CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-729
`
`'
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`

`

`EXCLUSIVITY SUMMARY
`
`NDA # 21—729
`
`SUPPL # 000
`
`HFD # 130
`
`Trade Name Abilify Discmelt 10, 15, 20, 30mg
`
`Generic Name aripiprazole orally disintegrating tablets
`
`Applicant Name Otsuka Pharmaceutical Co., Ltd.
`
`Approval Date, If Known June 7, 2006
`
`PART I
`
`IS AN EXCLUSIVITY DETERMINATION NEEDED?
`
`1. An exclusivity determination will be made for all original applications, and all efficacy
`supplements. Complete PARTS II and III ofth1s Exclusivity Summary only 1fyou answer "yes" to
`one or more of the following questions about the submission.
`
`a) Is it a 505(b)(1), 505(b)(2) or efficacy supplement?
`
`YES IE
`
`NO 1:}
`
`Ifyes, what type? Specify 505(b)(1), 505(b)(2), SE1, SE2, SE3,SE4, SE5, SE6, SE7, SE8
`
`505(b)(1)
`
`c) Did it require the review of clinical data other than to support a safety claim or change in
`labeling related to safety? (IfIt required review only of bioavailability or bioequivalence
`data, answer "no'
`
`YES [I
`
`NO IE
`
`If your answer is "no" because you believe the study is a bioavailability study and, therefore,
`not eligible for exclusivity, EXPLAIN why it is a bioavailability study, including your
`reasons for disagreeing with any arguments made by the applicant that the study was not
`simply a bioavailability study.
`
`If it is a supplement requiring the review of clinical data but it is not an effectiveness
`supplement, describe the change or claim that is supported by the clinical data:
`
`N/A
`
`d) Did the applicant request exclusivity?
`
`Page 1
`
`

`

`YES [I
`
`NO IXI
`
`If the answer to (d) is "yes," how many years of exclusivity did the applicant request?
`
`N/A
`
`e) Has pediatric exclusivity been granted for this Active Moiety?
`YES [:1
`
`NO E}
`
`If the answer to the above question in YESI is this approval a result of the studies submitted in
`response to the Pediatric Written Request?
`
`N/A
`
`IF YOU HAVE ANSWERED "NO" TO ALL OF THE ABOVE QUESTIONS, GO DIRECTLY TO
`THE SIGNATURE BLOCKS AT THE END OF THIS DOCUMENT.
`
`2. Is this drug product or indication a DESI upgrade?
`
`YES I:
`
`NOE
`
`IF THE ANSWER TO QUESTION 2 IS "YES," GO DIRECTLY TO THE SIGNATURE BLOCKS
`ON PAGE 8 (even if a study was required for the upgrade).
`
`PART II
`
`FIVE-YEAR EXCLUSIVITY FOR NEW CHEMICAL ENTITIES
`
`(Answer either #1 or #2 as appropriate)
`
`1. Single active ingredient product.
`
`Has FDA previously approved under section 505 of the Act any drug product containing the same
`active moiety as the drug under consideration? Answer "yes" if the active moiety (including other
`'esterified forms, salts, complexes, chelates or clathrates) has been previously approved, but this
`particular form of the active moiety, e.g., this particular ester or salt (including salts with hydrogen
`or coordination bonding) or other non-covalent derivative (such as a complex, chelate, or clathrate)
`has not been approved. Answer "no" if the compound requires metabolic conversion (other than
`deesterification of an esterified form of the drug) to produce an already approved active moiety.
`
`YES IX!
`
`NO [I
`
`If "yes," identify the approved drug product(s) containing the active moiety, and, if known, the NDA
`#(s).
`
`NDA# - 21—436
`
`Abilify Tablets
`
`Page 2
`
`

