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`DEPARTNIENT OF HEALTH & HUMAN SERVICES
`
`Publifi "Gall" SBMC6
`
`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. lngenito:
`
`Please refer to your new drug application (NDA) dated and received October 31, 2001, submitted
`under section 50S(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 (aiipiprazole) tablets for the treatment of
`schizophreniair.
`
`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 commtmication dated November 7, 2002.
`
`The final 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 Submission 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 '3‘, 2002,
`conduct the following postmarketing studies:
`
`to
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`NDA 21-436
`Page 2
`
`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 of the date of this letter
`
`We acknowledge that this timeline 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-
`negotiated with the Agency.
`
`Studies to determine whether or not doses lower than 10 mg are effective.
`
`Protocol Submission:
`
`Within 6 months of the date of this letter
`
`Study Start:
`Final Report Submission:
`
`Within 12 months of the date of this 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.
`
`to
`Studies to further characterize (e.g., reversibility, ftmctional correlates) and, if possible,
`determine the mecha.nism(s) underlying the retinal degeneration observed in the 26-week and
`2-year carcinogenicity studies in Sprague—Dawley rat.
`
`Protocol Submission:
`
`Within 5 months of the date of this letter
`
`Study Start:
`Final Report Submission:
`
`Within 8 months of the date of this letter
`Within 42 months of the date of this letter
`lb]
`
`_ _ Sprague-Dawley (SD)_ albino rats
`_
`lesion observed in _H___ __
`Since the retinal
`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 dire§_],_e_f_l_'ect of drug. Therefore, a one-month oral tolerability and
`toxicokinetic study in female ':__'_'—f"'--‘
`rats will be initiated in November, 2002 to
`detennine the suitability of this pigmented rat strain for studying the pathogenesis of the retiwil
`degen_eration_in SD rats. If the clinical tolerability and systemic exposure to aripiprazole in
`rats are comparable to that observed in Sprague-Dawley rats at doses resulting in re)--al
`changes, then a draft protocol for the definitive study evaluating the functional consequences,
`reversibility, and pathogenesis of retinal degeneration will be submitted within 5 monthsapf the
`approval letter. If clinical tolerability or systemic exposure to aripiprazole is lower in '_:_-mats
`than in SD rats at comparable doses, then an additional TKr'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 final report dates each.
`
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`NDA 21-436
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`Page 3
`
`4.
`
`Studies investigating the abuse liability of aiipiprazole.
`
`Protocol Submission:
`
`NIA
`
`Study Start:
`Final Report Submission:
`
`July 22, 2002
`Within 5 months of the date of this letter __
`
`We aclcnowledge 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 within 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,
`this product.
`IND for
`Submit clinical protocols to your
`manufacturing, and controls protocols and all study final reports to this NDA.
`In addition, under '21
`CPR 3l4.8l{b)(2)(vii) and 314.8l(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 final 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 314.55r‘21 CFR
`601.27] to this NDA. The Pediatric Rule has been challenged in court. On October 1?, 2002, the court
`ruled that FDA did not have the authority to issue the Pediatric Rule and has barred FDA from
`enforcing it. The government has not yet decided whether to seek a stay of the court's order.
`In
`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 the requirements of the Pediatric Rule as described below.
`In any event,
`we hope you will decide to conduct these pediauic studies to provide important information on the safe
`and effective use of 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 eflecriveness of
`the product in pediatric patients unless this requirement is waived or deferred (21 CFR 3i4.55).
`
`Based ‘on information submitted, we are deferring submission of pediatric studies until January I,
`2007.
`
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`NDA 21-436
`
`Page 4
`
`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/cderlpediatric) 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 2'4 months 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 final 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
`
`Roclcville, MD 2085?
`
`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
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`This is a represantat
`this page isthe rnani
`--uI-—n-—-
`
`is!
