’ CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`2 1 -729
`
`MEDICAL REVIEW
`
`

`

`M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`October 12, 2004
`
`FROM:
`
`Thomas P. Laughren, M.D.
`Team Leader, Psychiatric Drug Products -
`Division of Neuropharrnacological Drug Products
`HFD-120
`
`SUBJECT: Approvable Action for Aripipazole Orally Disintegrating Tablet (ODT)‘ —
`strengths (- 10, 15, 20, and 30 mg)
`
`TO:
`
`File for NDA 21—729
`
`[Note: Should be filed with 12—22-03 original submission]
`
`Background
`
`Abilify (aripiprazole) is currently available in oral tablet strengths (5, 10, 15, 20, and 30 mg) for
`the treatment of schizophrenia (approved 11—15—02, under NDA 21—436). This application
`provides data in support of an orally disintegrating aripiprazole tablet, ‘_—-
`for
`the same indication.
`The clinical program for this new formulation consisted of —
`bioequivalence studies (CN138067 —— that demonstrated equivalence between this
`new ODT formulation and currently approved tablets. These studies were conducted under IND
`62,181.
`
`The pharmacokinetic data in this application have been reviewed by Kofi Kumi, Ph.D., from
`OCPB, and the clinical data have been reviewed by Greg Dubitsky, M.D., from the clinical group.
`No new phann/tox data were submitted as part of this application, however, brief comments on
`pharm/tox issues have been submitted to the file by
`Sonia Tabacova, Ph.D.,
`from the
`pharmacology group. The CMC data for this application have been reviewed by Gurpreet Gill-
`Sangha, Ph.D., from the chemistry group.
`
`The sponsor’s proposed dosing for this new formulation is identical to that for the currently
`approved oral tablets.
`'
`
`Pharmacokinetic Findings
`
`The clinical program for this new formulation consisted of— bioequivalence studies ‘ ——
`
`“—— CN138067 —— were the definitive BE studies, and
`they compared the highest — strengths of the CDT formulation and the currently approved
`
`

`

`tablets (i.e., 30 '-—— , and bioequivalence was demonstrated~ OCPB also
`recommends that we accept the requested waiver for the 10, 15, and 20mg strengths. In these BE
`studies, the CDT tablets were administered without water, i.e., there was no treatment arm “with
`water” to test that method of administration. No food effect study was requested, since such
`studies have been conducted with the conventional tablets at 15 and 30 mg strengths. OCPB has
`also proposed dissolution specifications, and we are awaiting confirmation from the sponsor
`regarding acceptance of these revised specifications.
`
`Pharmacology/Toxicology Findings and Issues
`
`No new pharm/tox data were submitted with this application.- The only possible phann/tox
`- concern would be the question of whether or not toxic adducts might form by interaction of either
`of the two major excipients for this formulation with other ingredients in the formulation. The two
`major excipients are aspartame and crospovidone. Crospovidone is an inert polymer that is not
`absorbed.
`Apparently, compatability data for crospovidone with other ingredients of the
`formulation have been provided and reveal no concerns.
`In addition, crospovidone has been used
`as an inactive ingredient in many approved products at much higher doses than would be used'in
`this product. Aspartame is a bod additive, and compatability data for this excipient with other
`ingredients of the formulation have not been provided. Thus, compatability data would need to be
`provided for aspartame before final approval.
`
`CMC lssues
`
`The only CMC issue I am aware of is the fact that aspartame is a major excipient, and therefore,
`needs to be mentioned in labeling.
`In fact, they have included this fact in Precautions, Information
`for Patients, as required by regulations. Thus, in my view, this issue has been addressed.
`
`The proposed name Abilify Discmelt has been deemed acceptable by DMETS.
`
`Clinical Review
`
`There were no safety findings from the 3 clinical studies that would suggest any added risk from
`this new formulation. There was no need for efficacy data since efficacy was extrapolated from
`existing data.
`'
`'
`
`DSl Review
`
`One of the 2 pivotal BE studies was inspected (CN 138067), and was acceptable except for
`concentration data for 3 subjects. OCPB has analyzed the data with and without the data for these
`3 patients, with similar results.
`
`