`

`NDA#
`
`21 -71 3
`
`Abilify Oral Solution
`
`NDA#
`
`2. Combination product.
`
`If the product contains more than one active moiety(as defined in Part II, #1), has FDA previously
`approved an application under section 505 containing fly gn_e of the active moieties‘in the drug
`product? If, for example, the combination contains one never—before—approved active moiety and
`one previously approved active moiety, answer "yes." (An active moiety that is marketed under an
`OTC monograph, but that was never approved under an NDA, is considered not previously
`approved.)
`D
`E '
`
`YES
`
`NO
`
`If "yes," identify the approved drug product(s) containing the active, moiety, and, if known, the NDA
`#(s).
`
`NDA#
`
`NDA#
`
`' NDA#
`
`IF THE ANSWER TO QUESTION 1 OR 2 UNDER PART 11 IS "NO," GO DIRECTLY TO THE
`SIGNATURE BLOCKS ON PAGE 8. (Caution: The questions in part II of the summary should
`only be answered “NO” for original apprOvals of new molecular entities.)
`IF “YES,” GO TO PART III.
`'
`
`PART III
`
`THREE-YEAR EXCLUSIVITY FOR NDAs AND SUPPLEMENTS
`
`To qualify for three years of exclusivity, an application or supplement must contain ”reports of new
`clinical investigations (other than bioavailability studies) essential to the approval ofthe application
`and conducted or sponsored by the applicant." This section should be completed only if the answer
`to PART 11, Question 1 or 2 was "yes."
`'
`
`l . Does the application contain reports of clinical investigations? (The Agency interprets "clinical
`investigations" to mean investigations conducted on humans other than bioavailability studies.) If
`the application contains clinical investigations only by virtue of a right of reference to clinical
`investigations in another application, answer "yes," then skip to question 3(a). If the answer to 3(a)
`is "yes" for any investigation referred to in another application, do not complete remainder of
`summary for that investigation.
`
`YES D NO IX}
`
`Page 3
`
`

`

`IF "NO," GO DIRECTLY TO THE SIGNATURE BLOCKS ON PAGE 8.
`
`2. A clinical investigation is "essential to the approval" if the Agency could not have approved the
`application or supplement without relying on that investigation. Thus, the investigation is not
`essential to the approval if 1). no clinical investigation is necessary to support the supplement or
`application in light of previously approved applications (i.e., information other than clinical trials,
`such as bioavailability data, would be sufficient to provide a basis for approval as an ANDA or
`505(b)(2) application because of what is already known about a previously approved product), or 2)
`there are published reports of studies (other than those conducted or sponsored by the applicant) or
`other publicly available data that independently would have been sufficient to support approval of
`the application, without reference to the clinical investigation submitted in the application.
`
`(a) In light of previously approved applications, is a clinical investigation (either conducted
`by the applicant or available from some other source, including the published literature)
`necessary to support approval of the application or supplement?
`YES Ij
`
`NO |:|
`
`If "no," state the basis for your conclusion that a clinical trial is not necessary for approval
`AND GO DIRECTLY TO SIGNATURE BLOCK ON PAGE 8:
`
`to the safety and
`(b) Did the applicant submit a list of published Studies relevant
`effectiveness of this drug product and a statement that the publicly available data would not
`independently support approval of the application?
`
`YES [I
`
`NO |:|
`
`(1) If the answer to 2(b) is "yes," do you personally know of any reason to disagree
`with the applicant's conclusion? If not applicable, answer NO.
`
`YES |:|
`
`NO [I
`
`If yes, explain:
`
`(2) If the answer to 2(b) is "no, " are you aware ofpublished studies not conducted or
`sponsored by the applicant or other publicly available data that could independently
`demonstrate the safety and effectiveness of this drug product?
`
`YES [I
`
`NO |:]
`
`If yes, explain:
`
`Page 4
`
`

