CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -729
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEWQS)
`
`

`

`Clinical Pharmacology and Biopharmaceutics Comment
`21-729
`NDA:
`Aripiprazole Orally Disintegrating Tablet
`Drug:
`Abilify ODT Discmelt
`Trade Name:
`— 10 mg, 15 mg, 20mg, 30 mg Oral Disintegrating Tablets
`Strengths:
`Bristol Myers Squibb
`Applicant:
`Treatment of Schizophrenia
`Indication:
`Response to Approvable Letter
`Submission Type:
`12/ 12105
`Submission Date:
`DPP (HFD-l30)
`0ND Division:
`DCPBl (HFD-860)
`OCPB Division:
`Kofi A. Kumi, Ph.D.
`Reviewer:
`
`Team Leader: Raman Baweja, PhD.M
`
`Background
`
`The sponsor submitted NDA 21—729 for Abilify Discmelt Orally Disintegrating Tablets on
`December 22, 2003. An Approvable letter was issued on October 22, 2004. In this
`correspondence, the sponsor has submitted complete response to questions/comments that were
`included in the Approvable letter. This comment is related to Question No. 10, which was
`provided by OCPB to be included in the Approvable letter.
`
`Question: We request that you adopt the following dissolution method and specification
`
`Apparatus:
`Speed:
`Media:
`Volume:
`
`USP Apparatus 11 (Paddle)
`75 rpm
`pH 4 Acetate Buffer
`1000 mL
`
`Specification: Q NLT -- in 30 minutes -
`
`The sponsor has agreed to adopt the method but would like to adopt an interim dissolution
`specification of Q NLT '- in 30 minutes instead of a specification Q NLT II. in 30 minutes.
`
`The sponsor’s rationale for an interim specification is that the proposed specification has no
`clinical relevance because the dissolution specification for the tablet was Q NLT - . However,
`the proposed method for the DDT and that for the tablet are different. The dissolution method for
`the tablet is
`
`Apparatus:
`Speed:
`Media:
`Volume:
`
`USP Apparatus II (Paddle)
`60 rpm
`pH 1.2 USP Buffer
`1000 mL
`
`The Abilify tablet method was not chosen as the dissolution method for Abilifil Discmelt ODT
`due to rapid dissolution, high variability, and loss of discriminatory ability for detecting changes
`in the CDT. Also, the sponsor indicates that a Q NLT - would increase In requirement as
`compared to the frequency of — that would occur under the dissolution specification of Q
`NLT ‘- in 30 minutes. The sponsor argues that a dissolution specification tighter than NLT
`' O i in 30 minutes would not provide additional indication of product performance. Hence, the
`
`

`

`sponsor is proposing an interim dissolution specification of Q NLT .— in 30 minutes. A final
`dissolution specification would to be set for aripiprazole ODT once the sponsor gains experience
`in full-scale manufacturing of at least' -—— batches.
`
`Comment to Sponsor:
`
`1. The sponsor’s proposal for an interim specification of Q NLT -— in 30 minutes is
`acceptable. However, the sponsor should provide full dissolution profiles for at least —
`batches or batches produced fer 12 months, whichever'comes first, and should also
`provide data indicating how many —' would be performed if the specification is
`set at Q NLT .— A final specification would be set afier the data is provided and
`reviewed.
`
`2. The sponsor should provide the data requested in #1 above within 16 months of the date
`of the action letter
`
`3. Please forward cements 1 and 2 to sponsor.
`
`‘Kofi A. Kumi, PhD.
`
`RD/FT Initialed by Raman Baweja, PhD.
`
`
`
`CC2NDA 21-729, HFD—130, HFD—860 (Mehta, Baweja, KumiK), EDR (Biopharm)
`
`

`

`
`_-m_--------------------------------- '
`
`“um-II—dwn-----------—--------------—----------------
`
`This is a representation of an eleptronic record that was signed electronically and
`this page is the manifestation offithe electronic signature.
`
`/S/
`
`VKofi Kumi
`2/22/2006 12:25:30 PM
`BIOPHARMACEUTICS
`
`Raman Baweja
`2/22/2006 06:29:56 PM
`BIOPHARMACEUTICS
`
`

