'
`lbw) Study 41026
`
`
`
`
`Study 41026 was a
`' otal _b_VioequivaIence study of a sublingual tablet manufactured by
`(W (4) to the
`(4) clinical trial formulation. The reason given for this proposed changeIn
`,
`
`formulationwas that
`pine maleateIS bitter and this may improve the organoleptic characteristics.
`
`
`ThisIs reasonable as a slower dissolving tablet would minimize the bitterness However, the
`(4I
`
`:
`' bI(4I tablet was bio--inequivalent presumably due to the slower disintegration and dissolution
`resumngin more drug being swallowed.
`
`Subject 19 had elevated ALAT levels from Day 2 after treatment with the I tablet which
`
`5.6.3.1.4
`
`Paroxetine Drug Interaction Study - Study 25525
`
`In study 25525 subject 15 in sequence A dropped out due to elevated ALAT (main reason) and elevated
`ASAT at Day 15. The ALAT concentration increased to a maximal value of 474 U/L at Day 16 (Upper
`Normal Limit (ULN): 50 U/L). ALAT increased the day after paroxetine administration and 4 days after
`administration with dextromethorphan raising the concern that there may be increased risk of toxicity
`when administered with other drugs, whether this is due to interactions via CYP2D6 and shunting or
`pharmacodynamic interactions cannot be discerned from this study.
`
`Several other subjects had lessor degrees of increases in ALAT and ASAT, (see Figure 204 and Figure
`205).
`
`Figure 204 Text from Paroxetine DDI Study 25525
`
`Seven elinieeilv releverit abnormalities IIere ebeerweciin Sequence A
`
`Subgiect [212. had elevated ALAT {T3 UH.) and ASAT 1:188 LUL) starting at 3331" 1?, one
`day after administration ot’ the last trial medication in Sequence A. Both elevations
`were judged probable reieted to the trial meadilce’tien and of mile intensity. Ten days
`later ALAT and ASAT concentrations were decreased within normal ranges to 2‘1 and
`46 UfL, ‘respeotiveiy (ULNVS- for ALAT and ASAT are 50 UK. anti 49 UI‘L, respectively}.
`
`hec’i elevated ALAT {E59 WM starting at Day 1?, one day after
`F35
`Subject
`administration of the last triai medication in Sequence A {jueged possibly related to
`the triei medication and o?” miEd intensity Six days tater the ALATwas 85 UIIL
`deciining in EU UI‘L after i4 day's figurigeti to be abnormal but not clinieeily Ieievant).
`
`Su=b§eot 32 had an elereted cholesterol leveésj 8.4 mnnoliL) starting at Day §T one dew
`aft-er administration of the last triai medicationIn Sequence A {judged un Eiketi11 related
`to the triai meriicetiee and of miid intensrty}. Six {33yrs later the molesters! levei was
`decreased to 5.9 remote {judged to be ~ebnorn‘Iel but not ciinically reievant}.
`
`Subject 15 had an eievateci ALAT concentration {‘58 WE} starting at Day I", after 3
`days of efimiafistration 431’ i, 3 anti 5 mg asenapine bid, respectively (judged
`probabiy related to the triaal medication and o? .mederate intensity). The eLAT
`concentration increased to a ntaximei value of 4T4 $.92. at Day 113. Sebsequentiy, the
`ALAT concentration cieciined to T8 UIL in 14 days f§udged to be abnormei but not
`clinically retevanti Administration of trial medication was endetl after dosing of 5 mn
`PPR-CF Peg-or; Tempfaie 19‘ idly 2131335
`Report. versien ’s'fi Finat, June 2. ”BECKE-
`
`NDA 22-117 — Asenapine - Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 420 of 520
`
`