`

`(c)
`
`If the answers to (b)(l) and (b)(2) were both "no," identify the clinical
`investigations submitted in the application that are essential to the approval:
`
`Studies comparing two products with the same ingredient(s) are considered to be bioavailability
`studies for the purpose of this section
`
`3. In addition to being essential, investigations must be "new" to support exclusivity. The agency
`interprets "new clinical investigation" to mean an investigation that 1) has not been relied on by the
`agency to demonstrate the effectiveness of a previously approved drug for any indication and 2) does
`not duplicate the results of another investigation that was relied on by the agency to demonstrate the
`effectiveness of a previously approved drug product, i.e., does not redemonstrate something the
`agency considers to have been demonstrated in an already approved application.
`
`a) For each investigation identified as "essential to the approval," has the investigation been
`relied on by the agency to demonstrate the effectiveness of a previously approved drug
`product? (If the investigation was relied on only to support the safety of a previously
`approved drug, answer "no
`
`Investigation #1
`
`.
`
`I
`
`YES |:I
`
`NO El
`
`Investigation #2
`
`. YES El ,
`
`NO D
`
`If you have answered "yes"for One or more investigations, identify each such investigation
`and the NDA in which each was relied upon:
`
`b) For each investigation identified as "essential to the approval", does the investigation
`duplicate the results of another investigation that was relied on by the agency to support the
`effectiveness of a previously approved drug product?
`
`Investigation #1
`
`Investigation #2
`
`'
`
`YES El
`
`NO D
`
`YES |:|
`
`NO lj
`
`If you have answered "yes” for one or more investigation, identify the NDA in which a
`similar investigation was relied on:
`
`Page 5
`
`

`

`c) If the answers to 3(a) and 3(b) are no, identify each "new" investigation in the application
`or supplement that is essential to the approval (i.e., the investigations listed in #2(c), less any
`that are not "new" :
`
`4. To be eligible for exclusivity, a new investigation that is essential to approval must also have
`been conducted or sponsored by the applicant. An investigation was "conducted or sponsored by"
`the applicant if, before or during the conduct of the investigation, 1) the applicant was the sponsor of
`the IND named in the form FDA 1571 filed with the Agency, or 2) the applicant (or its predecessor
`in interest) provided substantial support for the study. Ordinarily, substantial support will mean
`providing 50 percent or more of the cost of the study.
`
`a) For each investigation identified in response to question 3(c): if the investigation was
`carried out under an IND, was the applicant identified on the FDA 1571 as the sponsor?
`
`NOE]
`Explain:
`
`! !
`
`!!
`
`NOEI
`Explain:
`
`Investigation #1
`
`IND #
`
`YES [I
`
`Investigation #2
`
`INDV#
`
`YES E]
`
`(b) For each investigation not carried out under an IND or for which the applicant was not
`identified as the sponsor, did the applicant certify that it or the applicant's predecessor in
`interest provided substantial support for the study?
`
`Investigation #1
`
`!
`
`YESEI
`Explain:
`
`!NO|:l
`! Explain:
`
`Page 6
`
`

`

`Investigation'#2
`
`!
`
`YESI:I
`Explain:
`
`iNOIZI
`! Explain:
`
`(0) Notwithstanding an answer of "yes" to (a) or (b), are there other reasons to believe that
`the applicant should not be credited with having "conducted or sponsored" the study?
`(Purchased studies may not be used as the basis for exclusivity. However, if all rights to the
`drug are purchased (not just studies on the drug), the applicant may be considered to have
`sponsored or conducted the studies sponsored or conducted by its predecessor in interest.)
`
`YES |:|
`
`NO [I
`
`If yes, explain:
`
`
`
`Name of person completing form: Keith Kiedrow, PharmD, LT USPHS
`Title: Regulatory Project Manager
`Date: 6/7/2006
`
`Name of Office/Division Director signing form: Thomas Laughren, MD
`Title: Director, Division of Psychiatry Products
`
`Form OGD-011347; Revised 05/10/2004; formatted 2/15/05 -
`
`Page 7
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Thomas Laughren
`6/11/2006 11:07:04 AM
`
`

