Drug Approval Package: Abilify (Aripiprazole) NDA #21-436
`
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`Drug Approval Package
`
`Abilify (Aripiprazole) Tablets
`Company: Otsuka Pharmaceutical Co., Ltd.
`Application No.: 21-436
`Approval Date: 11/15/2002
`
`• Approval Letter(s) (PDF)
`• Printed Labeling (PDF)
`• Medical Review(s)
`Part 1 (PDF)
`Part 2 (PDF)
`Part 3 (PDF)
`Part 4 (PDF)
`• Chemistry Review(s) (PDF)
`• Pharmacology Review(s)
`Part 1 (PDF)
`Part 2 (PDF)
`Part 3 (PDF)
`Part 4 (PDF)
`Part 5 (PDF)
`Part 6 (PDF)
`Part 7 (PDF)
`• Statistical Review(s)
`Part 1 (PDF)
`Part 2 (PDF)
`Part 3 (PDF)
`• Clinical Pharmacology Biopharmaceutics Review(s)
`Part 1 (PDF)
`Part 2 (PDF)
`Part 3 (PDF)
`Part 4 (PDF)
`Part 5 (PDF)
`• Administrative Document(s) & Correspondence
`Part 1 (PDF)
`Part 2 (PDF)
`
`Date created: March 07, 2003
`
`Back to Top Drugs@FDA7
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`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-436_Abilify.cfm
`
`2/23/2016
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 001
`
`

`
`Drug Approval Package: Abilify (Aripiprazole) NDA #21-436
`
`Page 2 of 2
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`http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-436_Abilify.cfm
`
`2/23/2016
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 002
`
`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`AJIJIIication Number 21- 'f 3 b
`
`APPROvAL LETTER
`
`--
`' ..
`
`·.
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 003
`
`

`
`("'"~ DEPARTMENT OF HEALTH & HUMAN SERVICES
`.... ::5'-
`
`Public Health Service
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA 21-436
`
`Otsuka Phannaceutical Co., Ltd.
`Attention: Gary Ingenito, M.D., Ph.D.
`President and Chief Operating Officer
`2440 Research Boulevard
`Rockville, MD 20850
`
`Dear Dr. Ingenito:
`
`Please refer to your new drug application (NDA) dated and received October 31, 2001, submitted
`under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Abilify (aripiprazole) 2, 5, 10,
`·•
`15, 20 and 30 mg Tablets
`
`We acknowledge receipt of your submissions of September 18, October 8, and October 16,2002.
`
`Your submission of September 18, 2002 constituted a complete response to our action letter of August
`29, 2002.
`
`This new drug application provides for the use of Abilify ( aripiprazole) tablets for the treatment of
`schizophrenia~:
`
`We have completed our review of this application, as amended. It is approved, effective on the date of
`this letter, for use as recommended in the agreed-upon labeling text.
`
`We note your agreement to the attached labeling as well as the Phase 4 commitments and their
`corresponding time frame completion dates in an e-mail communication dated November 7, 2002.
`
`The fmal printed labeling (FPL) must be identical to the attached labeling (text for the package insert).
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`product misbranded and an unapproved new drug.
`
`Please submit an electronic version of the FPL according to the guidance for industry titled Providing
`Regulatory Submissions in Electronic Format - NDA. For administrative purposes, designate this
`submission "FPL for approved NDA 21-436." Approval of this submission by FDA is not required
`before the labeling is used.
`
`We remind you of your agreed-upon commitments of September 28, and November 7, 2002, to
`conduct the following postmarketing studies:
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 004
`
`