`

`Labeling
`
`-— The
`OCPB has recommended a very modest change to labeling regarding dosing with
`sponsor has proposed that the ODTs can be taken with or without - Since the BE studies did
`not include “with -' ” arms, OCPB recommends taking without -' ', but nevertheless, adds
`that they can be taken with '_ if needed.
`I don’t object to this modest change.
`
`PREA Requirements
`
`We are recommending waiving these requirements since a pediatric program is already underway
`for the tablets.
`
`Conclusions/Recommendations
`
`I agree that this application is approvable, and I recommend that we issue the attached 'approvable
`letter with draft labeling, in anticipation of final approval.
`
`cc:
`
`’ Orig NDA 21—729/Aripiprazole ODT
`HFD- l 20/DivFile
`HFD- 1 20/TLaughren/RKatz/PAndreason/GDubitsky/SHardeman
`
`DOC: Memo Aripiprazole ODT AE1.doc
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Thomas Laughren
`10/12/04 03:48:34 PM
`MEDICAL OFFICER
`
`

`

`REVIEW AND EVALUATION OF CLINICAL DATA
`
`Application Information
`
`NDA# :
`
`Sponsor:
`
`Due Date:
`
`Drug Name:
`
`Generic Name:
`
`Trade Name:
`
`Drug Categorization:
`
`21—729
`
`Otsuka America Pharmaceutical
`
`October 22, 2004
`
`Aripiprazole Orally
`Disintegrating Tablets
`
`ABILIFY DISCMELT (proposed)
`
`Pharmacological Class:
`
`D2 Receptor Partial Agonist
`
`Proposed Indication:
`
`Schizophrenia
`
`Dosage Forms:
`
`Route:
`
`‘- 10, 15, 20, and 30mg
`
`Oral
`
`Review Information
`
`Clinical Reviewers:
`
`Gregory M. Dubitsky, M.D.
`
`Completion Date:
`
`March 23, 2004
`
`

`

`NDA 21-729
`Aripiprazole Orally Disintegrating Tablets
`TABLE OF CONTENTS
`
`Section
`
`Page
`
`EXECUTIVE SIIm/IARY
`
`I.
`
`Recommendations
`
`A.
`B.
`
`Recommendation on Approvability
`Recommendation for Phase 4 Studies
`
`II.
`
`Summary of Clinical Findings
`
`A.
`B.
`
`C.
`
`D.
`
`Brief Overview of Clinical Program
`Efficacy
`
`Safety
`
`Dosing
`
`Special Populations
`E.
`CLINICAL REVIEW
`
`I.
`
`Introduction
`
`A.
`
`B
`C.
`D
`
`E
`
`Background
`
`Major Safety Findings with Aripiprazole
`Administrative History
`Proposed Instructions for Use
`
`Foreign Marketing
`
`II. Clinically Relevant Findings from Consultant
`Reviews
`
`A. Biopharmaceutics
`
`B. Chemistry
`
`C. DSI Clinical Site Inspections
`D .
`DMETS
`
`III. Human Pharmacokinetics and Pharmacodynamics
`A.
`Pharmacodynamics
`B.
`Pharmacokinetics
`NDA Data Sources
`
`IV.
`
`A.
`B.
`
`Primary Development Program
`Published Literature
`
`V.
`
`_
`Clinical Review Methods
`A.
`Items Utilized in the Review
`
`Specific Methods Used to Evaluate Data
`B.
`Quality
`
`C.
`D.
`
`Adherence to Accepted Ethical Standards
`Evaluation of Financial Disclosure
`
`4
`4
`
`4
`4
`
`4
`
`5
`
`5
`
`5
`
`6
`6
`6
`
`7
`
`7
`
`7
`
`7
`7
`
`7
`7
`
`9
`10
`
`10
`
`10
`
`10
`11
`
`