`

`CONS-j T-IN -fi*-ONSE
`DIVISION OF MEDICATI a N ERRORS AND TECHNICAL SUPPORT
`
`DATE RECEIVED:
`
`OSE CONSULT #:
`
`May 4, 2006
`
`.
`
`May 29, 2006
`
`OFFICE OF SURVEILLANCE AND EPIDEMIOLOGY
`(DMETS;':WO 22, MAIL STOP 4447)
`
`
`
`DESIRED COMPLETION DATE:
`
`
`04-0091-1, 05-0198
`
`
`
`
`PDUFA DATE:
`DATE OF DOCUMENT:
`
`
`
`June 13’ 2006
`December 12, 2005
`
`
`
`
`
`
`Thomas Laughren, MD
`Director, Division of Psychiatry Products
`HFD-l30
`
`
` THROUGH: Alina Mahmud, R.Ph., M.S., Team Leader
`
`
`Denise Toyer, Pharm.D., Deputy Director
`
`
`Carol Holquist, R.Ph., Director
`Division of Medication Errors and Technical Support
`
`
`
`
`FROM:
`Kimberly Pedersen, R.Ph., Safety Evaluator
`'
`Division of Medication Errors and Technical Su .ort
`
`
`SPONSOR: Otsuka America Pharmaceutical, Inc.
`
`‘
`
`PRODUCT NAME:
`Abilify® DiscmeltTM
`(Aripiprazole Orally Disintegrating Tablets)
`‘10 mg, 15 mg, 20 mg and 30 mg
`
`1. DMETS has no objections to the use of the proprietary name, Abilify® DiscmeltTM. This is considered a final
`decision. However, if the approval of this application is delayed beyond 90 days from the signature date Of this
`document, the name must be re-evaluated. A re-review of the name will rule out any objectiOns base upon
`approval of other proprietary or established names from the Signature date of this document.
`
`
`
` NDA#: 21-729
`
`RECOMMENDATIONS:
`.
`
`
`
`
`
`
` 3. DDMAC finds the proprietary name Abilify® DiscmeltTM acceptable from a promotional perspective. DMETS would appreciate feedback of the final outcome of this consult. We would be willing to meet with the
`
`2. Subsequent to a review Of the post-marketing reports associated with the currently marketed Abilify drug
`product, DMETS recommends implementation of the label revisions outlined in Section III to minimize
`potential errors with the use of this product.
`
`
`
`
`
`
`
`Division for further discussion, if needed. If you have further questions or need clarifications, please contact
`
`Diane Smith, Pro'ect Manaer, at 301-796-0538.,
`
`
`
`

`

`Division of Medication Errors and Technical Support (DMETS)
`Office of Surveillance and Epidemiology
`W0 22, MAIL STOP 4447
`
`Center for Drug Evaluation and Research
`
`PROPRIETARY NAIWE REVIEW
`
`DATE OF REVIEW:
`
`May 16, 2006
`
`NBA #:
`
`21-729
`
`NAME OF DRUG:
`
`Abilify® DiscmeltTM
`(Aripiprazole Orally Disintegrating Tablets)
`10 mg, l5 mg, 20 mg and 30 mg
`
`NDA SPONSOR:
`
`Otsuka America Pharmaceutical, Inc.
`
`
`***NOTE: This review contains proprietary and confidential information that should not be
`
`released to the public.***
`
`I.
`
`INTRODUCTION
`
`This consult was written in response to a request from the Division of Psychiatry Products (HFD-130),
`for an assessment of the proprietary name Abilify® DiscmeltTM in regard to the potential name
`confusion with other proprietary or established drug names. Container labels (blister foils) and carton
`labeling were provided for review and comment.
`
`PRODUCT INFORMATION
`
`Abilify® DiscmeltTM is a psychotropic medication indicated for the treatment of schizophrenia. Abilify®
`DiscmeltTM is an orally disintegrating tablet available in 10 mg, 15 mg, 20 mg and 30 mg strengths,
`which will available in package sizes of thirty and one-hundred tablets. The recommended starting dose
`for schizophrenia is 10 or 15 mg daily Without regard to meals. The recommended starting dose for
`bipolar disorder is 30 mg once daily.
`
`Patients should open the blister when ready to administer. in order to open the blister package, the
`patient should peel back the foil to expose the tablet. Attempts to push the tablet through the foil could
`result in damage. Immediately after opening the package, the patient should remove the tablet with dry
`hands and place the tablet on the tongue. The tablet should disintegrate rapidly. The sponsor
`recommends the discmelt be taken without liquid; however, it can be used if needed. The patient should
`not attempt to split the tablet.
`
`

