CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-192
`
`RISK ASSESSMENT AND RISK MITIGATION
`
`REVIEW! S!
`
`

`

`
`
`Department of Health and Human Services
`Public Health Service
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`March 25, 2009
`
`v Thomas Laughren, lVfl), Director
`Division of Psychiatry Products
`
`Through:
`
`From:
`
`Subject:
`
`Todd Bridges, RPh, Team Leader
`Denise Toyer, PharmD, Deputy Director
`Division of Medication Error Prevention and Analysis
`
`Diane C. Smith, PharmD, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`
`Label and Labeling Review
`
`Drug Name(s):
`
`'
`
`Application 'Type/Numberzr
`
`Fanapt (lloperidone) Tablets
`1mg,2mg,4mg,6mg, 8mg, 10mgand 12mg
`NDA 22-192
`
`Applicant:
`
`Vanda Pharmaceuticals
`
`OSE RCM #:
`
`2009-7O
`
`

`

`1
`
`INTRODUCTION
`
`The Division of Medication Error Prevention and Analysis (DMEPA) completed a review ofthe
`labels and labeling for Fanapt (Iloperidone) in OSE Review# 2009-7O dated March 4, 2009, in
`which we made recommendations regarding the proposed container labels, carton labeling, and
`insert labeling. Revised labels and labeling were submitted on March 10, 2009. We held a
`teleconference with the Applicant on March 16, 2009, to address some additional concerns
`involving three outstanding issues from the revised labels and labeling: the use of similar colors
`for the 1 mg and 6 mg tablets, the use of the name "FANAPTpack" for the titration packaging
`configuration, and use of the abbreviations "am" and ‘Fpm” in the inside cover ofthe titration
`pack. Subsequently, the Applicant submitted their revisions addressing DMEPA’S requested
`changes on March 17, 2009. This memorandum is written in response to these revisions.
`
`2 MATERIAL REVIEWED
`
`DMEPA reviewed our labeling review for Fanapt signed on March 4, 2009 (OSE Review#
`2009-70). We also reviewed revised labels and labeling submitted on March 10, 2009 and
`March 17, 2009 (see Appendices A through E for images ofthe labels and labeling).
`0
`Trade Container Labels
`
`0
`
`0
`
`Professional Sample Container Labels (14 count tablet)
`
`Professional Sample Carton Labeling
`
`0 Commercial Titration Package Configuration
`
`0
`
`0
`
`Professional Sample Titration Package Configuration
`
`Package Insert Labeling (no image)
`
`'3 DISCUSSION
`
`The Applicant has revised the labels and labeling according to our recommendations and we have
`no further comments.
`
`4' CONCLUSION
`
`The Applicant has satisfactorily revised the labels and labeling per our March. 16, 2009,
`teleconference.
`
`If you have questions or need clarifications, please contact Abolade Adeolu, OSE Project
`Manager, at (301) 796—4264,
`
`

`

`5’ Page(s) Withheld
`
`Trade Secret / Confidential (b4)
`
`3
`
`Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Diane Smith
`3/26/2009 09:59:29 AM
`DRUG SAFETY OFFICE REVIEWER
`
`Todd Bridges
`3/26/2009 02:37:19 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Denise Toyer
`3/26/2009 06:20:28 PM
`DRUG SAFETY OFFICE REVIEWER
`
`

`

`
`
`Department of Health and Human Services
`Public Health Service
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Surveillance and Epidemiology
`
`March 4, 2009
`
`Thomas Laughren, MD, Director
`Division of Psychiatry Products
`
`Through:
`
`From:
`
`Todd Bridges, RPh, Team Leader
`Denise Toyer, PhannD, Deputy Director
`Carol Holquist, RPh, Director
`Division of Medication Error Prevention and Analysis
`
`Diane C. Smith, PharmD, Safety Evaluator
`Division of Medication Error Prevention and Analysis
`
`Subject:
`
`Label and Labeling Review
`
`Drug Name(s):
`
`Fanapt (Iloperidone) Tablets
`
`//‘
`
`1 mg, 2 mg, 4 mg 6 mg, 8 mg, 10 mg and 12 mg
`
`Application Type/Number:
`
`NDA # 22-192
`
`Applicant/Applicant:
`
`Vanda Pharmaceuticals
`
`OSE RCM #:
`
`2009-70
`
`