`

`Clinical Pharmacology and Biopharmaceutics Review
`NDA: 21—729
`
`Drug: Aripiprazole
`Trade: Abilifym ODT
`Strengths: -— 10 mg, 15 mg, 20mg, 30 mg Oral Disintegrating Tablets
`Applicant: Bristol Myers Squibb
`Indication: Treatment of Schizophrenia
`Submission Type: New Formulation
`Related IND and NDA: IND 62, 181 and NDA 21-436
`Submission Dates: 12/22/03, 3/31/04, 7/8/04, 8/4/04
`0ND Division: DNDP (HFD-120)
`OCPB Division: DPE] (HFD-860)
`Reviewer: Kofi A. Kumi, Ph.D.
`Team Leader (Acting): Sally Yasuda, PharmD.
`
`1. Executive Summary ........................... ; ........................................................................................ 2
`1.] Recommendation ................................................................................................................... 2
`1.2 Phase 4 Commitments ........................................................................................................... 2
`
`1.3. Summary of Important Clinical Pharmacology and Biopharmaceutics Findings ................ 2
`2. Question Based Review ............................................................................................................... 6
`2.1. General Atnzbutes ................................................................................................................ 6
`
`2.1.1. What pertinent regulatory background or history contributes to the current assessment
`of the clinical pharmacology and biopharmaceutics of this drug? .......................................... 6
`2.1.3. What are the proposed mechanism of action and therapeutic indication? ..................... 6
`2.1.4. What are the proposed dosage(s) and route of administration? ..................................... 6
`2. 2. General Clinical Pharmacology........................................................................................... 7
`2.2.1 What are the design features of the clinical pharmacology and clinical studies used to
`support dosing or claims? ........................................................................................................ 7
`2. 2. 2. Are the active moieties in the plasma (or other biological fluid) appropriately
`identified and measured to assess pharmacokinetic parameters and exposure response
`relationship? ............................................................................................................................ 7
`2.2.3.1. What safety profiles were reported? ................................................................. 7
`2.2.4. What are the Pharmacokinetic Characteristics of the Drug? ......................................... 8
`2.5.2. Are aripiprazole ODTs bioequivalent to the approved conventional tablets? ............. 10
`2 5 3. What data supp01t or do not support a waiver of in vivo bioequivalence for the 10 mg,
`15 mg and 20 mg ODT formulations? ................................................................................... 12
`
`2.5.4. WhatIS the Proposed Dissolution Method and Specification for Aripiprazole ODT
`
`Formulations? ........................................................................................................................13
`
`2.5.5. What dosing recommendations are necessary? ........................................................... 21
`2.5.6. What is the effect of food on the bioavailability of aripiprazole? ............................... 21
`2.5.7. Based 0 the Biopharmecutics Classificatin System (BCS) principles, in what class is
`Aripiprazole? ......................................................................................................................... 2 1
`2.6. AnalyticalSection ........................................................................ 21
`2.6.1. What analytical methods were used to identify aripiprazole and its metabolite,
`dehydro-aripiprazole? ............................................................................................................ 21
`3. Detailed Labeling Recommendations .................._...................................................................... 21
`4. Appendix ................................................................................................................................... 23
`4.]. Package Insert .................................................................................................................... 23
`4.2. DSI Report ............................................................................'.............................................. 56
`4.3. Individual StudyReview ..................................
`.............................. 59
`4.4. Cover Sheet and OCPB filing/reviewform ....................................................................... l 1 1
`
`