`

`II.
`
`RISK ASSESSMENT:
`
`The medicationerror staff of DMETS conduCted a search of several standard published drug product
`reference texts“as well as several FDA databases‘"‘V for existing drug names which sound-alike or
`look-alike to Abilify® DiscmeltTM to a degree where potential confusion between drug names could
`occur under the usual clinical practice settings. A search of the electronic online version of the US.
`Patent and Trademark Office’s Text and Image Database was also conductedV. The SAEGISVi
`Pharma—In-Use database was searched for drug names with potential for confusion. An expert panel
`discussion was conducted to review all findings from the searches.
`
`A. EXPERT PANEL DISCUSSION
`
`An Expert Panel discussion was held by DMETS to gather professional opinions on the safety of
`the proprietary name, Abilify® Discmeltm. Potential concerns regarding drug marketing and
`promotion related to the proposed name were also discusSed This group is composed of
`DMETS Medication Errors Prevention Staff with representation from the Division of Drug
`Marketing, Advertising, and Communications (DDMAC). The group relies on their clinical and
`other professional experiences and a number of standard references when making a decision on
`the acceptability of a proprietary name.
`
`1. DDMAC finds the proprietary name Abilify® DiscmeltTM acceptable from a promotional
`perspective.
`
`2. The Expert Panel identified the currently marketed Abilify tablets and Abilify oral solution as to
`having the potential for confusion with Abilify® DiscmeltTM. These products are listed1n Table
`1 (see below), along with the dosage forms available and usual dosage.
`
`“LA (look-alike)/SA (sound-alike).
`
`Aripiprazole
`Tablets:
`
`10 mg to 30 mg daily
`
`2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg
`Oral Solution:
`1 m mL, 150 mL bottle
`*Frequently used, not all-inclusive.
`
`Inc., 6200 South Syracuse Way, Suite. 300, Englewood,
`V MICROMEDEX Integrated Index, 2006, MICROMEDEX,
`Colorado 80111 -4740, which includes all products/databases within ChemKnowledge, DrugKnowledge, and RegsKnowledge
`Systems.
`” Facts and Comparisons, online version, Facts and Comparisons, St. Louis, Missouri.
`of
`database
`iiAMF Decision Support System [DSS], the Division of Medication Errors and Technical Supp01t [DMETS]
`Proprietary name consultation requests, New Drug Approvals 98-06, and the electronic online version of the FDA Orange
`Book.
`V
`IVPhonetic and Orthographic Computer Analysis (POCA)
`www location http://www.uspto.ggv/tmdb/indexhtml.
`Vi Data provided by Thomson & Thomson’s SAEGISTM Online service, available at www.thomson—thomson.com
`3
`
`'
`
`

`

`B. SAFETY EVALUATOR RISK ASSESSMENT
`
`I. AERS and DQRS Searches
`
`As there are two dosage forms of Abilify currently marketed (tablets and oral solution), DMETS
`determined the best method to ascertain if the potential for name confusion exists is to review the
`post-marketing safety reports in the FDA databasesL DMETS conducted searches of the FDA'
`Adverse Event Reporting System (AERS) and the Drug Quality Reporting System (DQRS) to
`determine the degree of post-marketing errors with Abilify. AERS was searched using the
`following MedDRA terminology and drug names: Preferred Term (PT) “Pharmaceutical Product
`Complaint” and High Level Group Term (HLGT) “Medication Errors” with “Abili%” and
`Aripi%” for drug names. This search strategy uncovered one—hundred eighty three reports
`(n=l83). The majority of these reports involved adverse events (including potential drug
`interactions), exposure in pregnancy, overdoses, and a number of duplicate reports. To further
`clarify, the overdose reports were related to and unrelated to the drug product of Abilify and
`included intentional and unintentional overdoses (including extra doses received and child
`exposures). These reports appear to relate to the indication of the drug product (i.e. multiple drug
`therapies, expected adverse events such as suicidal tendencies, etc); thus, DMETS will not
`discuss these errors further as they do not relate to the proprietary name,
`labels or labeling.
`Thirteen cases did, however, relate to the proprietary name, labels and labeling. These cases will
`be discussed further below.
`-
`
`3. Established Name Confusion (n=4)
`
`The established name of Abilify is Aripiprazole which contains the USAN stem for proton
`pump inhibitors (—prazole). However, Abilify or Aripiprazole is not a proton pump inhibitor.
`Thus it came as no surprise that there were four cases of confusion with the established name.
`One case was received in 2002 (the year of Abilify approval, November 2002) with the
`remaining three dated early 2003. Two cases noted formulary substitutions with lansoprazole,
`'which were caught prior to administration and the remaining two reporters addressed
`concerns with the name similarities. As these cases were received early in the approval of
`Abilify with no subsequent complaints, DMETS suspects practitioners have become familiar
`with the drug product’s established name and thus, no action is required at this time.
`
`b. Wrong Drug Product (n=2)
`
`Two cases described confusion with other marketed drug products. The first case (2006)
`described an error in which a prescription was filled with Abilify in lieu of Actos. This case
`was poorly documented, but DMETS notes that the drug products share similar strengths
`(15 mg and 30 mg), dosing frequency (daily), and dosage form (tablet). In addition, the
`products could share similar placement on the pharmacy shelves. However, the color schemes
`for the bottle trade dress are different (Actos in green/white and blue/white compared to the
`peach/yellow and blue of Abilify). The second case described a cognitive error by a nurse
`who called in a prescription for Zyprexa 2.5 mg BID, when Abilify 2.5 mg BID was intended.
`These drug products share indication (schizophrenia and bipolar disorder), strength (2.5 mg,
`5 mg, 10 mg, 15 mg and 20 mg), dosing frequency (daily), and dosage form (tablets). As
`there is only one case for each drug product, DMETS does not recommend regulatory action
`at this time, but will continue to monitor for any further confusion.
`
`

