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`Public Health Service
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`Food and Drug Administration
`Rockville, MD 20857
`
`NDA21-436
`
`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 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
`
`Weacknowledgereceipt 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 ofthis application, as amended. It is approved, effective on the date of
`this letter, for use as recommended in the agreed-upon labelingtext.
`
`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 November7, 2002.
`
`Thefinal printed labeling (FPL) must be identical to the attached labeling (text for the packageinsert).
`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 FDAis not required
`before the labeling is used.
`
`We remind you of your agreed-upon commitments of September 28, and November 7, 2002,
`conduct the following postmarketing studies:
`
`to
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`NDA 21-436
`Page 2
`
`1.
`
`A food effect study on the highest strength (30 mg).
`
`Within 2 monthsofthe date of this letter
`Protocol Submission:
`Within 4 monthsofthe date ofthis letter
`StudyStart:
`Final Report Submission: Within 15 months ofthe date of this letter
`
`Weacknowledgethat this timeline assumesthat there is no need for Agency feedback on the
`protocol(standard food effect design will be employed)andthat the 30 mgstrength 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 needto bere-
`negotiated with the Agency.
`
`2.
`
`Studies to determine whether or not doses lower than 10 mgare effective.
`
`Within 6 monthsofthe dateofthis letter
`Protocol Submission:
`Within 12 months ofthe date of this letter
`Study Start:
`Final Report Submission:|Within 42 months ofthe date ofthis letter
`
`This timeline incorporates 2 months for Agency review ofthe design ofthe protocol. If this .
`study demonstrates that lower doses are effective in the treatment of schizophrenia, the results"
`should be submitted to the NDAin the form ofan efficacy supplement.
`
`3.
`
`to
`Studies to further characterize (e.g., reversibility, functional correlates) and, if possible,
`determine the mechanism(s) underlying the retinal degeneration observed in the 26-week and
`2-year carcinogenicity studies in Sprague-Dawleyrat.
`
`Within 5 monthsofthe date ofthisletter
`Protocol Submission:
`Within 8 monthsofthe date ofthisletter
`Study Start:
`Final Report Submission:|Within 42 monthsofthe date ofthisletter
`(b)
`
`- Sprague-Dawley (SD)albino rats
`lesion observed in —
`Since the retinal
`administered high doses ofaripiprazole 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 direg$effect of drug. Therefore, a one-month oral tolerability and
`toxicokinetic study in female|=———~
`rats will be initiated in November, 2002 to
`determinethe suitability ofthis pigmented rat strain for studying the pathogenesis ofthe retigal
`degenerationin SD rats. If the clinical tolerability and systemic exposure to aripiprazoleiin —
`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 ofretinal degeneration will be submitted within 5 months,of the
`approvalletter.
`If clinical tolerability or systemic exposure to aripiprazole is lower in '—ats
`than in SD rats at comparable doses, then an additional TK/tolerability study in alternate strains
`of pigmentedrats will be conducted priortoinitiation of the definitive study. We acknowledge
`that this additional pilot study will add approximately 3 to 4 months to the timeline for protocol
`submission,studystart, and final report dates each.
`
`'
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`NDA 21-436
`Page 3
`
`4.
`
`Studies investigating the abuseliability of aripiprazole.
`
`Protocol Submission:
`Study Start:
`Final Report Submission:
`
`N/A
`July 22, 2002
`Within 5 monthsofthe date ofthis letter _
`
`We acknowledge that you are currently conducting an abuse liability study in monkeys in
`Japan. The timeline above incorporates roughly 2 months neededto 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 ofthe results of
`this study will be submitted within 30 days of the date of the approval letter. This submission
`should be submitted to the NDAasan efficacy supplement.
`
`Submit nonclinical and chemistry,
`this product.
`IND for
`Submit clinical protocols to your
`manufacturing, and controls protocols andall study final reports to this NDA.
`In addition, under 21
`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 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 314.55/21 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
`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 youwill decide to conduct these pediatric studies to provide important information onthe 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 assessmentof the safety and effectiveness of
`the product in pediatric patients unless this requirementis waived or deferred (21 CFR 314.55).
`
`Based on information submitted, we are deferring submission of pediatric studies until January 1,
`2007.
`
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`NDA21-436
`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 theFederal 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 website 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 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 packageinsert 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 methodsare being validated. Nevertheless, we expect
`your continued cooperation to resolve any problemsthat maybeidentified.
`
`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 Managerat
`(301) 594-5525.
`
`. Sincerely,
`
`{See appendedelectronic signature page}
`
`Robert Temple, M.D.
`Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Enclosure
`
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`eee “emeritiesADNOGITTTayThisisa representationofanelectronicrecordthatwassignedelectronicallyand
`this page is.the manifestation of the electronic signature.0mel
`
`oeeeeerence
`
`——=s
`
`/s/
`
`Robert Temple
`11/15/02 03:41:12 PM
`
`APPEARS THIS WAY
`ON ORIGINAL
`
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`Application Number 1-4 36_
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`is,
`
`al
`
`*
`
`walte
`
`%,
`
`
`
` € DEPARTMENTOFHEALTH&HUMANSERVICES PublicHealthService
`
`
`
`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 undersection 505(b) ofthe Federal Food, Drug, and Cosmetic Act for Abilify (aripiprazole) 2, 5,1 ,
`15, 20 and 30 mg Tablets.
`™
`
`Weacknowledgereceipt of your submissions as follows:
`
`
`
`
`
`
`
`
`
`
`
`
`
`a W
`
`ehave completed the review ofthis application, as amended, andit 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 forall strengths ofaripiprazoletablets (2, 5, 10,
`15, 20 and 30 mg):
`
`¢ Apparatus: USP Apparatus 2 (paddles) at 60 rpm
`
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`NDA 21-436
`Page 2
`
`900 mL of 0.1 NHCI (pH 1.2) at 3740.5 C°
`© Medium:
`*
`Specification: ——— in 30min
`
`Clinical
`
`Wenote that, for several patients, there were abnormal laboratory findings presentat the last visit, but no followup .
`information. Weaskthat you attemptto find and providefollowuplaboratory andother 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
`97202-71-19
`
`low platelet count
`low platelet count
`
`.
`
`—
`
`Chemistry
`
`Establishment Inspections:
`
`The Bristol drug product manufacturing, packaging, andreleasetesting facility located in Mayaguez, PR
`(CFN #2627673) was found to be unacceptable by the FDA's Office of Compliance. Wenote 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 forthe 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
`location anddate 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 nameof the bulk substance, the identifying lot or
`control number, and the storage condition for the drug substance.
`;
`in the method
`Please provide the limit of detection and the limit of quantitation for:
`-
`for the Determination of Impurities and Degradation Products.
`
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`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.
`
`
`
`TT
`" Please explain.
`Please provide a complete and detailed description of the secondary packaging systems for the
`HDPEbottles and blister strips. Your response should include specifications and in-process
`controls.
`On page 50 of volume1.4 youstate “In the case of the aluminum/aluminum cold-form blisters,
`the primary packaging components areidentical to those employed in the primary stability
`batches, exceptfor the foil lidding.
`In this case, papar-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 systemsare equivalent.
`On page 101 in the drug productstress stability section, you indicated that you wouldinclude data
`for the 2, 5, 10, 15, 20 and 30 mgtablets at 25C/60% RH and 40C/75% RH in the openpetri
`dish, however, you only included data for the 15, 20 and 30 mgtablets. Please providestability
`data for the 2, 5 and 10 mg tablets at 25C/60% RH and 40C/75% RH in the openpetri dish..
`Please provide updated drug substancestability data.
`Please provide updatedstability data for the 2, 5, 10, 15, 20 and 30 mgtablets manufactured at
`theMayaguez, Puerto Ricofacility.
`Please provide updated drug productrelease 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 proposedcarton andblister backing for the drug product has the nameAbilitat (aripiprazole)
`. Tablets listed as the’nameof the drug product. This name was not accepted by the Office of Post-
`Marketing Drug Risk Assessment (OPDRA). Please commit to submitting revised container
`closure information for the new proprietary name, Abilify.
`Labels for the secondary packagingof the cold-form blisters were provided, however, you did
`not providelabels for folding cartons (30, 60, 90 and 500 countbottles) 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-
`
`Werequire a review ofthestatusofall 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 takenthat
`have been negative, supplyinga full explanation ofthe viewsofall parties and the resolution ofthe matter. If
`
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`NDA21-436
`Page 4
`
`aripiprazole has been approved by any non-USregulatory bodies, we ask that you provide us any approved
`labeling for aripiprazole along with English translations when needed.
`
`World Literature Update
`
`Priorto the approvalofaripiprazole, we require an updated report on the world archival literature pertaining to
`the safety ofaripiprazole. This report should includeonlyliterature not covered in your previous submissions. We
`need your warrant that you have reviewed thisliterature 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
`howtheliterature search was conducted, by whom (their credentials) and whether it relied on abstracts orfull
`texts (includingtranslations) ofarticles. The report should emphasize clinical data, but new findings in pre-clinical
`reports ofpotential significance should also be described. Should any report orfinding be judged important, a
`copy(translated as required) should be submitted for our review.