`

`]. Executive Summary
`1.] Recommendation
`
`Based on the review of the data submitted to the Human Pharmacoknietics and Bioavailability
`Section of NDA 21-729 to fulfill section 320 and 201.5 of 21 CFR, the application is acceptable
`to the Office of Clinical Pharmacology and Biopharmaceutics (OCPB). OCPB supports a
`recommendation for approval provided that satisfactory agreement is reached between the
`sponsor and the agency regarding the language in the labeling.
`Labeling recommendations are provided in Section 3 of this review.
`
`1.2 Phase 4 Commitments
`
`There are no phase 4 commitments recommended.
`
`1.3. Summary of Important Clinical Pharmacology and Biopharmaceutics Findings
`
`Background: Aripiprazole (UPC—14597, EMS-337039), a dihydrocarbostyril (quinolinone)
`. derivative, is an antipsychotic. Aripiprazole (Abilifym) is currently approved (NDA 21—346) for
`the treatment of schizophrenia at the recommended starting and target dose of 10 or 15 mg/day
`administered on a once-a-day schedule without regard to meals. Abilify has been systematically
`evaluated and shown to be effective in the dose range of 10 to 30 mg/day. An orally
`disintegrating tablet (ODT) formulation was developed to provide an alternate means to
`administer aripiprazole to patients who have difficulties swallowing the tablet and, therefore, to
`increase compliance. The clinical program for the ODT formulation consisted of . -—
`W pivotal bioequivalence
`studies for the highest (30 mg) .__———__. I ODT formulations. These strengths
`correspond to the 30 mg ___ aripiprazole commercial tablets. A waiver for the in vivo
`bioequivalence studies for lower strength (i.e. 20, 15, and 10 mg) ODTs is being requested,
`because the lower strength ODTs have the same drug-to-excipient ratio as the 30 mg ODT
`formulation (see Section 2.5.3) and the in vitro dissolution profiles at pH values of 1.2, 4.0, and
`6.8 were found to be similar. Clinical studies to assess the safety and efficacy of the ODT
`formulations in patients with schizophrenia or schizoaffective disorders have not been performed.
`
`Bioequivalence: Aripiprazole ODT was determined to be bioequivalent to the conventional tablet
`(CT) formulations. The 30 mg ODT and 30 mg conventional tablet (CT) were bioequivalent.
`W The point estimates and 90%
`CI values for the aripiprazole geometric mean Cmax and AUC ratios of ODT to CT formulations
`all met the regulatory requirements for bioequivalence of 0.80-] .25. On the basis of their
`bioequivalence, it is unlikely there will be any significant difference in the clinical efficacy and
`tolerability of the ODT and CT formulations. These two formulations can be used
`interchangeably.
`
`

`

`Table l: Summa
`
`of Statistical Anal sis Results for Ari i razole Cmax and AUC
`
`Parameter
`
`Geometric Means
`
`- (Intra-sub‘ect»CV%)
`
`A: 30 mg Tablet
`
`(n*h/mL
`
`_
`
`'
`
`'
`
`(n*h/mL)
`
`Ratio of 30 mg ODT: 30 mg Tablet
`
`(Ad'ustedGeometricMeans
`
`Ratio B:A
`
`90% CI for Ratio
`
`.'
`
`.
`
`_
`
`(0.938, 1.084)
`
`(0.938, 1.081)
`
`Biowaiver: The sponsor is requesting a waiver of in vivo bioequivalence studies for lower
`strength (i.e., 20, 15, and 10 mg) ODTs. Bioequivalence between the highest (30 mg) strength of
`the CDT formulation proposed for marketing and the commercial tablet (30 mg) was established.
`The dissolution profiles for the 10 mg, 15 mg and 20 mg are similar to the 30 mg CDT. The
`qualitative and quantitative composition of the 10, 15 and 20 mg are similar to the 30 mg ODT.
`Therefore, the reviewer recommends that in vivo bioequivalence should be waived for
`aripiprazole 10 mg, 15 mg and 20 mg-ODT formulations. The 10, 15 and 20 mg ODT can also be
`switched for their respective CT if needed.
`
`Dissolution: After reviewing the dissolution data for the batches used in the pivotal
`bioequivalence and stability studies, there was not a significant difference in the dissolution
`
`W
`
`be adopted. Therefore, the reviewer recommends the following method and specification.
`
`Apparatus: USP Apparatus II (Paddle)
`Speed: 75 rpm
`Media: pH 4 Acetate Buffer
`Volume: 1000 mL
`
`Specification: Q NLTrd— in 30 mins
`
`