`
`Robert Temple
`l1fl5/U2 03:41:12 PM
`
`APPEARS THIS WAY
`OH ORIGINAL
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`h"I‘l u‘ f K
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`
`
`3" /(C DEPARTMENTorHEALTH&HUMANSERVICES I PublicHealthService
`
`Food and Drug Administration
`Roclwille MD 20857
`
`NDA 21-436
`
`Otsuka Pharmaceutical C0,, 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, 200] , received October 31, 2002,
`submitted under section 505(b) ofthe Federal Food, Drug, and Cosmetic Act for Ability (aripiprazole) 2, 5, IO_,
`15, 20 and 30 mg Tablets.
`
`We acknowledge receipt of your submissions as follows:
`
`December 21, 2001
`
`January 17, 2002
`
`February 1, 2002
`
`Febmary 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
`
`May 10, 2002
`
`'
`
`May 15, 2002
`
`May 31, 2002
`
`June 3, 2002
`June 7, 2002
`June 24, 2002
`Juw29.2oo2 —
`
`July 10, 2002
`
`We have completed the review ofthis 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 Pharmacolligy and Biopharmaceutlcs
`
`Please adopt the following dissolution method and specification for all strengths ofaripiprazole tablets (2, 5, 10,
`15, 20 and 30 mg):
`I
`
`- Apparatus: USP Apparatus 2 (paddles) at 60 rpm
`
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`NDA 21-436
`
`Page 2
`
`' 900 mL of 0.1 N HCl (pH 1.2) at 37=eo.5 c°
`- Medium:
`-
`Specification: """"""""'
`in 30min
`
`Clinical
`
`We note that, for several patients, there were abnomial laboratory 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-‘ll-19
`
`97202-89-6
`
`low platelet count
`
`138001-7-281
`
`low platelet count
`
`low platelet count
`
`Chemistry
`
`Establishment inspections:
`
`The Bristol drug product manufacturing, packaging. and release testing facility located in Mayaguez. PR
`(CFN #262?'673) 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.
`
`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 (5) referenced in the DMF. and their precise
`location 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 fort:
`for the Determination of Impurities and Degradation Products.
`
`in the method
`
`
`
`' "9‘or4"2 '
`
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`NDA 21-436
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`Page 3
`
`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
`HDPE 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 aluminumfalurninum cold-fonn blisters.
`the primary packaging components are identical to those employed in the primary stability
`batches. except for the foil lidding.
`In this case. paper-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 25CI60% 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 stability
`data for the 2. 5 and 10 mg tablets at 25C/60% RH and 40Ci75% 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 Abi1itat(an'piprazole)
`. Tablets listed as thename of the drug product. This name was not accepted by the Office of Post-
`Marketing Drug Risk Assessment (OPDRAJ. Please commit to submitting revised container
`closure 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.
`
`U1
`
`7.
`
`8.
`
`9.
`
`10.
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`Foreign Regulatory.Update!Labe|ing-
`
`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
`
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`Page 4
`
`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 ofaripiprazole, we require an updated report on the world archival literature pertaining to
`the safety ofaripiprazole. 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 ofaripiprazole. 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) ofarticles. The report should emphasize clinical data, but new findings in pre—clinical
`reports ofpotential 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 dmg. The labeling shlou-ld be identical in content to the enclosed
`(text for the package insert).
`
`-
`
`Ifadditional infonnation relating to the safety or effectiveness ofthis drug becomes available, revision ofthe
`labeling may be required.
`
`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 update of Februaiy 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 ofthe 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 ofthe 3 positive fixed dose studies, the lowest dose (10, 15, or 20 mg) was numerically 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 detennine
`whether or not doses lower than l0 mg are effective.
`
`To address the longer-terrn efficacy ofaripiprazole in the treatment ofadults with schizophrenia, we
`request that you submit, post-approval, the results of Study 138047.
`
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`NDA 21-436
`
`Page 5
`
`4.
`
`5.
`
`We ask that you commit to conducting,-postapproval, additional studies in order to further characterize
`(e.g. , reversibility, functional correlates) and, ifpossible, to determine the rnechanism(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 of4 monkeys exhibited withdrawal symptoms
`following abmpt cessation ofdosing 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 abnipt cessation ofclosing. Therefore, we ask that you corrunit to conducting,
`postapproval, additional studies investigating the abuse liability of aripiprazole.