`

`Figure 205 Text from Paroxetine DDI Study 25525 (continued)
`
`aaenapihe in the. morning of Day :5 Subject '15 had an elevated ASA? cencantration
`
`(53 UFL} starting at Day 13, after 6 days of administration of asahapine Elm, (jadged
`pmbabiy related to the trial, medication am? of mid intensity}. Twa days iater the ASAT
`
`was 13’? U11. declining ta 44 Llfl. in 8 days gaining-eat to be abnormal but not ciinirzalzly
`relevant}.
`
`85%}: starting at Bay '3', after 3 days at
`Subject 114 had ale-rated ALA? [31159
`administratioai at l 3 and 5 mg asenaplme bid“, respectively, {judged probably
`
`related to the trial medication Rite of immigrate intensity}. From Day 26 the AMT
`destined to 59 gUfE. 3’ days later [judged ta be abrtormal but not eiinécatiy relevant),
`
`Ne cééaically relevant: abnormalities were observed in Sequence 3.
`
`5.6.3.1.5
`
`Thorough QT Study - Study A7501001
`
`When examining the population pharmacokinetic report this reviewer observed that there a number of
`subjects with elevated bilirubins. The majority of these elevated bilirubins were in the thorough QT study.
`The medical reviewer was notified and lab values were requested from the sponsor, (see section 6.4
`Identification of Elevated Bilirubins and Medical Reviewer Notification and the Pop PK Thorough QT study
`A7501001 in section 5.6.1.3 because it was reported over 4 different study reports.
`
`There is some confusion regarding the units reported for some of these studies and whether conversion
`was done appropriately. However, what’s disconcerting is that the sponsor only reported laboratory
`values from before and after treatment and not during treatment.
`
`5.6.3.1.6
`
`Relative BE Study New Formulation - Study 41009
`
`This was a comparison of different polymorphic forms. One subject (0002) had ALT elevations of 5 fold
`ULN and a second subject (008) had ALT elevations of 3 fold ULN.
`
`NDA 22—1 17 — Asenapine - Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 421 of 520
`
`

`

`5.6.3.2
`
`Cardiotoxicity
`
`A number of cases of serious cardiotoxicity have been found in young healthy volunteers. These include
`myocardial infarction, AV block with junctional rhythms, and Afib. In addition a there have been a number
`of reported cases of tachycardia as well as bradycardia and syncope.
`
`Some of these are reported in the QT study report but were not highlighted by the QT team.
`
`it appears that there may be a concentration dependent effect on AV conduction that occurs at higher
`doses than QT prolongation, thus explaining the QT effect at the lower close but not at the higher dose.
`Whether this is due to differing effects at different concentrations and/or due to a metabolite formed via
`first pass from swallowed drug is presently unknown. if there is AV block we might expect to see a
`shortened QT at higher exposures.
`
`There is also some indication that the cardiac toxicity may be worse in individuals taking other drugs that
`might effect cardiac conduction or CYP2D6, e.g. paroxetine, etc.. Thus the risk with concomitant drugs
`such as lithium, paroxetine, carbamazepine, dextromethorphan, OTC sympathomimetics etc. needs to be
`investigated and assessed
`
`In study 25509 the sponsor indicates that the asenapine is unsafe at drug exposures obtained with
`clinical dosages and due to cardiotoxicity and direct hepatotoxicity.
`
`The fact that little information is included in this NDA regarding expected combination use with other
`drugs or use in women or the elderly and the increased risk the elderly have with this type of arrhythmia
`indicates further safety assessment is needed if development of the compound is pursued.
`
`Additional information on events indicative of cardiotoxicity follow:
`
`A summary of the selected cardiac AEs that were found in the limited time available (2 days) are shown in
`Table 192.
`
`NBA 22-117 - Asenapine — Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 422 of 520
`
`

`

`5.6.3.2.1
`
`IV Study - Study 25506 - Nov 1992
`
`Study 25506 was a pharmacokinetic study of intravenous administration of asenapine at four different
`doses, with each dose to be administered to two healthy male volunteers which was then to be followed
`by a pilot bioavailability study of 30 mg orally in the two volunteers who received the highest tolerated
`intravenous dose.
`
`The study was stopped after the first two subjects due to asystole requiring external cardiac massage and
`atropine, Although attributed by the sponsor to a vasovagal effect, an external cardiologist deemed it a
`serious AE of asenapine affecting the conducting system of the heart, (see Figure 206 to Figure 211).
`
`What is particularly worrisome is that this occurred at a dose of 0.7 mg shortly after a 30 minute infusion
`in a young healthy individual with no evidence of any cardiac disease. V\fith an average absolute
`bioavailability of 33% (and up to 50%) this translates into a sublingual dose of 1.4 mg - 2.1 mg and is
`unlikely due to metabolites. Thus arrhythmias are a concern with clinical doses.
`
`Figure 206 Text from IV Study 25506
`
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`
`Figure 207 Text from IV Study 25506 (Continued)
`
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`NDA 22—1 17 - Asenapine — Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 423 of 520
`
`