`

`Dosing Recommendation: The dosing recommendation for AbilifyTM ODT is the same as Abilify
`conventional tablets (CT). The following language is the current dosing recommendation for
`Abilify CT:
`
`The recommended starting and target dose for ABILIFY is 10 or 15 mg/day administered
`on a once-a-day schedule without regard to meals. ABILIFY has been systematically
`evaluated and shown to be effective in a dose range of 10 to 30 mg/day, however, doses
`higher than 10 or 15 mg/day, the lowest doses in these trials, were not more effective
`than 10 or 15 mg/day. Dosage increases should not be made before 2 weeks, the time needed to
`achieve steady state.
`
`Dosage in Special Populations
`Dosage adjustments are not routinely indicated on the basis of age, gender, race, or
`renal or hepatic impairment status (see CLINICAL PHARMACOLOGY: Special
`Populations).
`
`Dosage adjustment for patients taking aripiprazole concomitantly with potential
`CYP3A4 inhibitors: When concomitant administration of ketoconazole with
`
`aripiprazole occurs, aripiprazole dose should be reduced to one-half of the usual
`dose. When the CYP3A4 inhibitor is withdrawn from the combination therapy,
`aripiprazole dose should then be increased.
`Dosage adjustment for patients taking aripiprazole concomitantly with potential
`CYP2D6 inhibitors: When concomitant administration of potential CYP2D6 inhibitors
`such as qu'inidine, fluoxetine, or paroxetine with aripiprazole occurs, aripiprazole dose
`should be reduced at least to one-half of its normal dose. When the CYP2D6 inhibitor
`
`is withdrawn from the combination therapy, aripiprazole dose should then be increased.
`Dosage adjustment for patients taking potential CYP3A4 inducers: When a potential
`CYP3A4 inducer such as carbamazepine is added to aripiprazole therapy, the
`aripiprazole dose should be doubled (to 20 or 30 mg). Additional dose increases
`should be based. on clinical evaluation. When carbamazepine is withdrawn from the
`combination therapy, the aripiprazole dose should be reduced to 10 to 15 mg.
`
`

`

`Kofi A. Kumi, Ph.D.
`
`
`
`RD/FT Initialed by Sally Yasuda, Phaxm. D.
`
`
`
`CC: NDA 21-729, HFD-120 (Mehta, RahmanA, Baweja, Yasuda, KumiK), CDR (Biopharm)
`
`CPB Briefing Date and Attendees: 9/23/04, HFD-120 (Greg Dubitsky),
`ONDC (Gupreet Gill-Sangha), HFD—86O (Mehul Mehta, Atiqur Rahman, Sally Yasuda, Kofi
`Kumi), HFD—870 (Ting-eng Ong, Khoi Lam)
`
`

`

`2. Question Based Review
`
`2.1. General Attributes
`
`2.1.]. What pertinent regulatory background or history contributes to the current assessment of
`the clinical pharmacology and biopharmaceutics of this drug?
`
`The sponsor submitted preliminary dissolution information to IND 62, 181 requesting agency
`(OCPB) concurrence on the selection of their dissolution methOd. In a teleconference on
`10/23/03, OCPB requested that the sponsor evaluate two dissolution methods and include the two
`proposed dissolution methods for aripiprazole ODT in the NDA for further consideration as the
`regulatory method. One of the methods uses acetate buffer pH 4.0 (1000 mL), with USP
`Apparatus II (paddles) at 75 rpm -——\_—___ The second method uses acetate
`buffer pH 40 (1000 mL), with paddles at 50 rpm ’ -
`
`2.1.2. What are the highlights of the chemistry andphysical—chemical properties of the drug
`substance and the formulation of the drug product as they relate to clinical pharmacology and
`biopharmaceutics review?
`
`Abilify is a psychotropic drug indicated for the treatment of schizophrenia. The same drug
`substance that has been approved for the ABILIFY tablets has been used for development of the
`CDT dosage form and is proposed to be used in the commercial batches of aripiprazole ODT.
`The
`.———~
`, particle size, --’ and other solid state properties of aripiprazole
`remain unaltered with regard to its formulation in the CDT. This submission is for Abilify
`(aripiprazole) oral disintegrating tablets (ODT) — 10 mg, 15 mg, 20 mg and 30 mg.
`Calcium SilicateM Calcium silicate
`-——-—-—-—
`
`
`
`2.1.3. What are the proposed mechanism of action and therapeutic indication?
`
`The mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia, is
`unknown. However, it has been proposed that the efficacy of aripiprazole is mediated through a
`combination of partial agonist activity at D2 and 5—HT1A receptors and antagonist activity at 5-
`HTzA receptors. Aripiprazole is indicated for the treatment of schizophrenia.
`
`2.1.4. What are the proposed dosage(s) and route ofadministration?
`
`Aripiprazole ODT is intended for oral administration. The proposed regimen is similar 'to that
`approved for the tablet formulation. The recommended starting and target dose is 10 or 15
`
`