`
`Within 10 days after the date ofdue letter, you are required to amend the application, notify us ofyour intent to
`file an amendment, or follow one ofyour other options under 21 CFR 314.1 10. In the absence ofany 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 all _
`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 electroiiic signature page}
`
`Robert Temple, MD.
`Director
`
`-
`
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`attachment - labeling
`
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`Draft Labeling
`(not releasable;
`
`
`
`W
`
`Number of Pages
`Redacted 29‘
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`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.]
`
`ABILIFY"
`(a ripiprazole)
`Tablets
`
`~
`
`‘Rx only
`
`_
`DESCRIPTION
`ABILIFYW (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 fomiula is C231-l27ChN3O2 and its molecular weight is
`
`- '_.‘\
`448.38. The chemical structure is:
`.-"'
`
`’
`
`‘
`
`N-CH2CH2CH2C H20
`\_/
`
`vi)‘
`
`.7
`
`/
`
`pl‘
`
`0
`
`ABILIFY tablets are available in 2-mg, 5-mg, 10-mg, 15-mg, 20-mg, and 30-mg
`strengths. Inactive ingredients include lactose _monohydrate',. comstagch, micnocrystalline
`cell__i_1l§iie, hydroigjaropyl and‘
`stearate. Coloiants include fe1_'_ric
`oxide (yellow or red) and FD&.C li"u‘l'if1'e~'-l*;~lo.2 Alumiiimn I-zake.
`
`CLlNICAL'l’HARMACOLOGY
`
`Pharmacodyuamics
`
`Aripiprazole exhibits high affinity for dopamine D2 and D5, serotonin 5-HT“, and 5-HT”
`receptors (K, values of 0.34, 0.8, 1.7, and 3.4 nM, respectively), moderate affinity for
`dopamine D4, serotonin S-HT2c and 5-HT-;, alpha;-adrenergic and histamine I-I1 receptors
`(K, values of 44, 15, 39, 57, and 61 nM, respectively), and moderate affinity for the
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`serotonin reuptake site (K, = 98 nM). Aripipfazole has no appreciable affinity for
`cholinergic muscarinic receptors (IC50 5 1000 nM). Aripiprazole functions as a partial
`agonist at the dopamine Q and the serotonin 5-HT1A receptors, and as an antagonist at
`serotonin 5-HT2;. 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 Q and 5-
`HTIA receptors and antagonist activity at 5-HT2A receptors. Actions at receptors other
`than D2, 5-HT1A, and 5-HT“ 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. 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 Q 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 closing for both active moieties. Aripiprazole accumulation
`is predictable from single-dose pharmacokinetics. At steady state, the phannacokinetics
`of aripiprazole .are dose-proportional. Elimination of aripiprazole is mainly through
`hepatic metabolism involving two P450 isozymes, CYP2D6 and CYP3A4.
`
`A bsorption
`
`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 the 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
`
`following intravenous
`steady-state volume of distribution of aripiprazole
`The
`administration is high (40-t_l_ L or 4.9 Ukg), indicating extensive extravascular distribution.
`At therapeutic concentrations, aripiprazole and its major metabolite are greater than 99%
`bound to serum proteins, primarily to albumin. In healthy human volunteers administered
`0.5 to 30 mg/day aripiprazole for 14 days,
`there was dose-dependent D;-receptor
`occupancy indicating brain penetration of aripiprazole in humans.
`
`'Metabolism and Elimination
`
`pathways:
`biotransformation
`three
`by
`primarily
`is metabolized
`Aripiprazole
`dehydrogenation, hydroxylation, and N-deallcylation. Based on in virro studies, CYP3A4
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`and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of
`aripiprazole,
`and N-deallcylation is catalyzed by CYP3A4. Aripiprazole
`is
`the
`predominant drug moiety in the systemic circulation. At steady state, dehydro-
`aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.
`
`Approximately 8% of Caucasians lack the capacity to metabolize CYPZD6 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 CYPZD6, 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 7'5 hours and 146 hours for aripiprazole in EMS and PMs, respectively.
`Aripiprazole does not inhibit or induce the CYPZD6 pathway.