`

`CONTENTS
`
`EXECUTIVE SUMMARY ............................................................................................................. 3
`1
`BACKGROUND ..................................................................................................................... 3
`1.1 Introduction ............ 3
`
`Product Information ....................................................................................................... 3
`1.2
`2 METHODS AND MATERIALS ............................................................................................ 3
`
`3
`
`RESULTS ............., .................................................................................................................. 4
`
`3.1
`3.2
`
`All labels and labeling. .................................................................................................. 4
`Trade Container Labels .................................................................................................. 4
`
`Professional Sample Container Labels........................................................................... 5
`3.3
`Titration Package Configuration .................................................................................... 5
`3.4
`Package Insert Labeling ................................................................................................. 5
`3.5
`4 DISCUSSION ........................................... 5
`4.1
`Lack of Prominence ....................................................................................................... 5
`
`Strength Differentiation ............................ 6
`4.2
`Decreased Readability Due to Lack of Contrast ............................................................ 6
`4.3
`Location of Strength....................................................................................................... 6
`4.4
`Titration Package Configuration .................................................................................... 6
`4.5
`Insert Labeling ............................................................................................................... 7
`4.6
`Graphic Prominence ....................................................................................................... 7
`4.7
`CONCLUSIONS and RECOMMENDATIONS ..................................................................... 7
`
`5
`
`‘ Comments to theDivrswn................... 7
`V 5.1
`Comments to the Applicant............................................................................................ 7
`5.2
`APPENDIX ........................................................................................................................... 10
`
`6
`
`

`

`EXECUTIVE SUMMARY
`
`The results of the Label and Labeling Risk Assessment found that the presentation of information
`on the proposed container labels for Fanapt Tablets is vulnerable to confusion that could lead to
`medication errors. Specifically, we note the following issues on the container labels: the lack of
`color differentiation between the 4 mg and 10 mg tablets as well as the 6 mg and 12 mg product
`strengths, the lack of color contrast of the 2 mg product strength and the presentation of the
`established name. Additionally, on the professional sample container labels the presentation of the
`"Professional Sample" statement and the size of the product strength. We also note the
`inappropriate use of the term "Starter" on the professional titration packs as well as the titration
`schedule, the utilization of graphics in the instructions for use and the net quantity contained in the
`pack.
`
`The Division of Medication Error Prevention and Analysis believes the risks we have identified
`can be addressed and mitigated, and provides recommendations in Section 6.
`
`1
`
`BACKGROUND
`
`1.1
`
`INTRODUCTION
`
`This review was written in response to a request from the Division of Psychiatry Products for
`assessment of the container label, carton and insert labeling for Fanapt (Iloperidone). DMEPA
`completed a review of the proprietary name under a separate consult (OSE# 2009—69).
`
`1.2
`
`PRODUCT INFORMATION
`
`Fanapt is an atypical antipsychotic indicated for the acute treatment of schizophrenia in adults.
`
`The recommended dose is 12 mg to 24 mg per day administered twice daily (BID) based on
`clinical response. This target dose range should be achieved through the following daily dosage
`adjustments until the desired maintenance dose is achieved: 1 mg BID, 2 mg BID, 4 mg BID, 6 mg
`BID, 8 mg BID, 10 mg BID and 12 mg BID on days 1, 2, 3, 4, 5, 6 and 7, respectively.
`
`Fanat will be su nlied as follows:
`
`Professional
`
`Trade
`
`Professional
`
`Tablet Stren th
`
`Sample Bottle of Container of 60 Blister Cards
`14 tablets
`tablets
`
`2 METHODS AND MATERIALS
`
`This section describes the methods and materials used by DMEPA conducting a label, labeling,
`and/or packaging risk assessment. The primary focus of the assessment is to identify and remedy
`
`