`

`mg/day. ABILIFY has been systematically evaluated and shown to beieffective in the dose range
`of 10 to 30 mg/day given orally.
`'
`'
`
`2.2. General Clinical Pharmacology
`
`2.2.] What are the design features of the clinical pharmacology and clinical studies used to
`support dosing or claims?
`
`The clinical program for the aripiprazole ODT formulation was designed to demonstrate
`bioequivalence for the highest (i.e., 30 mg) ———-———————— ODT formulations
`proposed for marketing to the corresponding 30 mg —-
`aripiprazole commercial tablets.
`’ clinical studies were conducted.
`M
`
`M pivotal bioequivalence studies were
`performed. One study was conducted to demonstrate bioequivalence of the highest
`strength, 30 mg, ODT relative to the commercial tablet. ~__-—-—-——-
`
`WN
`
`. A waiver for the in vivo bioequivalence
`studies for lower strength (i.e., 20, 15, and 10 mg) ODTs is being requested because these lower
`strength ODTs have the same dmg-to—excipient ratio as the 30 mg ODT formulation and the in
`vitro dissolution profiles at pH values of 1.2, 4.0, and 6.8 are similar.
`
`2.2.2. Are the active moieties in the plasma (or other biologicalfluid) appropriately identified
`and measured to assess pharmacokinetic parameters and exposure response relationship?
`
`Yes the active moieties (aripiprazole and dehydro—aripiprazole) have been appropriately identified
`(See Section 2.6 Analytical Section). The Division of Scientific Investigations (HFD—48)
`inspected one of the pivotal studies (CN 138067). The inspector concluded the plasma
`aripiprazole concentrations of three subjects in the study should not be accepted by the agency for
`review because the accuracy of aripiprazole concentration could not be assured.
`
`2.2.3. Exposure-Response
`
`_ Exposure-response relationships were not evaluated for this application.
`Dosing recommendation for Aripiprazole is based on demonstrating comparable exposures that
`will be obtained after the administration of the approved tablet and the orally disintegrating
`tablets (ODT).
`
`2.2.3.]. What safety profiles were reported?
`
`For the ODT program, two-hundred twenty-one (221) AEs were reported in 71 (52.2%)
`of 136 subjects. The most common ABS (with frequencies of subjects >10%) were:
`headache (16.9%), nausea (16.2%), vomiting (15.4%), and lightheadedness (15.4%).
`Among the 221 AEs reported by subjects exposed to aripiprazole, 204 (92.3%) were
`considered by Investigators to be mild in intensity, 15 (6.8%) were considered by
`Investigators to be moderate in intensity, and 2 (1%) were considered by Investigators to
`be severe/very severe in intensity. The frequency of treatment—emergent ABS appeared to
`
`