`

`
`
`
`
`
`
`
`
` No adverse effects at the time of reporting
`
`30 mg
`
`5 mg
`
`5 mg
`
`
`
`
`Drowsy, “upset stomach”, emergency room visit with
`unSuecified treatment
`
`
`None indicated (poorly documented case)
`
`4212338-1
`(2002)
`
`4187681-5
`
`2003
`
`2003
`
`(2004
`4592412-0
`2005
`
`4675409-1
`2005
`4675497—2
`(2005
`4755617-1
`2005
`
`
`
`
`
`
`
`
`
`c. Wrong Strength (n=7)
`
`implicate confusion
`Seven medication error cases, all occurring at the pharmacy level,
`between the strengths, of Abilify. Four of the seven cases implicate selection error as the error
`involved a refill (n=3) or the correct label but wrong drug (n=l). There is no consistency
`based on the strength ordered and the incorrect strength dispensed (see table 2).
`
`
`Table 2
`
`AERS #
`(Yea r)
`
`
`
`Patient
`Age
`ears
`
`
`New or
`Refill
`
`Ordered
`
`Dispensed
`
`
`Outcome
`' (note)
`
`'
`
`New
`
`g
`
`5 mg
`
`15 mg
`
`Lethargy, difficult to arouse, gasping, dilated pupils
`2"d occurrence in retail pharmacy setting
`
`Refill -“ Chest pain and tachycardia
`
`5 mg
`
`5 mg
`
`---
`
`5 mg
`
`“
`
`Refi
`
`
`--m
`.Somnolence (poorly documented case)
`
`
`
`
`mg
`
`
`
`
`
`DMETS would like to acknowledge that the majority of these cases involve children (n=5).
`However, the product labeling denotes that the safety and effectiveness of Abilify in the
`pediatric and adolescent populations has not been established. The majority of the cases
`resulted in a negative outcome, but none appeared to result in hospitalization or other
`“severe” outcomes. It is difficult to ascertain causality from the cases based on the
`information provided.
`
`'
`
`Upon review of the labels and labeling, DMETS notes that the strengths are differentiated
`with different colors that correspond to the color of the tablet. DMETS believes that this
`helps patients and practitioners identify the strength of Abilify once it is dispensed. DMETS
`notes that the labels/labeling and the tablet color of the 10 mg and 30 mg strengths have
`similar coloring schemes. However, no medication errors have been reported between the
`10 mg and 30 mg strengths. The ordered strength in six of the seven cases was 5 mg,
`however 10 mg, 15 mg, and 30 mg strengths were dispensed in error. There is no similarity
`in color between the 5 mg tablets and these other strengths. However, the sponsor’s trade
`dress utilizes colors that dominate the labels and distracts attention away from the
`presentation of the product strength. Other factors that could have contributed to these errors
`include increased Abilify prescription writing, busy pharmacies (lack of appropriate attention
`to detail), computer selection error (of the correct strength), or proximity on the shelf (literal
`mispull from the shelf). DMETS recommends that the labels and labeling for the proposed
`Abilify Discmelt be completely different than those currently marketed for Abilify tablets.
`Additionally,
`to address the current confusion within the Abilify Tablet product line we
`recommend increasing the presentation of the strength so that
`it
`is more prominently
`displayed.
`'
`
`