`

`Figure 208 Text from IV Study 25506 (Continued)
`
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`NDA 22—117 - Asenapine — Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 424 of 520
`
`

`

`Figure 210 Cardiologist’s Report from IV Study 25506
`
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`
`NDA 22—1 17 - Asenapine - Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 425 of 520
`
`

`

`Figure 211 Cardiologist’s Report from IV Study 25506 (Continued)
`
`kiwrwfilr. ”5&3 glmaa: acg-r‘Lgfigil} ragga L4} {31:- alwsaed am a; drug irédiimzd‘ Effie-3:, 33:2;
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`NDA 22—117 - Asenapine - Original Submission —— OCP Review
`5/15/2008 11:20:41 AM
`
`Page 426 of 520
`
`

`

`5.6.3.2.2 Multiple Rising Oral Dose Study - Study 25501 —
`June1993
`
`Study 25501 was a multiple rising dose study to examine the pharmacokinetics in 12 young, healthy,
`male volunteers using Org 5222 both after a single oral dose (30 mg) and at steady state (5 days, 15 mg
`twice daily orally).
`
`One subject had asystole for 8.7 seconds with a junctional escape rhythm. Even though this was a single
`oral dose of 30 mg and the asenapine exposures was low compared to what is typically seen with
`sublingual dosing, the N—desmethylasenapine exposures were similar to those seen in multiple dose
`studies with sublingual dosing, (see Table 191). It’s noteworthy that the sponsor did not include the data
`range for the most important study in any of the summary tables for the pharmacokinetlcs. In addition, the
`study durations were short, (5 and 6 days), and with a half—life in some cases of a couple of days and
`likely time dependent kinetics for desmethyl-asenapine the true exposures at steady—state are likely
`underestimated.
`
`Figure 212 Text from P0 MRD Study 25501
`
`A previous study showed that multiple dosing with Org 5222 15mg twice daily for six or
`
`more days increased serum alanine aminotransfemse and aspaitate aminotmnsfemse in three
`
`out of six healthy, male subjects.
`
`Figure 213 Text from P0 MRD Study 25501 (Continued)
`
`in a pffi‘k’iflufi study at {313.3% Eustavensus 01g 5222. was asmmatetl with a carats: attest.
`
`Afifir amt ssmiaamiim ma bimvaiiabifiity of Qrg am as mama: it: most subjscts.
`
`Figure 214 Conclusions from P0 MRD Study 25501
`
`
`
`
`
`
`
`the single, era} dose sf org 5222 to the six subjects of
`Aft
`the first grads,
`the stufiy was tsrminated sue to a sariaus
`adversa event it: sine subject.
`‘
`was hsurs, 25 minutes past dosing the suhfieet sufifered an 8.?
`second asystalic episode followed by junefiisnal escape rhythm
`until sinus rhythm.wss restated. a subsequent 24-hour ECG was
`normal and no abnarmaiities Were detected on ache
`cardiagrayfiy. Thsre were no other serious events. In general,
`subject’s supine based pressure ans pulse rate shaved unly the
`randem flustuatiuns expected. Apart from the subject who
`suffered the asystuiie episuée, there'were as clinically,
`signifisant nhangss in the lawless—ECG recordings following
`92g 5222 in the S ether subjeatsi share ware no clinically
`significant: abnarmalitias can either physimai examination,
`multistixm urinalysis, clinical chemistry or haematology,
`
`NDA 22—117 — Asenapine — Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 427 of 520
`
`