`
`NDA 21-436
`Page 2
`
`1.
`
`A food effect study on the highest strength (30 mg).
`
`Within 2 months of. the date of this letter
`Protocol Submission:
`Within 4 months of the date of this letter
`Study Start:
`Final Report Submission: Within 15 months ofthe date of this letter
`
`We acknowledge that this tirneline assumes that there is no need for Agency feedback on the
`protocol (standard food effect design will be employed) and that the 30 mg strength is tolerated
`by healthy volunteers. If this strength is not tolerated by healthy volunteers resulting in the
`need to conduct this study in schizophrenics, the timeline will be impacted and need to be re(cid:173)
`negotiated with the Agency.
`
`2.
`
`Studies to determine whether or not doses lower than 10 mg are effective.
`
`Protocol Submission:
`Study Start:
`Final Report Submission:
`
`Within 6 months of the date of this letter
`Within 12 months of the date ofthis letter
`Within 42 months of the date of this letter
`
`--
`
`This timeline incorporates 2 months for Agency review of the design of the protocol. If this .
`study demonstrates that lower doses are effective in the treatment of schizophrenia, the results~
`should be submitted to the NDA in the form of an efficacy supplement.
`
`· 3.
`
`Studies to further characterize (e.g., reversibility, functional correlates) and, if possible, to
`determine the mechanism(s) underlying the retinal degeneration observed in the 26-week and
`2-year carcinogenicity studies in Sprague-Dawley rat.
`
`Protocol Submission:
`Study Start:
`Final Report Submission:
`
`Within 5 months of the date of this letter
`Within 8 months of the date of this letter
`Within 42 months of the date of this letter
`
`lbl
`
`Sprague-Dawley (SD)_ albino rats
`Since the retinal lesion observed in
`administered high doses of aripiprazole has morphologic features characteristic of light-induced
`retinopathy, it is critical that the potential for aripiprazole-related ocular changes be
`investigated in a pigmented rat strain .that is less susceptible to light-induced retinal
`degeneration to rule out a diretr1i~f!ect of drug. Therefore, a one-month oral tolerability and
`rats will be initiated in November, 2002 to
`toxicokinetic study in female ·___ _ ·
`determine the suitability of this pigmented rat strain for studying the pathogenesis of the reti~_
`degeneration._ in SD rats. If the clinical tolerability and systemic exposure to aripiprazole in -:(cid:173)
`rats are comparable to that observed in Sprague-Dawley rats at doses resulting in re)--al
`changes, then a draft protocol for the defmitive study evaluating the functional consequences,
`reversibility, and pathogenesis of retinal degeneration will be submitted within 5 month~pf the
`approval letter. If clinical tolerability or systemic exposure to aripiprazole is lower in '::::_ dts
`than in SD rats at comparable doses, then an additional TK/tolerability study in alternate strains
`of pigmented rats will be conducted prior to initiation of the definitive study. We acknowledge
`that this additional pilot study will add approximately 3 to 4 months to the timeline for protocol
`submission, study start, and fmal report dates each.
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 005
`
`

`
`,_
`
`NDA 21-436
`Page 3
`
`4.
`
`Studies investigating the abuse liability of aripiprazole.
`
`N/A
`Protocol Submission:
`July 22, 2002
`Study Start:
`Final Report Submission: Within 5 months of the date of this letter .
`
`We acknowledge that you are currently conducting an abuse liability study in monkeys in
`Japan. The timeline above incorporates roughly 2 months needed to translate the protocol into
`English.
`
`5.
`
`Submit the results of Study 138047 to address the longer-term efficacy of aripiprazole in the
`treatment of adults with schizophrenia.
`
`We acknowledge that this study has already been completed and that the safety data were
`reported as part of the 120 Day Safety Update. However, a formal submission of the results of
`this study will be submitted witrun 30 days of the date of the approval letter. This submission
`should be submitted to the NDA as an efficacy supplement.
`
`--
`
`Submit nonclinical and chemistry,
`Submit clinical protocols to your IND for this product.
`In addition, under 21
`manufacturing, and controls protocols and all study final reports to this NDA.
`CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you should include a status summary of each
`commitment in your annual report to this NDA. The status summary should include expected
`summary completion and fmal report submission dates, any changes in plans since the last annual
`report, and, for clinical studies, number of patients entered into each study. All submissions, including
`supplements, relating to these postmarketing study commitments must be prominently labeled
`"Postmarketing Study Protocol", "Postmarketing Study Final Report", or "Postmarketing Study
`Correspondence."
`
`The text in italics below addresses the application of FDA's Pediatric Rule at [21 CFR 314.55/21 CFR
`601.27] to this NDA. The Pediatric Rule has been challenged in court. On October 17, 2002, the court
`ruled that FDA did not have the authority to issue the Pediatric Rule and has barred FDA from
`In
`enforcing it. The government has not yet decided whether to seek a stay of the court's order.
`addition, the government has not yet decided whether to appeal the decision; an appeal must be filed
`within 60 days. Therefore, this letter contains a description of the pediatric studies that would be
`required under the Pediatric Rule, if the Pediatric Rule remained in effect and/or were upheld
`on appeal. Please be aware that whether or not these pediatric studies will be required will depend ·
`upon the resolution of the litigation. FDA will notify you as soon as possible as to whether this
`application will be subject to th~ requirements of the Pediatric Rule as described below. In any event,
`we hope you will decide to conduct these pediatric studies to provide important information on the safe
`and effective use o( this drug in the relevant pediatric populations.
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens must contain an assessment of the safety and effectiveness of
`the product in pediatric patients unless this requirement is waived or defe"ed (21 CFR 314.55).
`
`Based ·on information submitted, we are defe"ing sub~ission of pediatric studies until January 1,
`2007.
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 006
`
`