`

`be comparable between the CDT (34.7%) and the commercial tablet (36.4%) formulations.
`Overall, the safety profile of aripiprazole ODT formulations in healthy subjects was reported to
`be similar to that of the commercial tablets.
`
`2.2.3.2. Does this drug prolong the QT 01' QTc interval?
`
`According to OCPB review of the original NDA 21-436, no change in QTc was detected as a
`function of dose or concentration within the recommendeddosage range of 15 — 30 mg; However,
`at doses of 45 — 90 mg, the original review of NDA 21-436 indicated larger increases in QTc
`were observed.
`
`2.2.4. What are the Pharmacokinetic Characteristics of the Drug?
`
`The pharmacokinetics of aripiprazole were characterized in NDA 21-436 for the tablet
`formulation. Based on the conclusions of the reviewer of NDA 21-436 and information in the
`
`_
`
`approved label, aripiprazole is wellabsorbed after oral administration with peak plasma
`concentrations occurring within 3—5 hours after dosing. The absolute oral bioavailability of the
`tablet formulation is 87%. Aripiprazole is widely distributed (Vd = 4.94 L/kg after l.V.
`'
`administration) despite plasma protein binding in excess of 99%. Aripiprazole is mainly
`metabolized with less than 1% of an oral dose excreted in the urine unchanged. Approximately
`18% is excreted in the feces unchanged. Aripiprazole is metabolized by Cytochrome P450 (CYP)
`3A4 and CYP2D6. Aripiprazole is the major moiety in the system circulation; the active
`metabolite (dehydro—aripiprazole) represents about 40% of aripiprazole AUC in plasma at steady
`. state. The mean elimination half-life of aripiprazole is about 75 hours. The pharmacokinetics of
`aripiprazole is reported to be linear between 5 to 30 mg after administration of the tablet dose.
`Also, the OCPB review of NDA 21—436 indicated that the pharmacokinetics of aripiprazole
`appears to be linear between 30 to 75 mg in schizophrenic patients. In OCPB review of NDA 21—
`436, intersubject variability was 16 — 57% for Cmax and 16 — 57% for AUC in healthy subjects
`and patients. The intra-subject variability in the pivotal ODT bioequivalence studies ranged from
`7.7 % to 27.6%.
`
`2.3. Intrinsic Factors
`
`According to the OCPB review of NDA 21-436 and information in the approved label, dosage
`adjustments is not recommended for renal and hepatic impairment patients, due to gender, age
`differences or for ethnic differences.
`
`2.4. Extrinsic Factors
`
`According to the OCPB review of NDA 21-436 and information in the approved label for the
`tablet, ethanol blood concentrations Were not significantly affected by co-administration'of
`ethanol and aripiprazole. Dosage adjustment is not recommended based on ethanol or smoking
`status. In NDA 21—436, several drugs were evaluated for their effect on aripiprazole
`pharmacokinetics. Famotidine decreased aripiprazole Cmax approximately 37% and valproate
`decreased aripiprazole Cmax and AUC approximately 25%. No dosage adjustments were
`recommended when aripiprazole is administered concomitantly with famotidine or valproate.
`Ketoconazole, quinidine and carbamazepine have greater effects on exposure (>50% changes)
`and dosage adjustments are recommended for aripiprazole when co-administered with these
`drugs.
`
`

`

`2.5. General Biopharmaceutics
`
`2.5.]. What is the composition of aripiprazole oral disinlegrating tablet?
`
`The composition of the various strengths of aripiprazole ODT is provided in the following table
`
`Table 3: Quantitative Composition of Aripiprazole Orally Disintegrating Tablets
`
`
`
` Component Reference
`l-‘umlion
`-
`.Aripipr‘arxile
`NC
`A?!
`Calcium Silicate
`Nf’
`
`Quantity (mg) yer nnil dost
`
`10 mg
`\ Ii) 00
`
`15mg
`i5 ()0
`
`20 mg
`:0 00
`
`3C! mg
`30.00
`
`(Tmsmmtellose Sodium
`
`Crospnvirlone
`
`'
`
`Siiimn Dioxide
`
`Xyliml
`
`NF
`
`NF
`
`NF
`
`NF
`
`Ni"
`Mlcmcxysuzliine Cellulose “
`CM
`
`Aspamme
`ACCSUll-fll'lti: Potassium
`
`Creme Ele Vanilla (Natural
`8.— Anmcml Flavors)
`Tarlziric Acid
`
`Magnesmm Sammie-
`Red Ferric Oxific
`Yellow Ferric Oxide
`
`-
`
`F138: C Blue 5i 2 Aluminum
`Lake
`
`N?
`EP
`
`DMFC
`NF
`
`N37
`NF
`NF
`
`FDEtC
`
`Table: Weight
`
`--
`
`-‘
`
`20093
`
`100.09
`
`159.00
`
`200 [JG
`
`300,013
`
`NC mm compmdinl
`
`