`
`Following a single oral dose of [”C]-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 fimction, or renal function (see DOSAGE AND
`ADMINISTRATION: Dosage in Special Populations).
`The phannacokinetics of
`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 Child-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:"min), Cmax of
`aripiprazole (given in a single dose of 15 mg) and dehydro-aripiprazole increased by 36%
`and 53%, re'§pectively, but AUC was 15% lower for aripiprazole and 7% higher for
`dehydro—aripiprazole. Renal excretion of both unchanged aripiprazole and dehydro-
`aripiprazole is less than 1% of the dose. No dosage adjustment is required in subjects
`with renal impairment.
`
`Elderly
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`In formal single-dose phannacokinetic studies (with aripiprazole given in a single dose of
`15 mg), aripiprazole clearance was 20% lower in elderly (265 years) subjects compared
`to younger adult subjects (18-64 years). There was no detectable age effect, however, in
`the
`population
`pharmacokinetic
`analysis
`in
`schizophrenia
`patients. Also,
`the
`phannacokinetics of aripiprazole after multiple doses in elderly patients appeared similar
`to that observed in young healthy subjects. No dosage adjustment is recommended for
`elderly patients. (see PRECAUTIONS: Geriatric Use).
`
`Gender
`
`Cmax and_AUC of aripiprazole and its active metabolite, dehydro-aripiprazole, are 30-
`-40% higher in women than in men, and correspondingly, the apparent oral clearance of
`aripiprazole is lower in women. These differences, however, are largely explained by
`differences in body weight (25%) between men and women. No dosage adjustment is
`recommended based on gender.
`
`Race
`
`Although no specific pharmacokinetic study was conducted to investigate the effects of
`race on the disposition of aripiprazole, population pharmacokinetic evaluation revealed
`no evidence of clinically significant race-related differences in the pharmacokinetics of
`aripiprazole. No dosage adjustment is recommended based on race.
`
`Smoking
`
`Based on studies utilizing human liver enzymes in virro, aripiprazole is not a substrate for
`CYP1A2 and also does not undergo direct glucuronidation. Smoking should, therefore,
`not have an effect on the pharmacokinetics of aripiprazole. Consistent with these in virro
`results, population pharmacokinetic
`evaluation did not
`reveal
`any
`significant
`pharmacokinetic differences between smokers and nonsmokers. No dosage adjustment is
`recommended based on smoking status.
`
`Drug-Drug Interactions
`
`Potentialfor Other Drugs to Aflect ABILIFY
`
`Aripiprazole is not a substrate‘ of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8,
`CYPZC9, CYP2Cl9, or CYP2El enzymes. Aripiprazole also does not undergo direct
`glucuronidation. This suggests that an interaction of aripiprazole with inhibitors or
`inducers of these enzymes, or other factors, like smoking, is unlikely.
`
`Both CYP3A4 and CYPZD6 are responsible for aripiprazole metabolism. Agents that
`induce CYP3A4 (eg, carbamazepine) could cause an increase in aripiprazole clearance
`and lower blood levels. Inhibitors of CYP3A4 (cg, ketoconazole) or CYP2D6 (eg,
`quinidine,
`fluoxetine, or paroxetine) can inhibit aripiprazole elimination and cause
`increased blood levels.
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`Potentialfor ABILIFY to Aflect Other Drugs
`
`Aripiprazole is unlikely to cause clinically important pharmacokinetic interactions with
`drugs metabolized by cytochrome P450 enzymes.
`In in vivo studies, 10- to 30-mg/day
`doses of aripiprazole had no significant
`effect on metabolism by CYPZD6
`(dextromethorphan), CYPZC9 (warfarin), CYP2C19
`(omeprazole, warfarin),
`and
`CYP3A4 (dextromethorphan)
`substrates. Additionally, aripiprazole and dehydro-
`aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vttro
`(see Precautions: Drug-Drug Interactions).
`'
`
`Arrpiprazofe had no clinically important interactions with thefotlowing drugs:
`
`Famotidine: Coadministration of aripiprazole (given in a single dose of 15 mg) with a 40-
`mg single dose of tlie H; antagonist famotidine, a potent gastric acid blocker, decreased
`the solubilit