`
`NDA 21-436
`Page4
`
`The pediatric exclusivity provisions of FDAMA as reauthorized by the Best Pharmaceuticals for
`Children Act are not affected by the court's ruling. Pediatric studies conducted under the terms of
`section 505A of the· Federal Food, Drug, and Cosmetic Act may result in additional marketing
`exclusivity for certain products (pediatric exclusivity). You should refer to the Guidance for Industry
`on Qualifying for Pediatric Exclusivity (available on our web site at www.fda.gov/cder/pediatric) for
`details. If you wish to qualify for pediatric exclusivity you should submit a "Proposed Pediatric Study
`Request". FDA generally does not consider studies submitted to an NDA before issuance of a Written
`Request as responsive to the Written Request. Applicants should obtain a Written Request before
`submitting pediatric studies to an NDA.
`
`Please note that we have approved an expiration date of 24· month~ for all strengths of this drug
`product.
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials-in draft or mock-up form, not fmal print. Send one copy to
`this division and two copies of both the promotional materials and the package insert directly to:
`
`Division of Drug Marketing, Advertising, and Communications, HFD-42
`Food and Drug Administration
`5600 Fishers Lane
`Rockville, MD 20857
`
`--
`
`Validation of the regulatory methods has not been completed. At the present time, it is the policy of
`the Center not to withhold approval because the methods are being validated. Nevertheless, we expect
`your continued cooperation to resolve any problems that may be identified.
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`If you have any questions, call Steven D. Hardeman, R.Ph., Senior Regulatory Project Manager at
`(301) 594-5525.
`
`Sincerely,
`
`{See appended electronic signature page)
`
`Robert Temple, M.D.
`Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Enclosure
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 007
`
`

`
`· - - - - - - - - - - · - - - - - - - - - - - · - - - - - - - - - · - -
`This is a representation o f an electronic record that was signed electronically and
`- - - · - - - - - - - - · - - - - - - - - - - - - - - - - - - - - - - - - - - -
`th is page is. the manifestation o f the electronic signature.
`
`/ s /
`R o b e r t T e m p l e
`1 1 / 1 5 / 0 2 0 3 : 4 1 : 1 2 PM
`
`...
`
`APPEARS THIS WA'i
`ON ORIGINAL
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 008
`
`

`
`CENTER FOR DRUG EYAI,UATION AND RESEARCH
`AppUr,ation Number Z l·t.f 3' .
`
`APPROYABLE LET'l'ER
`
`--.
`
`·.
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 009
`
`