`

`Appears This way
`On Original
`
`2.5.2. Are aripiprazole ODTs bioequivalent to the approved conventional tablets?
`
`Aripiprazole 30 mg DDT and 30 mg conventional tablet (CT) were bioequivalent. __
`W The point estimates and
`90% CI values for the aripiprazole geometric mean Cmax and AUC ratios of CDT to CT
`formulations all met the regulatory requirements for bioequivalence of 080—1 .25. On the basis of
`their bioequivalence of aripiprazole, there is unlikely to be any substantial difference in the
`clinical efficacy and tolerability of the DDT and CT formulations. These two formulations can be
`used interchangeably.
`'
`
`In Study CN138067, the sponsor conducted a study to determine whether aripiprazole 30 mg
`ODT was bioequivalent to 30 mg CT. This was a single-site, single—dose, open-label, randomized,
`three-period, two-treatment, crossover study in healthy subjects. Forty-eight (48) subjects were
`enrolled to ensure that 32 subjects completed the study. Each subject was to be fasted for at least
`10 hours and then was to receive 30 mg aripiprazole administered as a l X 30 mg CT (Treatment
`A) and as a l X 30 mg ODT (Treatment B) in a sequence determined by a computer generated
`randomization schedule. In Period 3, each subject was to receive the same treatment as in Period
`2 (i.e., the treatment was repeated). At the time of dosing, 240 mL of water was to be
`administered to the subject along with the commercial tablet (Treatment A). Treatment B was to
`be administered without any fluid. The subject was to be instructed to place the ODT directly on
`the tongue and keep it there until it “melted” (disintegrated) completely before swallowing.
`Subjects were permitted to consume water ad libitum following 15 minutes post dose for
`Treatment B. Subjects were to remain supine for up to 8 h after dosing in each period. There was
`to be a washout period of 2 28 days between each treatment administration. Blood samples were
`collected for PK analysis for up to 384 hours (17 days) post dose. Summary of the statistical
`analysis are provided in the following table
`,
`‘
`
`
`Table 4: Summary of Statistical Analysis Results for Aripiprazole Cmax and AUC
`
`Parameter
`Geometric Means
`Ratio of 30 mg ODT: 30 mg Tablet
`
`
`
`(Intra—subj ect CV%)
`Geometric Means
`
`
`
`A: 30 mg Tablet
`B: 30 mg ODT
`Pt. Estimate of
`
`
`
`
`Ratio B:A
`101.6
`
`
`
`Cmax (ng/mL)
`(27.6)
`(12.3)
`
`
`
`
`
`1.01
`AUC(0-T)
`
`(n*h/mL)
`
`
`
`(0.938, 1.081)
`
`
`
`
`
`
`
`
`
`
`(0.938, 1.084)
`
`The Division of Scientific Investigation (HFD-48) inspected the site for the pivotal bioequivalent
`study CN138067. They concluded that plasma aripiprazole concentration data from three subjects
`
`10
`
`

`

`(14, 19 and 29) should not be accepted because the accuracy of aripiprazole concentration was
`not assured (Details of report is provided in appendix). The reviewer reanalyzed the
`pharrnacokinetic data excluding these three patients. The 90% CI were within the regulatory
`criteria for declaring two products bioequivalent. Deleting the data for subjects 14, 19 and 29 did
`not alter the conclusion. Hence, aripiprazole 30 mg ODT is bioequivalent to 30 CT. Summary of
`statistical analysis after the data was reanalyzed is contained in the data following
`
`
`Table 5»: Point Estimate and 90% CI for Study CN138067 Without Sub'ects 14, 19 and 29
`
`Pharmacokinetic Parameter
`Ratio of 30 m ODT: 30 mg Tablet
`Pt. Estimate of Ratio B:A
`90% CI for Ratio
`
`0.92, 1.08
`
`
`(0.88, 1.06)
`
`
`
`ll
`
`

`

`2.5.3. What data support or do not support a waiver of in viva bioequivalence for the 10 mg, 15
`mg and 20 mg ODTformulations?
`
`The sponsor is requesting a waiver of in vivo bioequivalence studies for lower strength (i.e., 20,
`15, and 10 mg) ODTs. Bioequivalence between the highest (30 mg) strength of the CDT
`formulation proposed for marketing and the commercial tablet (30 mg) was established. The
`rationale for exemption of bioequivalence studies for the lower strength _ ODTs are
`presented below. The reviewer recommends that-in vivo bioequivalence should be waived for
`aripiprazole 10 mg, 15 mg and 30 mg ODT formulations. The 10, 15 and 20 mg ODT can also be
`switched for their respective CT if needed.
`
`The qualitative composition of the different strengths of ODT formulation is the same. Except for
`differences in coloring agents : <—————————_.——u—I—
`— u used in the formulation, the excipient composition and proportion of aripiprazole to each
`of the other therapeutically inert ingredients in the 10, 15, and 20 mg aripiprazole ODT
`formulations are identical to the highest dose strength (30 mg) ODT formulation. The sponsor
`usedW
`————_
`The chemistry reviewer indicated that ~—
`#
`
`proportional to the dose of DDT for the 10, 15, 20 and 30 mg ODT. The chemistry reviewer
`stated that the sponsor indicated thatN
`ODT and maintain a total tablet weight that is proportional to dose for the 10, 15, 20, 30 mg
`ODT.
`_7————_\—___~‘
`
`The composition of the various aripiprazole ODT strengths is provided in Table 3
`~
`Section 2.5.1.
`.
`
`The clinical pharmacokinetics of aripiprazole administered in conventional tablets up to
`the highest therapeutic dose of 30 mg have been demonstrated to be linear and dose—proportional.
`
`The 10, 15, and 20 mg aripiprazole ODT formulations have similar dissolution characteristics to
`the 30 mg aripiprazole ODT formulation. The 30 mg ODT has been demonstrated to be
`I
`bioequivalent to the 30 mg aripiprazole tablet formulation. Therefore, it is expected that the 10,
`15, and 20 mg aripiprazole ODT formulations will also have in vivo bioequivalence relative to
`their respective Strength tablets.m
`
`A Overall, the dissolution profiles of the 10, 15, and 20 mg strength ODTs
`were similar to the reference 30 mg strength formulation in all 3 dissolution media (i.e., at pH 1.2,
`4.0, and 6.8).
`
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`‘ 8
`
`Page(s) Withheld
`
`\/ Trade Secret / Confidential
`
`Draft Labeling
`
`Deliberative Process
`
`Withheld Track Number: Clin Pharm/Bz'o— 5
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`