`

`potential sources of medication error prior to drug approval. DMEPA defines a medication error
`as any preventable event that may cause or lead to inappropriate medication use or patient harm
`while the medication is in the control of the health care professional, patient, or consumer. 1
`
`The label and labeling of a drug product are the primary means by which practitioners and patients
`(depending on configuration) interact with the pharmaceutical product. The container label and
`carton labeling communicate critical information including proprietary and established name,
`strength, dosage form, container quantity, expiration, and so on. The insert labeling is intended to
`communicate to practitioners all information relevant to the approved uses of the drug, including
`the correct dosing and administration.
`
`Given the critical role that the label and labeling has in the safe use of drug products, it is not
`surprising that 33 percent of medication errors reported to the United States Pharmacopeia—
`Institute for Safe Medication Practices Medication Error Reporting Program may be attributed to
`the packaging and labeling of drug products, including 30 percent of fatal errors.2
`
`Because the DMEPA staff analyzes reported misuse of drugs, the DMEPA staff is able to use this
`experience to identify potential errors with all medications similarly packaged, labeled or
`prescribed. DMEPA uses Failure Mode and Effects Analysis (FMEA) and the principles of
`human factors to identify potential sources of error with the proposed product labels and insert
`labeling, and provide recommendations that aim at reducing the risk of medication errors.
`
`DMEPA reviewed the following labels and labeling submitted by the Applicant on
`November 19, 2008 for our review (see Appendices A through D).
`
`0
`
`o
`
`0
`
`0
`
`Professional Sample Container Labels ( 14 count tablet)
`
`Titration Package Configuration
`
`Trade Container Labeling
`
`Package Insert Labeling (no image)
`
`3 RESULTS
`
`3.1 ALL LABELS AND LABELING
`
`The "F" that appears above the proprietary name, Fanapt, is large in size and uses too much room
`on the label.
`
`The established name is less than half the size of the proprietary name.
`
`3.2
`
`TRADE CONTAINER LABELS
`
`The lavender color on the 4 mg product strength is too similar to the light grey color used for the
`10 mg product. Additionally, there are similar concerns involving the colors used for the
`6 mg and 12 mg product strengths.
`
`The light yellow color font used for the'2 mg product strength is difficult to read on the white
`background.
`.
`
`1 National Coordinating Council for Medication Error Reporting and Prevention.
`http://www.nccmerp.orgaboutMedErrorshtml. Last accessed 10/11/2007.
`
`2 Institute ofMedicine. Preventing Medication Errors. The National Academies Press: Washington DC.
`2006. p275.
`
`

`

`3.3
`
`PROFESSIONAL SAMPLE CONTAINER LABELS
`
`As currently presented, the product strength»(i.e., 6 mg) may not appear onthe principal display
`panel.
`
`The statement "Professional sample" is small and difficult to read.
`
`3.4
`
`TITRATION PACKAGE CONFIGURATION
`
`The term —-~~ is inappropriately used on the professional sample.
`
`----———-——-—-—"
`4
`..
`The current insert labeling recommends that all patients are '
`mg.»
`
`11(4)
`
`The dosing instructions utilize graphics of the "sun and moon" to depict that patients should take
`in the morning and evening.
`
`The front cover does not adequately convey to healthcare practitioners the specific contents of
`each titration pack.
`
`The November 19, 2008, submission references the inclusion of a commercial titration pack,
`however, the electronic file depicts a professional sample pack.
`The white text font on the green background is difficult to read (i.e., white lettering on green '
`background).
`
`3.5
`
`PACKAGE INSERT LABELING
`
`The Applicant uses the abbreviation BID throughout the labels and labeling.
`
`4 DISCUSSION
`
`Our review of the proposed labels and labeling identified several areas of needed improvement.
`These areas are outlined below.
`
`4.1
`
`INFORMATION ON LABELS AND LABELING LACKS PROMINENCE
`
`4.1. 1 Established. Name
`
`The established name is less than half the size of the proprietary name and does not have the
`prominence commensurate with the proprietary name taking into account all pertinent factors,
`including typography, layout, contrast, and other printing features in accordance with 21 CFR
`201 .10(g)(2). This makes the established name less prominent. The established name is an
`important feature on the labels and labeling and should be prominently displayed on the principal
`display panel.
`
`4.1.2 Professional Sample
`
`The statement "Professional sample" on the container labels is small and difficult to read.
`Increasing the size of this statement will allow healthcare practitioners to clearly identify
`professional samples.
`
`