`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`Public Health Service
`
`Food and Drug Administration
`Rockville MD 20857
`
`NDA 21-436
`
`Otsuka Pharmaceutical Co., Ltd.
`Attention: Gary Ingenito, M.D., Ph.D.
`President and Chief Operating Officer
`2440 Research Boulevard
`Rockville, MD 20850
`
`Dear Dr. Ingenito:
`
`Please refer to your new drug application (NDA) dated October 31, 2001, received October 31, 2002,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for Abilify ( aripiprazole) 2, 5, 10,
`15,20 and 30 mg Tablets.
`~-
`
`We acknowledge receipt of your submissions as follows:
`
`December 21, 200 1
`
`January 17, 2002
`
`February 1, 2002
`
`February 12, 2002
`
`February 25, 2002
`
`February 27, 2002
`
`March 15, 2002
`
`March 20, 2002
`
`March 22, 2002
`
`March 29, 2002
`
`April 4, 2002
`
`April 10, 2002
`
`April 15, 2002
`
`April 16, 2002
`
`April 29, 2002
`
`May 8, 2002
`
`May 9, 2002
`
`June 3, 2002
`
`July 29, 2002
`
`May 10,2002
`
`May 15,2002
`
`June 7, 2002
`
`June 24, 2002
`
`May 31,2002
`
`July 10, 2002
`
`We have completed the review of this application, as amended, and it is approvable. Before this application may
`be approved, however, it will be necessary for you to address the following:
`
`Clinical Pharmacology and Biopharmaceutics
`
`Please adopt the following dissolution method and specification for all strengths of aripiprazole tablets (2, 5, 10,
`15, 20 and 30 mg):
`
`• Apparatus: USP Apparatus 2 (paddles) at 60 rpm
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 010
`
`

`
`NDA 21-436
`Page 2
`
`900 mL ofO.l N HCl (pH 1.2) at 37±0.5 C0
`• Medium:
`in 30 min
`• Specification: ·
`
`Clinical
`
`We note that, for several patients, there were abnonnallaboratory findings present at the last visit, but no followup .
`information. We ask that you attempt to find and provide followup laboratory and other information on the
`following patients:
`
`138001-33-102
`
`elevated SGOT
`
`97201-36-18
`
`elevated SGOT
`
`138001-7-458
`
`elevated CPK
`
`97202-89-6
`
`low platelet count
`
`138001-7-281
`
`low platelet count
`
`97202-71-19
`
`low platelet coimt
`
`Chemistry
`
`Establishment Inspections:
`
`.~-.
`
`The Bristol diug product manufacturing, packaging, and release testing facility located in Mayaguez, PR
`(CFN #2627673) was found to be unacceptable by the FDA's Office of Compliance. We note that your
`application describes other facilities that perform these functions. If you plan to utilize the Mayaguez,
`PR site (CFN ·#2627673), a satisfactory inspection will be needed, otherwise the site should be
`withdrawn from the NDA.
`
`Drug Substance and Drug Product:
`
`1.
`2.
`
`3.
`
`4.
`
`Please provide detailed methodology for the identification of aripiprazole drug substance by IR.
`Please provide detailed information supporting the use of your drug substance packaging. Any
`relevant DMF information should include appropriate letters of authorization (LOAs), which
`clearly indicate (by name, part number, etc.) the item(s) referenced in the DMF, and their precise
`locatio·n and-date of inclusion in the DMF.
`Please include a sample of the label to be used for the drug substance during shipping and
`storage. The label should clearly indicate the name of the bulk substance, the identifying lot or
`control number, and the storage condition for the drug substance.
`Please provide the limit of detection and the limit of quantitation fon
`for the Determination of Impurities and Degradation Products.
`
`in the method
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 011
`
`