`

`2.5.5. What dosing recommendations are necessary?
`
`The dosing recommendation for aripiprazole ODT are the same as that approved for the
`conventional tablets in NDA 21-436.
`
`2.5.6. What is the eflect offood on the bioavailability ofaripiprazole?
`
`Food did not affect the exposure (AUC and Cmax) of the conventional tablet formulation. Food is
`not expected to have an effect on the bioavailability of aripiprazole after administration of
`aripiprazole ODT
`’
`
`2.5. 7. Based 0 the Biopharmecutics Classificatin System (BCS) principles, in what class is
`Aripiprazole?
`
`The sponsor reported that aripiprazole falls under BCS class 2. HoWever, based on the solubility,
`and permeability information submitted and reviewed under NDA 21-436, the reviewer of NDA
`21—436 concluded that aripiprazole can be classified as a BCS class 4 drug. Aripiprazole,
`according to current BCS principles, does-not qualify as BCS class 2.
`
`2.6. Analytical Section
`
`2.6.1. What analytical methods were used to identijy aripiprazole and its metabolite, dehydro-
`aripiprazole?
`
`Plasma samples from all clinical studies were analyzed for aripiprazole and dehydro-
`aripiprazole using a liquid chromatography tandem mass spectrometry (LC/MS/MS)
`method. The standard curves ranged from 1.0 to 250.0 ng/mL for both analytes. A report
`on the assay validation was provided in the original marketing application for aripiprazole tablets
`' (NDA 21—436) and was found to be acceptable by the reviewer of NDA 21-436.
`
`Aripiprazole‘—
`were extracted frorn human plasma ————_—-——'
`
`m —
`
`_——- The lower limit of quantitation (LLQ) was established by analyzing a
`single aliquot from six independent sources of control plasma. Quality Control samples (QC)
`prepared in human plasma were analyzed to determine accuracy and within run precision of the
`different methods. The deviations of the predicted concentrations from the nominal
`concentrations (% Deviation) values were within i 15% for both analytes. Aripiprazole and
`dehydro-aripiprazole were stable (within i15% of nominal concentrations) ‘
`W in process
`control for each study report is provided in the individual study reports.
`
`3. Detailed Labeling Recommendations
`
`The reviewer agrees with the sponsor’s changes in the clinical pharmacology (CP) and dosage
`and administration sections of the proposed label except the statement ——
`———-—_—_fhe recommended changes by the sponsor in the CP are
`
`21
`
`

`

`underlined and OCPB changes are double underlinedin the proposed label in the appendix and
`provided below
`‘
`
`l. Pharmacokinetics
`
`Pharmacokinetic studies showed that Abilifi;TM orally disintegrating tablets are bioeguivalent to
`Abilify tablets
`
`l. Dosage and Administration
`
`Directions for Use of AbilifyTM Orally Disintegrating Tablet
`
`Do not open the blister until ready to administer. For single tablet removal, open the package and
`peel back the foil on the blister to expose the tablet. Do not push the