`

`4.2
`
`STRENGTH DIFFERENTIATION
`
`The colors used to differentiate the product strengths are too similar in appearance. The lavender
`color on the 4 mg product strength is too similar to the light grey color used for the 10 mg product
`strength. Additionally, we have similar concerns involving the colors utilized for the 6 mg and 12
`mg strengths. Using similar colors increases the risk of selection errors especially when these
`bottles will be stored side-by-side on a pharmacy shelf. Selection errors may not be caught prior ,
`to administration which can lead to overdose and potentially result in adverse events.
`
`4.3 DECREASED READABILITY OF PRODUCT STRENGTH DUE TO LACK OF CONTRAST
`
`The light yellow text used for the 2 mg product strength is difficult to read adjacent to the white
`background. This color combination does not provide sufficient contrast to one another. The text
`font color used should maximize the contrast between the text and the background to ensure
`readability.
`
`4.4
`
`LOCATION OF STRENGTH
`
`Although, the strength is prominently displayed on the professional sample container labels, it
`does not appear immediately following the established name but appears in the lower right hand
`corner. This container configuration will be likely be small and when the container label is placed
`on the container the current presentation of the product strength may not be visible when looking
`at the front panel of the container label ( i.e., the portion of the label containing the product
`strength may wrap around to the side panel). Practitioners are accustomed to seeing the
`proprietary and established names and strength clearly displayed on the front panel, without
`having to turn the container. If the product strength does not immediately follow the established
`name, or when such items appear in different locations, it takes longer to locate the information or
`information in its place can be confused. It would be best if the strength appeared on the principal
`display panel underneath the established name.
`
`4.5
`
`TITRATION PACKAGE CONFIGURATION
`
`4.5.] Proposed Titration Regimen
`
`The current insert labeling recommends that ______._..—-————-——-—-——-~——-
`
`However, some patients may require further titration up to maximum daily dose
`of 12 mg two times a day. The proposed titration package configuration includes additional doses
`of W” DMEPA believes that the titration package should stop after day
`four to eliminate potential confusion in patients who require additional increases in the dose.
`
`13(4)
`
`4.5.2 Starter Pack Terminology
`
`The Applicant uses the term ”M” an the titration package configuration. This is not in
`accordance with - M““‘m- which states a drug product which is to be given to a patient by a
`physician as a sample cannot use the term —"
`
`13(4)
`
`4.5.3
`
`Inappropriate Graphics
`
`The applicant utilizes a “sun” and “moon” graphic to depict the tablets should be taken in the
`morning and evening. The use of these graphics can be a source of confusion because patients can
`misinterpret exactly when the tablets should be taken. If prominently displayed, the wording
`(”Take 1 mg tablet in the morning and 1 mg tablet in the evening") is sufficient for patient
`understanding.
`
`

`

`4.5.4 Decreased Readability Due to Font Size
`
`The white font on the green background is hard to read. This may be due to the font size since this
`color combination is used on other Fanapt labels and labeling. Increasing the font size will
`increase readability of important information such as the statement "Take 1 mg tablet in the
`morning and 1 mg tablet in the evening" and the contents of the titration pack.
`
`4.5.5 Inappropriate Presentation ofNet Quantity
`
`The front cover does not adequately convey to healthcare practitioners the specific contents of
`each titration pack. This information should be clearly stated on the front cover to ensure that
`healthcare practitioners understand the exact strengths and quantities contained in each pack.
`
`4.6
`
`INSERT LABELING
`
`The Applicant uses the abbreviation "BID" throughout the labeling. Though it is unlikely that
`medication errors may occur from the abbreviation ‘BID’, we recommend avoiding the use of any
`abbreviation or acronym (e.g., BID) in the labels and labeling.
`
`4.7 GRAPHIC PROMINENCE
`
`The "F" that appears above the proprietary name may draw attention away from important
`information on the principal display panel. The most prominent information on the principal
`display panel should be the proprietary and established names and the product strength. Decreasing
`the prominence will allow healthcare practitioners to clearly recognize the products name and
`product strength.
`
`5 CONCLUSIONS AND RECOMMENDATIONS
`
`The Label and Labeling Risk Assessment findings indicate that the presentation of information
`and design of the proposed container labels, carton and insert labeling introduces vulnerability to
`confusion that could lead to medication errors. Specifically, DMEPA notes problems with the
`presentation of the established name, strength differentiation, lack of contrast of Fanapt 2 mg,
`location of strength, titration package configuration information, graphic prominence and the use
`of abbreviations in the insert labeling. DMEPA believes the risks we have identified can be
`addressed and mitigated prior to drug approval, and provide recommendations in Section 5.1.
`
`5.]
`
`COMMENTS T0 THE DIVISION
`
`The Division of Medication Error Prevention and Analysis would appreciate feedback of the final
`outcome of this review. We would be willing to meet with the Division for further discussion, if
`needed. Please copy DMEPA on any communication to the Applicant with regard to this review.
`If you have further questions or need clarifications, please contact Bola Adeolu, OSE project
`manager, at 301-796-4264.
`
`5.2
`
`COMMENTS TO THE APPLICANT
`
`Based upon our assessment of the labels and labeling, DMEPA identified the following areas of
`needed improvement.
`
`All Labels and Labeling:
`
`1. Decrease the prominence of the "F" that appears above the proprietary name, Fanapt,
`ensuring it is not more prominent than the proprietary name or the established name.
`
`2.
`
`Increase the size of the established name, ensuring it is 1/2 the size of the proprietary name
`taking into account all pertinent factors, including typography, layout, contrast, and other
`printing feature in accordance with 21 CFR 201.10(g)(2).
`
`