`

`2. Abilify® DiscmeltTM Name Review
`
`Abilify Discmelt is the latest product extension to Abilify. Abilify is currently approved-as a
`tablet and oral solution dosage form. Since the currently marketed Abilify and proposed Abilify
`Discmelt share the same root name, there is concern that confusion may occur if the “Discmelt”
`modifier is omitted, overlooked, or disregarded. Since the search of the FDA databases found
`confusion between the different strengths of the currently marketed Abilify tablets, DMETS has
`reason to suspect that this may occur within the proposed orally disintegrating tablet strengths
`and between this proposed tablet and the currently marketed tablet. Both products share the same
`product characteristics (Le. strength, dosing frequency, etc).' However, the package insert details .
`that the products are bioequivalent. Thus if the patient were to receive the incorrect dosage form,
`there would be no resultant harm. However, DMETS is concerned if the bioequivalency would
`be identical if the drug product Were incorrectly administered. If the prescription was written for
`the disintegrating tablet and the oral tablet dispensed, would the patient experience any adverse
`effects from chewing the tablet? Conversely, would the efficacy be comparable if the
`disintegrating tablet were swallowed? The package insert reads that the disintegrating tablet is
`preferred to be administered without water, but what occurs when administered with water (as in
`usual tablet ingestion)? DMETS has contacted the review Division for answers to these.
`questions.
`
`,
`
`DMETS suspects dispensing errors will be inevitable when the proposed product is initially
`marketed. However suggestions to. help minimize confusion such as differentiating trade dress
`and establishing educational campaigns/marketing plans are included in detail in Section III.
`
`3. The modifier DiscmeltTM
`
`A search of the standard pharmaceutical databases and proposed names in DMETS found many
`drug products available in orally disintegrating tablet dosage forms with and without modifiers to
`discern this different dosage form. DMETS notes that there is no universal modifier for
`indicating a product as an orally disintegrating tablet. Additionally, since the term “discmelt”
`sounds like a dosage form and not a novel drug product name such as Zydis, we believe the
`possibility for drug identification confusion is limited. When the term “Zydis” was first
`introduced, healthcare practitioners thought Zydis meant a different product rather than an orally
`disintegrating tablet. There will likely be confusion when Abilify Discmelt is first marketed,
`practitioners may not be aware of the existence of the orally disintegrating tablet. Thus, DMETS
`recommends the sponsor educate patients and practitioners on the availability of this dosage form
`and its respective modifier.
`
`

`

`LABELING, PACKAGING, AND SAFETY RELATED ISSUES
`
`In review of the Abilify® DiscmeltTM container label (blister'foils) and carton labeling, DMETS has
`attempted to focus on safety issues relating to possible medication errors. DMETS has identified the
`following areas of possible improvement, which might minimize potential user error.
`
`1. GENERAL COMMENTS
`
`As this is the introduction of another dosage form to a currently marketed product line with
`existing and continued errors in dosing and administration, DMETS recommends the sponsor
`educate patients and health care practitioners on the availability of the new dosage form and the
`proper use of this product.
`
`CONTAINER LABEL (Individual Blisters)
`
`a.
`
`As currently presented (see below on left), the directions to open the package are not clear
`(“Fold and Hold Down Comer, Tear at Slit”). As the orally disintegrating tablets are fragile,
`errors in opening could result in tablet damage. DMETS recommends the sponsor better
`describe how to open the foil blister by further descriptive terms or by indication (by dotted
`line, see Advil example below) specifically where to open the package.
`
`y-i‘ifffiaiufiwitisflifil" ; 'Afliur'v'nsclm‘'1" 1.
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`.'
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`'
`
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`
`.
`
`
`
`mucous-twin“ 1_ "name:
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`_
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`,
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`
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`
`To assure the tablets maintain their integrity, DMETS recommends the sponsor add a
`statement to warn the patient that attempting to push the tablet through the foil could result in
`damage to the tablet. This could be printed on the front or back of the foil blister.
`
`In order to better recognize the blister contents, DMETS recommends the strength be
`relocated adjacent
`to or immediately following the established name and given greater
`prominence. There should be no intervening matter between the name and the strength. As
`currently presented, DMETS fears the strength may be lost
`in the color pattem and
`lot/expiration information.
`
`Adjust the font size and font style of the established name (both aripiprazole and orally
`disintegrating tablet) so that they are uniform.
`-
`
`