`

`VI. Review of Efficacy
`
`VII. Integrated Review of Safety
`
`A. Methodology of the Safety Review
`
`B. Safety Findings
`1. Deaths and Other Serious AE’s
`
`2. Dropouts due to Adverse Events
`3. Oral Irritation
`
`C. Adequacy of Exposure & Safety Assessments
`
`D. Assessment of Data Quality & Completeness
`E.
`Summary of Important Safety Findings
`VIII. Dosing, Regimen, and Administrative Issues
`
`IX. Use in Special Populations
`
`Review of Proposed Labeling
`X.
`XI. Conclusions and Recommendations
`
`ll
`
`ll
`
`11
`
`12
`
`13
`
`13
`
`l3
`
`l4
`
`l4
`
`l4
`
`l4
`
`l4
`
`peCHSTHB‘NGN
`on Origmc“
`
`

`

`EXECUTIVE SUMMARY
`
`I.
`
`Recommendations
`
`A.
`
`Recommendation on Approvability
`
`From a clinical perspective at this time; it is recommended'
`that this NDA be approved. Consultant reviews
`(biopharmaceutics, chemistry, DSI, DMETS) are not yet
`complete and any significant issues raised by_those reviews
`will need to be resolved prior to approval.
`
`B.
`
`Recommendation for Phase 4 Studies
`
`I have no recommendations for Phase 4 studies.
`
`II.
`
`Summary of Clinical Findings
`
`A.
`
`Brief Overview of the Clinical Program
`
`the approval of a
`This application is intended to support
`fast dissolving oral tablet formulation of aripiprazole for
`the management of patients with schizophrenia.
`The basis
`of this application is bioequivalence between aripiprazole
`ODT and currently marketed Abilify tablets, as demonstrated
`by cl- key bioequivalence studies, CNl38067 .—_———-
`
`B.
`
`Efficacy
`
`The sponsor provides no new efficacy data in this
`application. Efficacy relies on extrapolation from
`'investigations conducted with the standard aripiprazole
`tablets which were approved under NDA 21-436.
`
`C.
`
`Safety
`
`The small amount of safety data derived from the
`bioequivalence studies suggests no hazard associated with
`this product that would preclude its approval or warrant a
`major change to product labeling.
`The determination of
`safety for this product relies almost entirely on
`extrapolation from investigations conducted with the
`standard aripiprazole tablet.
`
`

`

`D.
`
`Dosing
`
`Dosing will be essentially identical to that for Abilify
`tablets.
`The vulnerability of this product to moisture
`requires that it be stored in blister packaging until
`immediately before use.
`
`F.
`
`Special Populations
`
`The development plan included no studies in special
`populations.
`
`CLINICAL REVIEW
`
`I.
`
`Introduction
`
`A.
`
`Background
`
`Aripiprazole, a quinolinone derivative,
`
`is a novel
`
`psychotropic agent that exhibits partial agonism at D2
`receptors and 5—HTm receptors and antagonism at 5—HTm
`
`receptors.‘ Aripiprazole tablets were approved as Abilify,
`for the acute treatment of schizophrenia in adults on
`11—15—02 and data regarding longer—term safety and efficacy
`were submitted in supplement 8—001, which was approved on
`8—28-03.
`
`Otsuka has developed a fast disintegrating tablet
`formulation of aripiprazole for use in treating patients
`with schizophrenia (referred to as aripiprazole orally
`disintegrating tablets or aripiprazole CDT in this review).
`This product has been developed under IND 62,181 and has
`the currently proposed proprietary name of ABILIFY
`DISCMELT.
`The rapid disintegration characteristic is
`intended to provide an alternative dosage form of
`‘aripiprazole, particularly for patients who have difficulty
`swallowing tablets.
`
`Otsuka is seeking approval of.aripiprazole CDT on the basis
`of bioequivalence to currently approved aripiprazole
`tablets. This application is supported by' -- key
`bioequivalence studies, CN138067
`-Q-___-.
`The former
`
`study evaluated the highest approved strength of the
`tablets , 30mgM
`-——--—.
`The sponsor is requesting a waiver of the
`requirement to demonstrate bioequivalence for the 10, 15,
`and 20mg tablets.
`A food effect study has not been
`
`