`

`Trade Container Labels
`
`1.
`
`The lavender color on the 4 mg product strength is too similar to the light grey color used
`for the 10 mg product strength. There are similar concerns involving the colors utilized
`for the 6 mg and 12 mg strengths. Revise the colors used for these strengths to provide
`better differentiation.
`
`The light yellow color used for the 2 mg product strength is difficult to read on the white
`background. Revise the color for the 2 mg product strength to increase the color contrast
`between the yellow text and the white background color. Ensure that the revised color is
`not similar to the appearance of any other product strength. (See previous comment)
`
`Professional Sample Container Labels
`1.
`
`The container configuration will likely be small and when the container label is placed on
`the container the current presentation of the product strength may not be visible when
`looking at the front panel of the container label ( i.e., the portion of the label containing
`the product strength may wrap around to the side panel) Relocate the strength to
`immediately follow the established name ensuring it appears on the principal display panel
`(i.e., as presented on the trade size container labels).
`
`The statement "Professional sample" is small and difficult to read. Increase the size of this
`statement.
`
`Titration Package Configuration
`1. The use of the term -.—- on the professional samples in not in accordance with f‘
`f»— .. drug product which is to be given to a patient by a physician as a sample cannot
`not use the term —-: Delete the term ‘ -—-- ‘rom the professional samples.
`
`-
`.
`The current insert labeling recommends that a
`m However, some patients may require further titration up to
`_
`maximum daily dose of 12 mg two times a day. The proposed titration package
`configuration includes additional
`._———-—-—-—-—-
`.,
`’ DMEPA believes
`that the titration package should stop after day four to eliminate potential confusion in
`patients who require additional increases in the dose. Revise the titration package
`configuration so that the package configuration only contains a four day supply which is
`congruent with the recommended starting titration dose schedule.
`
`The white text font on the green background is difficult to read (i.e., white lettering on
`green background). Increase the size of the font size to improve readability of important
`information such as the instructions for use and the contents of the package.
`
`We note the utilization of the "sun" and "moon" graphic to depict when the tablets should
`be taken in the morning and evening. The use of these graphics can be a source of
`confusion because patients can misinterpret exactly when the tablets should be taken.
`Remove the "sun and moon" graphics.
`
`The front cover does not adequately convey to healthcare practitioners the specific
`contents of each titration pack. Revise the product strength statement so healthcare
`practitioners and patients understand theexact strengths and quantities contained in the
`titration carton. Revise to read:
`
`This package contains:
`
`Two 1 mg tablets
`
`Two 2 mg tablets
`
`Two 4 mg tablets
`
`M4)
`
`

`

`Two 6 mg tablets
`
`5. We note your November 19, 2008, submission references the inclusion of a commercial
`titration pack. However, upon review of the file, we nOte that the carton labeling is for a
`professional sample titration pack. Please clarify whether or not you plan to market a
`commercial titration pack.
`
`Insert Labeling
`
`We note the use of the abbreviation BID throughout the labels and labeling. We recommend
`avoiding the use of any abbreviations and acronyms (e.g., BID) in the labeling. Eliminate the use
`of the abbreviation “BID” throughout the package insert labeling. Revise all references to read
`“two times a day”.
`
`. APPEARS THIS WAY ON ORIGINA:
`
`