`
`NDA 21-436
`Page 3
`
`5.
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`Please provide a certificate of analysis for each of the drug product excipients.
`
`"'
`.
`" Please explain.
`Please provide a complete and detailed description of the secondary packaging systems for the
`HOPE bottles and blister strips. Your response should include specifications and in-process
`controls.
`On page 50 of volume 1.4 you state "In the case of the aluminum/aluminum cold-form blisters.
`the primary packaging components are identical to those employed in the primary stability
`batches, except for the foil lidding. In this case. papw-backed aluminum foil laminate was used
`for the primary stability batches, whereas the batches intended for marketing will use either the
`same ... or a plain (non-paper-backed) aluminum foil laminate of identical structure, composition
`and moisture and oxygen barrier properties." Please provide the appropriate data to demonstrate
`that these packaging systems are equivalent.
`On page 101 in the drug product stress stability section, you indicated that you would include data
`for the 2. 5, 10, 15, 20 and 30 mg tablets at 25C/60% RH and 40C/75% RH in the open petri
`dish, however. you only included data for the 15, 20 and 30 mg tablets. Please provide stabil~~
`data for the 2, 5 and 10 mg tablets at 25C/60% RH and 40C/75% RH in the open petri dish ..
`Please provide updated drug substance stability data.
`Please provide updated stability data for the 2. 5, 10, 15, 20 and 30 mg tablets manufactured at
`.the Mayaguez, Puerto Rico facility.
`Please provide updated drug product release specifications which reflect the biopharm dissolution
`recommendation.
`The 1987 FDA Guidance for Submitting Samples and Analytical Data for Methods Validation
`indicates that four copies of the Methods Validation Package should be included with your
`original submission. Accordingly. we request that you submit two additional copies of the
`Methods Validation Package.
`The proposed carton and blister backing for the drug product has the name Abilitat (aripiprazole)
`, Tablets listed as the' name of the drug product. This name was not accepted by the Office of Post(cid:173)
`Marketing Drug Risk Assessment (OPDRA). Please commit to submitting revised container
`dosure information for the new proprietary name. Abilify.
`Labels for the secondary packaging of the cold-form blisters were provided, however, you did
`not provide labels for folding cartons (30, 60, 90 and 500 count bottles) of the drug product.
`Please indicate if you plan to use secondary packaging for these bottles and if so please provide
`draft labeling for each strength.
`
`Foreign Regulatory_ Update/Labeling·
`
`We require a review of the status of all aripiprazole actions taken or pending before foreign regulatory
`authorities. Approval actions can be noted, but we ask that you describe in detail any and all actions taken that
`have been negative, supplying a full explanation of the views of all parties and the resolution of the matter. If
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 012
`
`

`
`NDA 21-436
`Page4
`
`aripiprazole has been approved by any non-US regulatory bodies, we ask that you provide us any approved
`labeling for aripiprazole along with English translations when needed.
`
`·world Literature Update
`
`Prior to the approval of aripiprazole, we require an updated report on the world archival literature pertaining to
`the safety of aripiprazole. This report should include only literature not covered in your previous submissions. We
`need your warrant that you have reviewed this literature systematically, and in detail, and that you have discovered
`no finding that would adversely affect conclusions about the safety of aripiprazole. The report should also detail
`how the literature search was conducted, by whom (their credentials) and whether it relied on abstracts or full
`texts (including translations) of articles. The report should emphasize clinical data, but new findings in pre-clinical
`reports of potential significance should also be described. Should any report or finding be judged important, a
`copy (translated as required) should be submitted for our review.
`
`Labeling
`
`Please submit revised draft labeling for the drug. The labeling shouid be identical in content to the enclosed labefuig
`(text for the package insert).
`
`If additional information relating to th~ safety or effectiveness of this drug becomes available, revision of the
`labeling may be req'!lired.
`
`Safety Update
`
`Our assessment of the safety of aripiprazole is based on our review of all safety information provided
`in your original and subsequent submissions, including your safety up~te ofFebtuaiy 27, 2002. Please provide ·
`a final serious events update to include serious adverse events up to a more recent cutoff date.
`
`Post Approval (Phase 4) Commitments
`
`1.
`
`2.
`
`3.
`
`Due to the limited solubility ofaripiprazole and non-rapid dissolving nature of the tablet in gastric pH (pH
`1.2), we ask that you commit to conducting a food effect study on the highest strength (30 mg).
`
`In each of the 3 positive fixed dose studies, the lowest dose (1 0, 15, or 20 mg) was nwnerically superior
`to all the higher doses. You have thus not adequately explored the lower end of the dose response curve
`for effectiveness. We ask that you commit to conducting, postapproval, additional studies to determine
`whether or not doses lower than 10 mg are effective.
`
`To address the longer-term efficacy of aripiprazole in the treatment of adults with schizophrenia, we
`request that you submit, post-approval, the results of Study 138047.
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 013
`
`