`

`conducted since such a study has been performed with the
`‘15mg approved tablet and a food effect study with the 30mg
`approved tablet is currently underway.
`
`B.' Major Safety Findings with Aripiprazole
`
`In patients with schizophrenia, aripiprazole is not known
`to possess any remarkable toxicities.
`
`C. Administrative History
`
`I?”
`
`Subsequently, protocols for -' definitive bioequivalence
`studies using a selected --
`formulation were
`to
`submitted:
`protocol CN138067, submitted on 1—13—03,
`evaluate the 30mg strength ———————.
`
`WV
`
`The above studies were completed and this NDA was submitted
`and received on 12—22—04.
`A Refuse—to—File meeting was
`convened on 2/9/04 and the application was deemed to be
`fileable}
`A consult was sent to the Division of Scientific
`
`inspection of study
`Investigations on 2—11—04 to request
`CN138067. Also, a consult was forwarded to the Division of
`
`Medication Errors and Technical Support on 3—9—04 to
`evaluate the trade name extension “ABILIFY DISCMELT."
`
`D.
`
`Proposed Instructions for Use.
`
`The instructions for use provided in the proposed labeling
`advise that the blister packaging should not be opened
`until the drug is to be taken. Directions for opening the
`blister are given and, using dry hands,
`the tablet is to be
`placed on the tongue.
`It can be taken with or without
`--- The tablet should not be split.
`
`

`

`E.
`
`Foreign Marketing
`
`There is no foreign postmarketing data for aripiprazole
`ODT.
`
`II. Clinically Relevant Findings from Consultant Reviews
`
`A.
`
`Biopharmaceutics
`
`The review of the bioequivalence studies by the Office of
`Clinical Pharmacology and Biopharmaceutics is pending
`completion at this time.
`
`B.
`
`Chemistry
`
`The review of chemistry, manufacturing and controls data by
`the Office of New Drug Chemistry has not yet been
`completed.
`
`C.
`
`DSI Clinical Site Inspection
`
`The Division of Scientific Investigations was requested to
`inspect study CN138067. This inspection is pending at the
`current time.
`‘
`
`D.
`
`DMETS
`
`The Division of Medication Errors and Technical Support was
`consulted to evaluate the acceptability of the sponsor’s
`trade name proposal, ABILIFY DISCMELT.
`The report of this
`assessment has not yet been completed.
`
`'
`
`III. Human Pharmacokinetics and Pharmacodynamics
`
`A.
`
`Pharmacodynamics'
`
`No new pharmacodynamic data are presented in this NDA.
`
`B.
`
`Pharmacokinetics1
`
`The aripiprazole ODT development program is comprised of
`-__. bioavailability/bioequivalence trials that were
`conducted in healthy adult subjects, ‘—
`
`1'The information presented is based on the Summary of
`PK data
`Bioequivalence/Bioavailability provided in this submission.
`will be reviewed in detail in a separate review by staff from the
`Office of Clinical Pharmacology and Biopharmaceutics (OCPB).
`
`