`

`g
`
`Page(s) Withheld
`
`—.——_
`
`Trade Secret / Confidential (b4)
`
`X
`
`Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Diane Smith
`3/4/2009 11:50:53 AM
`DRUG SAFETY OFFICE REVIEWER
`
`Denise Toyer
`3/4/2009 01:46:46 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Carol Holquist
`3/4/2009 01:55:58 PM
`‘DRUG SAFETY OFFICE REVIEWER
`
`

`

`,,
`_-_SEALD LABELING REVIEW i,
`
`Template version: November, 2008
`
`i DRUG NAME
`SUBMISSION DATE
`
`NBA 22-192
`Vanda Pharmaceuticals
`
`5 Iloeridone
`
`_
`‘
`_
`
`
`
`
`
`SEALD REVIEW DATE
`SEALD REVIEWER S
`
`E
`f 1-29-09
`Kim Shile BSN and Laurie Burke RPh MPH
`
`‘
`3
`
`
`

`

`021'
`
`Page(s) Withheld
`
`Trade Secret / Confidential (b4)
`
`X
`
`Draft Labeling (b4)
`
`X Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`/s/
`
`Kimberly Shiley
`1/30/2009 12:44:48 PM
`cso
`
`SEALD Comments sent to Review Division on 1—29-09
`
`Laurie Burke
`2/10/2009 05:34 :35 PM
`INTERDI SCIPLINARY
`
`

`

`
`
`Date:
`
`To:
`
`Department of Health and Human Services
`Public Health Service
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`June 26, 2008
`
`Thomas Laughren, M.D., Director
`Division of Psychiatry Products
`
`Through:
`
`‘
`
`Todd Bridges, RPh, Team Leader
`Denise Toyer, PharmD., Deputy Director
`Division of Medication Error Prevention
`
`From:
`
`Subject:
`
`Diane C. Smith, PharmD, Safety Evaluator
`Division of Medication ErrorPrevention
`
`Labeling Review for Fanapta
`
`Drug Name(s):
`
`Fanapta (lloperidone) Tablets 1 mg, 2 mg, 4 mg, 6 mg, 8 mg
`10 mg and 12 mg
`
`Application
`Type/Number:
`
`NDA 22-192
`'
`
`Applicant/sponsor:
`
`Vanda Pharmaceuticals Inc.
`
`OSE RCM #:
`
`2007-538
`
`

`

`CONTENTS
`
`EXECUTIVE SUMMARY ............................................................................................................. 1
`1
`BACKGROUND ..................................................................................................................... 1
`
`* 1 .1
`
`Introduction .................................................................................................................... 1
`
`Product Labeling ............................................................................................................ l
`1.2
`2 METHODS AND MATERIALS ............................................................................................ 2
`
`3
`
`4
`
`5
`
`RESULTS ................................................................................................................................ 3
`
`Label and Labeling Risk Assessment ............................................................................ 3
`3.1
`DISCUSSION ......................................................................................................................... 4
`
`CONCLUSIONS AND RECOMMENDATIONS .................................................................. 6
`
`5.1
`
`Comments to the Applicant............................................................................................ 6
`
`

`

`EXECUTIVE SUMNIARY
`
`The Division of Medication Error Prevention’s Label and Labeling Risk Assessment found that
`the proposed container label, carton labeling and insert labeling introduce vulnerability to
`confusion that could lead to medication errors. Iftitration is variable depending upon patient, the
`proposed blister titration carton packaging configuration is not appropriate and increases the risk
`of medication errors because it requires removal of tablets or supplemental tablets to
`accommodate each individual patient/schedule.
`‘
`
`We believe the remaining risks we have identified can be addressed and mitigated prior to
`approval with revisions to the labels and labeling. Such improvements include elimination of
`error-prone abbreviations in the package insert and improvements to the design ofthe titration
`pack. We provide recommendations in Section 5.1 and request these revisions be made prior to
`approval in order to minimize the risk of dispensing and administration errors.
`
`1
`
`BACKGROUND
`
`1.1
`
`INTRODUCTION
`
`This review was written in response to a request from the Division of Psychiatry Products to
`evaluate the container label, carton and insert labeling for Fanapta (iloperidone) 1 mg, 2 mg,
`4 mg, 6 mg, 8 mg, 10 mg and 12 mg tablets.
`
`1.2
`
`PRODUCT LABELING
`
`Fanapta a dopamine D(2) and serotonin 5-HT2 antagonist, is a psychotropic agent indicated for
`the treatment of schizophrenia. The recommended target dose range is 12 mg to 24 mg/day
`administered twice daily during the acute phase. Titration to target dosage range should be
`achieved in daily dosage adjustment, for example 1, 2, 3, and 4 days respectively, to reach the
`target 12 mg/day dose. Alternatively, the starting dose can begin at 2 mg twice a daily. During
`the maintenance phase the target dose of 1- —_-—_r can be administered once daily or twice
`daily. Fanapta available as a 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg tablets. Fanapta
`will be supplied as followed:
`'
`
`W“
`
`Package Configuration
`
`Tablet Strength
`
`Bottle of 14
`
`Bottle of 60
`
`Blister Cards
`
`1mg
`
`2mg
`
`4mg
`
`6mg
`
`8mg
`
`10mg
`
`l2mg
`
`'
`
`.
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X '
`
`X
`
`X .
`
`X
`
`