`
`NDA 21-436
`Page 5
`
`4.
`
`5.
`
`We ask that you commit to conducting,-postapproval, additional studies in ord~r to further characterize
`(e.g., reversibility, functional correlates) and, if possible, to determine the mechanism( s) underlying the
`retinal degeneration observed in the 26-wk and 2-yr carcinogenicity studies in Sprague-Dawley rat.
`
`The data from studies conducted in rhesus monkey suggest that aripiprazole may have some abuse
`liability. One of 4 monkeys trained to self-administer cocaine continued to self-administer when
`aripiprazole was substituted for cocaine. In addition, 4 of 4 monkeys exhibited withdrawal symptoms
`following abrupt cessation of dosing with aripiprazole. Although self-stimulation was not observed in rats
`when aripiprazole was substituted for cocaine, there was a tendency for animals to exhibit withdrawal
`symptoms following abrupt cessation of dosing. Therefore, we ask that you commit to conducting,
`postapproval, additional studies investigating the abuse liability of aripiprazole.
`
`Within I 0 days after the date of this letter, you are required to amend the application, notify us of your intent to
`file an amendment, or follow one of your other options under 21 CFR 314.110. In the absence of any such action
`FDA may proceed to withdraw the application. Any amendment should respond to all the deficiencies listed.
`We will not process a partial reply as a major amendment nor will the review clock be reactivated until ~Q. .
`deficiencies have been addressed.
`
`The drug product may not be legally marketed until you have been notified in writing that the application is
`approved.
`-
`
`Ifyou have any questions, call Steven D. Hardeman, R.Ph., Senior Regulatory Project Manager, at (301)
`594-5525.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Robert Temple, M.D.
`Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`attachment - labeling
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 014
`
`

`
`--- ················· ----
`
`· Number of Pages
`Redacted · ;?cr.·
`
`..................
`• • •
`
`Draft Labeling
`(not releasable)
`.. G
`
`..
`·-----
`
`-.
`-- ...
`
`--- ................. ---
`
`.. ,
`
`. ; .
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 015
`
`

`
`·
`CENTER FOR DRUG Irf ALUATION ANDRE
`. SEARCH
`
`AppUcation Number 21·· 1/ 36
`
`FJNAI, PRINTED LABELING
`
`....
`
`-;.
`
`·.
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 016
`
`

`
`Enclosure
`
`[We note your agreement to the labeling below in an electronic
`communication dated November 15, 2002. Additionally, we note
`that, at this time, you intend to market only the 10 mg, 15 mg, 20
`mg, and 30 mg dosage strengths. However, the Agency is
`approving all of the following dosage strengths: 2 mg, 5 mg, 10
`mg, 15 mg, 20 mg, and 30 mg. Additionally, for completeness, we
`are including these dosage strengths into the labeling.)
`
`ABILIFYDI
`( aripiprazole)
`Tablets
`
`·Rx only
`
`DESCRIPTION
`ABILIFYTM (aripiprazole) is a psychotropic drug that is available as tablets for oral
`administration. Aripiprazole is 7 -[ 4-[ 4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy ]-3,4-
`dihydrocarbostyril. The empirical formula is C23H2~~N 302 and its molecular weight is
`448.38. The chemical structure is:
`
`--.
`
`. )" ;: ..
`
`ABIL'IFY tablets are available in 2-mg, 5-mg, 1 0-mg, 15-mg, 20-mg, and 30-mg
`strengths. Inactive ingredients include lactose _monohydrate~ _cornStaq:h, microcryStalline
`cell~§ie. hydro~ropyl ~iiiii(i~e, and. magriesi~ ste~e. Col~nmts include fe~c
`oxiae (yellow or red) and FD&C Btuec.No.2 Alumiiium take.
`
`CLU«CALPHARMACOLOGY
`
`Pharmacodynamics
`Aripiprazole exhibits high affinity for dopamine Dz and D.h serotonin 5-HTIA and 5-HT2A
`receptors (Ki values of 0.34, 0.8, 1.7, and 3.4 nM, respectively), moderate affinity for
`dopamine~. serotonin S-HT2c and S-HT1, alpha1-adrenergic and histamine ll receptors
`(Ki values of 44, 15, 39, 57, and 61 nM, respectively), and moderate affinity for the
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 017
`
`