`

`W Studies which
`
`demonstrated the bioequivalence between 30mg -- ODT’s
`with corresponding reference commercial tablets (CN138067
`—————-——_ .
`These studies are summarized
`below.
`
`Study CN138067
`
`two—
`three—period,
`This was a randomized, open—label,
`treatment crossover study in 48 healthy adult subjects.
`Each subject received a 30mg aripiprazole commercial tablet
`(Treatment A) and a 30mg ODT (Treatment B)
`in randomized
`sequence.’
`In the third period, subjects received the-same
`treatment as in the second period.
`‘—"—-
`W Serial blOOd
`
`samples for PK assessments were collected over a period of
`384 hours (17 days) post—dose.
`There was a washout period
`of at least 28 days between treatments.
`
`Twenty subjects discontinued from the study prematurely.
`Thirty subjects had data for both formulations and only
`data from these subjects were included in the statistical
`analysis. Based on parent drug levels,
`the 30mg ODT was
`bioequivalent to the 30mg reference tablet with respect to
`Cmax, AUC(O—tau), and AUC(inf). Although the ranges for
`
`

`

`the median
`Tmax were the same for both (1.5—12.0 hours),
`Tmax for the CDT was one hour later than that for the
`commercial tablet.
`
`Frequent early PK sampling was done to examine for the
`possibility of buccal absorption after ODT administration.
`Aripiprazole levels in the first 2 hours after dosing
`revealed no substantial difference between the two
`formulations.
`
`IV. Description of Clinical Data Sources
`
`A.
`
`Primary Development Program
`
`The clinical development plan for aripiprazole ODT
`comprised the -.
`bioequivalence/bioavailability studies
`described above.
`
`In these trials, a total of 136 subjects received at least
`one dose of aripiprazole in a dose of ---—-.
`30mg;
`118 of these subjects received aripiprazole as an ODT.
`
`

`

`the mean
`Among all 136 subjects who received aripiprazole,
`age was 30.6 years and the age range was 18—45 years. Most
`of the subjects (80%) were male. Also, most of the
`subjects were Black (21%), Hispanic (46%), or White (33%).
`
`No Phase 2/3 clinical trials were conducted with
`
`aripiprazole ODT.
`
`B.
`
`Published Literature
`
`The sponsor provided no systematic search of the published
`literature.
`
`I searched PubMed for relevant articles using
`On 3—22—04,
`the search string “(OPC—l4597 OR aripiprazole) AND
`(disintegrating ‘- ).” Only one article was
`retrieved using this search: Kelleher JP, et al. Advances
`in atypical antipsychotics for the treatment of
`
`schizophrenia: new formulations and new agents. CNS Drugs
`2002;16(4):249—6I. This article was examined and revealed
`no significant safety problems associated with the use of
`aripiprazole.
`It contained no specific mention of the
`aripiprazole ODT formulation.
`
`V.
`
`A.
`
`Clinical Review Methods
`
`Items Utilized in the Review
`
`All materials examined in this review Were provided
`electronically by the sponsor on 12—22—03 and were reviewed
`in the CDER Electronic Document Room (EDR).
`'
`
`B.
`
`Specific Methods Used to Evaluate Data Quality
`
`The Division of Scientific Investigations has been
`requested to inspect study CN138067.
`The report of that
`inspection has not been completed.
`
`C.
`
`Adherence to Accepted Ethical Standards
`
`All three studies were conducted in accordance with Good
`Clinical Practice.
`
`10
`
`

`

`D.
`
`Evaluation of Financial Disclosure
`
`Requests for financial disclosure information were sent to
`the 3 principal investigators and 5 sub—investigators who
`participated in the ‘-- trials in this NDA. All
`individuals responded and none had disclosable information.
`
`VI. Review of Efficacy
`
`The bioequivalence studies were not designed to evaluate
`the efficacy of aripiprazole DDT and no clinical efficacy
`data was reviewed in conjunction with this NDA.
`
`VII. Integrated Review of Safety
`
`A. Methodology of the Safety Review
`
`This safety review will be abbreviated compared to that
`conducted for most NDA’s and will focus on: 1) any serious
`adverse experiences (i e., deaths, non—fatal serious
`
`adverse events, and adverse events that led to premature
`discontinuation) that might suggest a particular hazard
`
`related to aripiprazole ODT treatment and 2)
`for oral irritation with aripiprazole ODT.
`
`the potential
`
`B,
`
`1.
`
`Safety Findings
`
`Deaths and Other Serious Adverse Events
`
`In these studies, serious adverse events were defined as
`
`is life—threatening,
`any occurrence that results in death,
`requires inpatient hospitalization or prolongs existing
`hospitalization, results in persistent or significant
`disability or incapacity,
`is a cancer,
`is a congenital
`anomaly or birth defect, an overdose, results in the
`development of drug dependency or drug abuse, or is
`otherwise considered medically important
`(such as a
`convulsion that does not result in hospitalization).
`
`There were no deaths or other serious adverse events
`
`reported among the 136 subjects exposed to aripiprazole in
`these three trials.
`
`A listing of all treatment—emergent adverse events reported
`in these trials was examined to detect any other medically
`
`.One such event was identified: syncope
`significant event.
`was reported in 3 subjects in study CN138067.
`In two of
`
`‘11
`
`