`

`2 METHODS AND MATERIALS
`
`This section describes the methods and materials used by medication error prevention staff to
`conduct a label, labeling, and/or packaging risk assessment. The primary focus of the
`assessments is to identify and remedy potential sources of medication error prior to drug
`approval. The Division of Medication Error Prevention defines a medication error as any
`preventable event that may cause or lead to inappropriate medication use or patient harm while
`the medication is in the control ofthe health care professional, patient, or consumer. I
`
`The label and labeling of a drug product are the primary means by which practitioners and
`patients (depending on configuration) interact with the pharmaceutical product. The container
`labels and carton labeling communicate critical information including proprietary and established
`name, strength, form, container quantity, expiration, and so on. The insert labelinglS intended to
`communicate to practitioners all information relevant to the approved uses of the drug, including
`the correct dosing and administration.
`
`Given the critical role that the label and labeling has in the safe use of drug products, it is not
`surprising that 33 percent of medication errors reported to the USP-ISMP Medication Error
`Reporting Program may be attributed to the packaging and labeling of drug products, including
`30 percent of fatal errors.2
`
`Because medication error prevention staff analyze reported misuse of drugs, we are able to use
`this experience to identify potential errors with all medication similarly packaged, labeled or
`prescribed. We use FMEA and the principles of human factors to identify potential sources of
`error with the proposed product labels and insert labeling, and provided recommendations that
`aim at reducing the risk of medication errors.
`
`For this product the review division forwarded on April 18, 2008 the following labels and
`labeling for our review (see Appendix A, B, C and D for images):
`
`0 Container Label: (1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg) 60 tablet count
`
`0
`
`Professional Sample Container Label: (4 mg, 6 mg, 8 mg, 10 mg and. 12 mg) 14 tablet
`count
`
`0 Blister Cards 14 tablet count
`
`0
`
`0
`
`0
`
`Professional Sample Blister Card
`
`Professional Sample Carton Labeling 14 tablet count
`
`Package Insert Labeling (no image)
`
`I National Coordinating Council for Medication Error Reporting and Prevention.
`ht_tp://wwwnccmerp.orglaboutMedErrors.html. Last accessed 10/11/2007
`
`2 Institute ofMed1c1ne Preventing Medication Errors. The National Academies Press: Washington DC.
`2006. p275.
`
`

`

`3 RESULTS
`
`3.1
`
`LABEL AND LABELING RISK ASSESSMENT
`
`Review of the container label and carton labeling identified several areas of vulnerability that
`could lead to potential medication error, specifically with respect to the presentation of the blister
`card labeling and the instructions in the dosage and administration section ofthe package insert
`labeling.
`
`3.1.1 All Labels and Labeling
`
`The graphic “F” above the proprietary name is distracting.
`
`The letter “p’” in the proprietary name bisects the established name and dosage form.
`
`The established name appears to be smaller than half the size of the trade name due to the font
`type, color, and presentation of the trade name.
`
`3.1.2 Trade Container Labels
`
`The strength colors for the 4 mg and 10 mg tablets look almost identical.
`
`The yellow font color scheme for the 2 mg is difficult to read.
`
`3.1.3 Professional Sample Bulk Container Labels
`
`The 14—count bottle as currently presented may not include the product strength on the principal
`display panel.
`'
`
`