`
`serotonin reuptake site (Ki = 98 nM). Aripipfazole has no appreciable affinity for
`cholinergic muscarinic receptors (ICso > 1000 nM). Aripiprazole functions as a partial
`agonist at the dopamine I)z and the serotonin 5-HTtA receptors, and as an antagonist at
`serotonin 5-HT 2A receptor.
`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 I)z and 5-
`HTtA receptors and antagonist activity at 5-HT2A receptors. Actio"ns at receptors other
`than ~. 5-HTtA, and 5-HT2A may explain some of the other clinical effects of
`aripiprazole, eg, the orthostatic hypotension observed with aripiprazole may be explained
`by its antagonist activity at adrenergic alpha 1 receptors.
`
`Pharmacokinetics
`
`ABILIFY activity is presumably primarily due to the parent drug, aripiprazole, and to a
`lesser extent, to its major metabolite dehydro-aripiprazole, which has been shown to have
`affinities for I)z receptors similar to the parent drug and represents 40% of the parent
`drug exposure in plasma. The mean elimination half-lives are about 75 hours and 94
`hours for aripiprazole and dehydro-aripiprazole, respectively. Steady-state concentrations
`are attained within 14 days of dosing for both active moieties. Aripiprazole accumulation
`is predictable from single-dose pharmacokinetics. At steady state, the pharmacokinetics
`of aripiprazole .are dose-proportional. Elimination of aripiprazole is mainly through
`hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4.
`
`....
`
`Absorption
`
`Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3 to 5
`hours; the absolute oral bioavailability of the tablet formulation is 87%. ABILIFY can be
`administered with or without food. Administration of a 15-mg ABILIFY tablet with a
`standard high-fat meal did not significantly affect tlie Cmax or AUC of aripiprazole or its
`active metabolite, dehydro-aripiprazole, but delayed Tmax by 3 hours for aripiprazole
`and 12 hours for dehydro-aripiprazole.
`
`Distribution
`
`intravenous
`following
`The steady-state volume of distribution of aripiprazole
`administration is high (404 Lor 4.9 L/kg), indicating extensive extravascular distribution.
`At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99%
`bound to serwn proteins, primarily to albumin. In healthy human volunteers administered
`0.5 to 30 mg/day aripiprazole for 14 days, there was dose-dependent ~-receptor
`occupancy indicating brain penetration of aripiprazole in humans.
`
`·Metabolism and Elimination
`
`three biotransformation pathways:
`is metabolized primarily by
`Aripiprazole
`dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4
`
`2
`
`Roxane Labs., Inc.
`Exhibit 1009
`Page 018
`
`

`
`and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of
`aripiprazole, and N-dealkylation
`is catalyzed by CYP3A4. Aripiprazole
`is
`the
`predominant drug moiety in the systemic circulation. At steady state, dehydro(cid:173)
`aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.
`
`Approximately 8% of Caucasians lack the capacity to metabolize CYP2D6 substrates and
`are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers
`(EM). PMs have about an 80% increase in aripiprazole exposure and about a 30%
`decrease in exposure to the active metabolite compared to EMs, resulting in about a 60%
`higher exposure to the total active moieties from a given dose of aripiprazole compared to
`EMs. Coadministration of ABILIFY with known inhibitors of CYP2D6, like quinidine in
`EMs results in a 112% increase in aripiprazole plasma exposure, and dosing adjustment is
`needed (see PRECAUTIONS: Drug-Drug Interactions). The mean elimination half-lives
`are about 75 hours and 146 hours for aripiprazole in EMs and PMs, respectively.
`Aripiprazole does not inhibit or induce the CYP2D6 pathway.
`
`Following a single oral dose of [14C]-labeled aripiprazole, approximately 25% and 55%
`of the administered radioactivity was recovered in the urine and feces, respectively. Less
`than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% of
`the oral dose was recovered unchanged in the feces.
`
`_., .
`
`Special Populations
`
`In general, no dosage adjustment for ABILIFY is required on the basis of a patient's age,
`gender, race, smoking status, hepatic function, or renal function (see DOSAGE AND
`The pharmacokinetics of
`ADMINISTRATION: Dosage in Special Populations).
`aripiprazole in special populations are described below.
`
`Hepatic Impairment
`
`In a single-dose study ( 15 mg of aripiprazole) in subjects with varying degrees of liver
`cirrhosis {:hild-Pugh Classes A, B, and C), the AUC of aripiprazole, compared to
`healthy subjects, increased 31% in mild HI, increased 8% in moderate HI, and decreased
`20% in severe HI. None of these differences would require dose adjustment.
`
`Renal Impairment
`
`In patients with severe renal impairment (creatinine clearance < 30 mL/rnin), Cmax of
`aripiprazole (giv