`

`these subjects (#15_and #29), syncope occurred 4 hours and
`1.5 hours, respectively, after dosing with aripiprazole
`30mg ODT.
`In the other subject
`(#40), syncope occurred 12
`hours after dosing with the aripiprazole 30mg commercial
`tablet.
`Thus,
`the reporting rate for syncope was 1.7%
`(2/118) with ODT and 0.8% (1/121) with the commercial
`
`A causal relationship to aripiprazole cannot be
`tablet.
`ruled out and it is possible that the risk may be higher
`with ODT exposure although the difference in reporting
`rates is not statistically significant
`(p=0.6, 2—tailed
`Fishers exact test).
`These rates are not very different
`from those observed in the original short—term trials of
`aripiprazole in schizophrenia, although the overall placebo
`rate exceeded the drug rate in that pool of studies (0.6%
`for aripiprazole and 1.0% for placebo).
`
`2.
`
`Dropouts due to Adverse Events
`
`In these -- trials, a total of eight patients dropped
`out due to adverse events.
`
`Four of these patients discontinued study participation due
`to vomiting which started within a few hours of receiving
`aripiprazole '—————.
`two had received the
`reference tablet and two had received ODT.
`
`Overall, vomiting was experienced by 9.3% of subjects after
`ODT and 9.1% of subjects after standard tablet.
`It was
`
`dose—related, occurring in 27% of subjects after 30mg of
`aripiprazole and 9% -----
`this pattern was consistent
`when examined by formulation. Thus, it is likely that
`vomiting was causally related to aripiprazole
`administration in these trials but
`the risk of vomiting
`appeared to be independent of the formulation administered.
`
`Other dropouts due to adverse events are summarized below:
`
`0 Patient #39 in study C‘ dropped out due to
`dysphagia, fever, and lymphangitis on study day 3 after
`receiving aripiprazole --— _
`These events were
`
`accompanied by a tachycardia (130 bpm) and leukocytosis
`(WBC=16,700). All events had resolved on follow—up.
`0 Patient #21 in study CN138067 discontinued due to
`
`pharyngitis beginning on day 27 after receiving
`aripiprazole 30mg standard tablet and lasting 16 days.
`
`12
`
`