`
`Labeling
`
`Please submitrevised draft labelingforthedrug. The labeling should be identicalincontenttothe enclosed labeling
`
`(text for the package insert).
`
`Ifadditional information relating to the safety oreffectivenessofthis drug becomesavailable, revision ofthé
`labeling may be required.
`
`Safety Update
`
`Our assessmentofthe safety of aripiprazole is based on our review ofall safety information provided
`in your original and subsequent submissions,including your safety update of February 27, 2002. Please provide ~
`a final serious events update to include serious adverse events up to a more recentcutoff date.
`
`Post Approval (Phase 4) Commitments
`
`1.
`
`2.
`
`3.
`
`Dueto the limited solubility ofaripiprazole and non-rapid dissolvingnature 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 eachofthe 3 positive fixed dose studies,the lowest dose (10, 15, or 20 mg) was numerically superior
`to all the higher doses. You havethus not adequately explored the lower endof the dose response curve
`for effectiveness. We ask that you committo conducting, postapproval, additional studies to determine
`whetheror not doses lowerthan 10 mgare effective.
`
`To address the longer-term efficacy ofaripiprazole in the treatmentofadults with schizophrenia, we
`request that you submit, post-approval, the results of Study 138047.
`
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`NDA21-436
`Page 5
`
`4,
`
`5:
`
`Weaskthat you committo conducting,postapproval, additionalstudiesin order to further characterize
`(e.g., reversibility, functional correlates) and, ifpossible, to determine the mechanism(s) underlying the
`retinal degeneration observedin the 26-wk and 2-yr carcinogenicity studies in Sprague-Dawleyrat.
`
`The data from studies conducted in rhesus monkey suggestthat aripiprazole may have some abuse
`liability. One of 4 monkeystrained to self-administer cocaine continued to self-administer when
`aripiprazole was substituted for cocaine. In addition, 4 of4 monkeys exhibited withdrawal symptoms
`following abrupt cessation ofdosing with aripiprazole. Although self-stimulation was notobserved in rats
`whenaripiprazole was substituted for cocaine, there was a tendency for animals to exhibit withdrawal
`symptoms following abrupt cessation ofdosing. Therefore, we ask that you commit to conducting,
`postapproval, additional studies investigating the abuseliability of aripiprazole.
`
`Within 10 daysafter the date ofthisletter, you are required to amendthe application, notify us ofyour intent to
`file an amendment, or follow one ofyour other options under 21 CFR 314.110. In the absence ofany such action
`FDA mayproceed to withdraw the application. Any amendment should respondtoall the deficiencieslisted.
`Wewill not processa partial reply as a major amendmentnorwill the review clockbe reactivated until all _
`deficiencies have been addressed.
`
`The drug product may notbe legally marketed until you have beennotified in writing that the applicationis
`approved.
`
`Ifyou have any questions,call Steven D. Hardeman, R.Ph., Senior Regulatory Project Manager,at (301)
`594-5525.
`
`Sincerely,
`
`{See appendedelectronic signature page}
`
`Robert Temple, M.D.
`Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`attachment- labeling
`
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`
`
`Numberof Pages
`
`Redacted_<7_
`
`
`Draft Labeling
`(not releasable,
`
`
`
`
`|
`
`—
`
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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 strengthsinto the labeling.]}
`
`ABILIFY™
`(aripiprazole)
`Tablets
`
`.
`
`‘Rx only
`
`;
`DESCRIPTION
`ABILIFY™ (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 C)3H27CkN3O> and its molecular nemis
`
`448.38. The chemical structure is:
`
`a
`om
`
`“joe
`
`-
`
`cl
`
`cl
`
`/\
`N
`—_N-CH)CH2CH2CH20
`7 NS
`
`N~
`H
`
`~O
`
`ABILIFY tablets are available in 2-mg, 5-mg, 10-mg, 15-mg, 20-mg, and 30-mg
`mirengths. Inactive ingredients include lactose monohydrate, cornstarch, microcrystalline
`
`cellulose, hydroxypropyl cellu€ellulose,
`and magnesium stearate. Colorants include ferric
`oxide (yellow or red) and FD&C Blite-No.2 Alumiiium Lake.