`

`3. CARTON LABELING
`
`a.
`
`As reports from the FDA databases indicate confusion between strengths of the currently
`marketed Abilify tablets, we can anticipate similar confusion with the Discmelt product as
`well as confusion between the Discmelt and oral tablets. Thus, it is imperative to distinguish
`between the proposed “discmelt” and the currently marketed tablets. DMETS notes that the
`color scheme (blue and yellow) for the Abilify product line is identical (see Table 3). This
`color scheme dominates the labels and labeling which distracts attention away from the
`presentation of strength. Furthermore, DMETS notes that the colors used for the matching
`strengths of the orally disintegrating tablets and currently marketed tablets are identical with
`the exception of the speckles (see Table 3). Therefore, in order to minimize medication errors
`we recommend the following:
`
`i. DMETS recommends that a different trade dress and color scheme be utilized for the
`
`proposed orally disintegrated tablets. This color scheme should not dominate the labels
`and labeling. As currently presented, the established name and strength are lost in the
`stylized background. Information, such as the proprietary name, established name and
`strength should be the most prominent information presented on the principal display
`panel. Revise to eliminate these colors or mute them.
`'
`
`ii. The corresponding color of the strengths on the carton labeling are the same for both the
`Abilify and Abilify Discmelt tablets. DMETS does not recommend using the same colors
`for both products. DMETS recommends that the colors used for the presentation of the
`strength either be identical to the actual color of the tablets (e.g., yellow with scattered
`specks for the 15 mg orally disintegrating tablet) or use entirely different colors where
`none of the strengths overlap the currently marketed Abilify Tablets. Regardless of the
`method used the color of the Abilify Tablet strengths and Abilify Discmelt strengths
`should be clearly differentiated from each other.
`
`
`
`Table 3:
`_ Tam...
`Abilify 10 mg
`:
`i
`:
`V
`
`,
`5-, .3?
`
`4
`
`.
`
`Discmelt
`uoc sens-mes
`1m Tableu
`Cmmncmuimommmotabletspersmp.
`
`ABILIFY® D l SC M E LT
`(aripiprazole)
`mm
`Orally Disintegrating Tablets
`
`Orally Disintegrating Tablets
`
`'
`'
`Ablhfy 15 mg
`
`_.' —“
`Q-
`
`.
`H-
`
`momma
`'
`washout-as
`Cartwconmtowipswifllwlahlatsperstrip.
`
`ABILIFYC" D l SC ME LT
`(aripiprazole)
`Maw
`
`

`

`b.
`
`c.
`
`d.
`
`The presentation of the established name should be in the same font style and size as the
`dosage form. As currently presented,
`the “Orally disintegrating Tablets” does not have
`prominence which may result in a lack of name recognition leading to medication error.
`
`In order to accommodate for the changes to the established name, the “Rx only” statement
`can be relocated to the lower third of the principal display panel.
`
`Revise the net quantity “100 Tablets Carton contains 10 strips with 10 tablets per strip” to
`read “100 tablets (10 X 10)” in order to reduce the amount of clutter on the principal display
`panel.
`
`4.
`
`INSERT LABELING
`
`a.
`
`Dosage and Administration
`
`i. Under “Directions for Use of Abilify Discmelt...”, DMETS questions what occurs if the
`tablet is taken with water? If there