`

`0 Patient #21 ——----—-—___.
`
`dropped out due to fever
`
`which lasted 3 days with onset on study day 4 after
`reCeiving aripiprazole - standard tablet.
`0 Patient #48
`'—\ discontinued from the trial
`
`fever,
`due to chills, headache, chest congestion,
`laryngitis, pharyngitis, and voice alteration which began
`on day l and lasted for 8 days after receiving aripiprazole
`,—— standard tablet. This subject was also noted to have
`slightly elevated bilirubin levels of 2.1 mg/dl and 2.2
`mg/dl on days 28 and 56, respectively (normal value less
`than or equal to 2 mg/dl).
`
`3.
`
`Oral Irritation
`
`No specific assessments for oral irritation were performed
`in these studies.
`The listing of all treatment—emergent
`adverse events for these studies was examined for any.
`events that might suggest oral irritation.
`The following
`pertinent events were reported:
`dental disorder
`(toothache), mouth disorder (white film in mouth), dry
`mouth, pharyngitis, dysphagia, and gingivitis.
`Each of
`these was reported in one subject after ODT dosing except
`for toothache, which was reported in one subject after each
`formulation, and pharyngitis, which was reported in 3
`subjects after ODT and 5 subjects after the commercial
`tablet.
`
`C.
`
`Adequacy of Patient Exposure and Safety Assessments
`
`The safety assessment of aripiprazole ODT relies primarily
`on the safety experience with aripiprazole, which was
`I
`approved based on safety data from over 4,700 patients in
`Phase 2/3 clinical trials and has been marketed for over a
`
`year in the U.S.
`
`Specific assessment of mouth irritation in the submitted
`trials under this NDA would have been useful. Nonetheless,
`
`adverse event findings, while not highly sensitive for
`detecting such an event, suggest that mouth irritation
`after aripiprazole ODT administration is neither common nor
`severe.
`
`D.
`
`Assessment of Data Quality and Completeness
`
`Based on my review of this submission,
`appear to be reasonably complete.
`
`the clinical data
`
`13
`
`

`

`inspection of the site which conducted study CN138067
`A DSI
`is pending.
`
`E.
`
`Summary of Important Safety Findings
`
`This review revealed no safety concerns which would
`
`preclude the approval of aripiprazole ODT or new safety
`issues that would require a change to the labeling of
`Abilify.
`'
`
`VIII. Dosing, Regimen, and Administration Issues
`
`In view of the tendency of aripiprazole ODT’s to rapidly
`disintegrate, it is important to protect the tablets from
`moisture during storage and during placement on the tongue.
`Proposed labeling does appropriately advise that the ODT’s
`should be maintained in blister packaging until immediately
`before use and that the tablets should be handled with dry
`hands. Also,
`labeling cautions against damaging the
`tablets during removal from blister packaging and splitting
`the tablets.
`
`IX. Use in Special Populations
`
`This NDA provides no information about
`
`the use of
`
`aripiprazole ODT in special populations.
`
`X.
`
`Review of Proposed Labeling
`
`The labeling proposed by the sponsor very closely parallels
`the approved labeling for Abilify. Additional
`information
`regarding the ODT has been added to the following sections:
`DESCRIPTION, CLINICAL PHARMACOLOGY/PharmaCOkinetiCS,
`
`PRECAUTIONS (new Section entitled “Phenylketonurics” is
`added), DOSAGE AND ADMINISTRATION, and HOW SUPPLIED.
`
`The directions for taking aripiprazole ODT under DOSAGE AND
`ADMINISTRATION appear to be acceptable from a clinical
`viewpoint. Other sections will be reviewed by the
`biopharmaceutics and chemistry reviewers.
`
`XI. Conclusions and Recommendations
`
`On face, aripiprazole ODT appears to be bioequivalent to
`the Abilify tablets and is expected to be reasonably safe
`and effective.
`At this time, consultant reviews
`
`(biopharmaceutics, chemistry, DSI, DMETS) have not yet been
`
`14
`
`

`

`thus, any significant issues raised by those
`completed and,
`reviews will need to be resolved prior to approval.
`
`From a clinical perspective at this time,
`
`I have no
`
`objection to the approval of this marketing application.
`
`Gregory M. Dubitsky, M.D.
`March 23, 2004
`
`CC:
`
`NDA 21-729
`
`HFD—lZO/Division File
`
`HFD—lZO/GDubitsky
`/TLaughren
`/PAndreason
`/SHardeman
`
`15
`
`

`

`This is a representation of an electronic record that-was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Greg Dubitsky
`3/23/04 02:55:30 PM
`MEDICAL OFFICER
`
`Thomas Laughren
`10/12/04 03:53:19 PM
`MEDICAL OFFICER
`
`I agree that this NDA is approvable——TPL
`
`