`

`‘Figure 215 PK from P0 MRD Study 25501
`
`Wee,
`
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`
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`
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`
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`
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`
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`
`3.33 the six 3133318335
`
`Table 191 Comparison of Selected Pharmacokinetic Metrics for Study 22501 and Multiple Dose
`PK Studies.
`
`_.
`X6days'
`
`'10mg‘s‘LBID
`x5days
`
`039+018
`0,—14 0.88
`
`5.5732 36
`0,—94 881
`
`8.84
`2.17-155
`
`3731.2
`1.-9 5.0
`
`2823:1330
`6—0 535
`
`37.3
`18-5 581
`
`
`
`3.8 :l: 0.62
`3.33 - 4.93
`
`3.14312
`0.48 — 5.16
`
`Desmethyl-
`Asenapine
`
`a
`
`
`
`
`
`
`
`
`Text'in red was not reportedin clinical study report or in any summary tables had to be extracted from raw data
`For single dose study AUC= AUCinf
`
`1.33
`1.23 - 1.42
`
`44.1:i:10.8
`29.8 — 58.4
`
`31.81143
`4.7 —- 53.8
`
`12.7
`11.0 - 14.4
`
`NDA 22-117 - Asenapine — Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 428 of 520
`
`

`

`5.6.3.2.3
`
`Initial SL Single Rising Dose Study - Study 25509
`
`The following is the background safety information from the initial sublingual dose study with a dose
`range of 10 - 100 mcg, (see Figure 216 and Figure 217).
`
`What noteworthy about this summary is that it is precludes chronic Lei dosing of greater than 4 mg / day
`due to safety reasons, which is equivalent to 8 — 12 mg /day administered sublingually. in addition it
`indicates that subjects with high Cmax’s have serious AEs, and that interindividual variability results in
`greater risk in some individuals. Although it’s reported that high Cmax’s are potentially related to serious
`AEs individual Cmax’s from these studies are not reported and it’s unclear if this is related to asenapine
`or desmethyl-asenapine concentrations.
`
`This was another study that this reviewer was told not to review as it did not include the proposed clinical
`dose range.
`
`Figure 216 Text from SL SRD Study 25509
`
`3 .2,
`
`Summary of retevant safety data
`
`(brig SL594 appears to be safe in endocrimiogisat, biochemical anti haematotogical terms,
`
`hewever single: high doses cf Qrg 5134 may induce sardicvascuiar arts/arse experiences in
`
`animals and humans.
`
`Singic 305:: M. administration of Org $1194 to rats at dose levels up to 21 mglkg caused
`
`no mafiaiities but was emaciated with neuroéogicaE sympmmst The L»: toxicity studies in
`
`rats and dogs, with daily administration fer 2 ”wrecks at (3058 tevets up to 3 mglkg caused no
`
`overt signs of toxicity, Results from sardtotoxécity studies strggcsted that Org SL94 may
`
`cause postural hypotension at high dosasi
`
`In the £11§tiai Phase: 1 studies in healthy mate voiumeers, singie oral doses up to 30 mg Org
`
`3134 did mt cause: any safety prebtems. In a two week muitiple arise: study oral doses up
`
`to 15 mg twice daily were administered Time and dose dependent increases in AL? and
`
`AST serum isvels were observed.
`
`in two subsequent Studies with heating! make vciun'teers, two serious adverse experiences
`
`(SAES) were observed. The first SAE (cardiac arrhymmia — asystole) occurred 15 min
`
`after the iv; infusion of Q7 mg {kg SL534 (given. over 30 rain), when the sntajeet was
`
`asked to sit up. "He: required brief enema? cardiac: massage and atropine and made a fuli
`
`NDA 22—1 17 - Asenapine — Original Submission - OCP Review
`5/15/2008 11:20:41 AM
`
`Page 429 of 520
`
`