`
`CLINICALPHARMACOLOGY
`
`Pharmacodynamics
`
`Aripiprazole exhibits high affinity for dopamine D, and D3, serotonin 5-HT,,4 and 5-HT2,
`receptors (Kj values of 0.34, 0.8, 1.7, and 3.4 nM, respectively), moderate affinity for
`dopamine Dy, serotonin 5-HT2c and 5-HT7, alphaj-adrenergic and histamine H, receptors
`(Kj values of 44, 15, 39, 57, and 61 nM,respectively), and moderate affinity for the
`
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`serotonin reuptake site (Kj = 98 nM). Aripiptazole has no appreciable affinity for
`cholinergic muscarinic receptors (ICs9 > 1000 nM). Aripiprazole functions as a partial
`agonist at the dopamine D, and the serotonin 5-HT), 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 D, and 5-
`HT receptors and antagonist activity at 5-HT24 receptors. Actions at receptors other
`than Dj, 5-HTja, and 5-HT2, may explain some of the other clinical effects of
`aripiprazole, eg, the orthostatic hypotension observed with aripiprazole may be explained
`by its antagonistactivity at adrenergic alpha, receptors.
`
`Pharmacokinetics
`
`ABILIFYactivity 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 D, receptors similar to the parent drug and represents 40% ofthe 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 the Cmax or AUCofaripiprazoleorits
`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 (404 L or 4.9 L/kg), 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
`Anpiprazole
`dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4
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`and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of
`aripiprazole,
`and N-dealkylation is catalyzed by CYP3A4. Anipiprazole
`is
`the
`predominant drug moiety in the systemic circulation. At steady state, dehydro-
`aripiprazole, the active metabolite, represents about 40% ofaripiprazole AUCin 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 doseof aripiprazole compared to
`EMs. Coadministration of ABILIFY with known inhibitors of CYP2D6,like quinidine in
`EMsresults in a 112% increase in aripiprazole plasma exposure, and dosing adjustmentis
`needed (see PRECAUTIONS: Drug-DrugInteractions). The mean elimination half-lives
`are about 75 hours and 146 hours for aripiprazole in EMs and PMs, respectively.
`Aripiprazole does notinhibit or induce the CYP2D6 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 ofa patient’s age,
`gender, race, smoking status, hepatic function, or renal function (see DOSAGE AND
`ADMINISTRATION: Dosage in Special Populations).
`The pharmacokinetics 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 ofthese 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%, respectively, 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 pharmacokinetic studies (with aripiprazole given in a single dose of
`15 mg), aripiprazole clearance was 20% lower in elderly @65 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
`pharmacokinetics ofaripiprazole 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 ofaripiprazole 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
`recommendedbased 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 ofclinically significant race-related differences in the pharmacokinetics of
`aripiprazole. No dosage adjustment is recommendedbased onrace.
`
`-=
`
`Smoking
`
`Based onstudies utilizing human liver enzymesin vitro, 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 vitro
`results, population pharmacokinetic
`evaluation did not
`reveal
`any
`significant
`pharmacokinetic differences between smokers and nonsmokers. No dosage adjustmentis
`recommendedbased on smokingstatus.
`
`Drug-Drug Interactions
`
`Potentialfor Other Drugs to Affect ABILIFY
`
`Anpiprazole is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8,
`CYP2C9, CYP2C19, or CYP2E1 enzymes. Anipiprazole 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 CYP2D6are responsible for aripiprazole metabolism. Agents that
`induce CYP3A4 (eg, carbamazepine) could cause an increase in aripiprazole clearance
`and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole) or CYP2D6 (eg,
`quinidine,
`fluoxetine, or paroxetine) can inhibit aripiprazole elimination and cause
`increased blood levels.
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`Potentialfor ABILIFYto Affect 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 CYP2D6
`(dextromethorphan), CYP2C9 (warfarin), CYP2C19
`(omeprazole, warfarin),
`and
`CYP3A4 (dextromethorphan)
`substrates. Additionally, aripiprazole and dehydro-
`aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro
`(see Precautions: Drug-Drug Interactions).
`,
`
`Aripiprazole had noclinically important interactions with thefollowing drugs:
`
`Famotidine: Coadministration of aripiprazole (given in a single dose of 15 mg) with a 40-
`mg single dose of the Hh antagonist famotidine, a potent gastric acid blocker, decreased
`the solubility of aripiprazole and, hence, its rate of absorption, reducing by 37% and 21%
`the Cmax ofaripiprazole and dehydro-aripiprazole, respectively, and by 13% and 15%,
`respectively, the extent of absorption (AUC). No dosage adjustment of aripiprazole is
`required when administered concomitantly with famotidine.
`
`_
`
`in
`
`Valproate: When valproate (500-1500 mg/day) and aripiprazole GO mg/day) were co-
`administered at steady state, the Cmax and AUC ofaripiprazole were decreased by 25%.
`No dosage adjustment of aripiprazole is r