`

`Figure 217 Text from SL SRD Study 25509 (Continued)
`
`recovery. He was never unconscious for more than 30 seconds: The second SAE occurred
`
`2 h 35 min after a single oral dose of 30 mg Org SL94' without an obvious precipitating
`
`factor, This sub}ect coiiapsed whilst already sitting and recovered spontaneousiy. His ECG
`
`at the time of the coiiapse showed a prolonged sinus pause. The pharmacokinctic {emits
`
`revealed large inter—individual variation in oral {kg $1.94 piasma icvels and relatively high
`
`(‘1‘Rm values were. obsetved in the ”individuals exhibiting serious adverse events. I-{oweven
`
`in view of the Iimited data it
`
`is not possible to draw definite conclusions as to the
`
`quantitative relationship between Crm and the SAE. The oral bioavaiiability of Org 81.34
`
`was calcuiaied to be approximateiy 1%.
`
`Three I’hase II studies have been; conducted with orally administered Org SL534 in the
`
`treatment of schizophrenic patients. The rcsults indicate that the highest dose applicd (4
`
`anglclay) may be considered the minimai effective dose. No safety problems were
`
`encountered.
`
`From a safety point of View, chronic administration of dam higher than 4 mgfday is
`
`precluded for two reasons:
`
`I) the risk of hepatotcxicity 2’) dab to the fact that Eow orai
`
`bioavaiiabiiity piedisposes to highiy variable piasma levels, patients may hit out at
`
`increased risk for cardiovascular adverse cxgeriemtcs.
`
`5.6.3.2.4
`
`- Study A7501015
`The sponsor states that there were 12 serious AEs however other than indicating the number of AEs they
`are not identified in any way. In addition two subjects withdrew due to "hypotension" 2 withdrew consent
`and 2 for other reasons however they were not identified so even the hypotension cannot be verified.
`
`Pivotal BE Study
`
`In the background information the co—sponsor (Pfizer) identified the above cardiac arrhythmias as
`Neurally Mediated Reflex Bradycardia, (see Figure 218). It is inconceivable to this reviewer how the
`sponsor can make this statement.
`
`Figure 218 Pfizer’s Discussion of Previously Observed Cardiotoxicity — Study A7501015
`
`In early trials; a total of 4 young healthy an e volunteers experienced an lmtowarcl adverse
`experience identified a5 Naturally Mediated Reflex Braclytmdia lfim) with sumspause; its:
`1 subj eat after receiving 0.15 mg asenapine by the sublingual route. 1 after receiving placebo Via
`the subiingual route, 1 after receiving 30 mg via the oral route: and one 4.3 minutes after
`rec Biking 0.? 1115330 min asc’napine intravenous. All occurred after the first dose and after
`postural challenge. This reflex is seen in 59’6—10‘3‘6 of the general population and is benign and
`self-homing.
`It. occurs typically secondary to postural Changes, younger age, and high waged tone
`(low resting heart rate}.
`
`NDA 22-117 — Asenapine - Original Submission — OCP Review
`5/15/2008 11:20:41 AM
`
`Page 430 of 520
`
`

`

`5.6.3.2.5
`
`Pivotal BE Study (TBM vs. CTF) - Study A7501016
`
`Study A7501016 was a pivotal bioequivalence studyof a_T-oBe-Marketed formulation using;
`e CIInIcal-
`'
`
`
`
`' (b) 4 ormulatIon that used "
`
`
`
`The following is from the clinical study report:
`
`“During telemetry monitoring, 10 subjects experienced bradycardia; eight subjects experienced
`tachycardia; seven subjects experienced sinus pause, 3 subjects experienced junctional rhythm; and 1
`Subject experienced bradycardia with junctional rhythm (Appendix 89.3).”
`
`This was a single dose study with a 5 mg dose that included both healthy men and women. Due to the
`lack of time further evaluation was not feasible but needs to be done, including evaluation of exposure
`response.
`
`5.6.3.2.6
`
`V’Piv
`
`t IBE Study— Study 41026“
`
`
`
`
`For study 41026 with single 5 mg doses and low bioavailability in young healthy volunteers the sponsor
`reported a variety of AEs that may be indicative of cardiotoxicity. The sponsor’s descriptions follow: It's
`unclear if these are the same or different subjects and if they refer to the same AEs or not. A minimum of
`4 subjects