CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-372/8008/8010
`
`OTHER REVIEW! S)
`
`

`

`
`
`Thru:
`
`From:
`
`Subject:
`
`Department of Health and Human Services
`Public Health Service
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`
`February 29, 2008
`
`Donna Griebel, MD, Acting Director
`Division of Gastroenterology Products
`
`Kristina Amwine, PharmD, Acting Team Leader
`Denise Toyer, PharmD, Deputy Director
`Carol Holquist, RPh, Director
`Division of Medication Errors and Technical Support
`
`Bill Bender, RPh Safety Evaluator
`Division of Medication Errors and Technical Support
`
`Aloxi Labeling Supplement
`
`Drug Name(s):
`
`Aloxi (Palonosetron HCL Injection)
`
`Submission Number:
`
`SE1-008
`
`(b) (4)3E1—010
`
`Application Type/Number:
`
`NDA 21-372
`
`Applicant/sponsor:
`
`OSE RCM #:
`
`Helsinn Healthcare
`
`2008-232
`
`(b) (4)
`
`

`

`CONTENTS
`
`EXECUTIVE SUMMARY ............................................................................................................. 2
`
`1
`
`BACKGROUND ..................................................................................................................... 2
`
`1 . 1
`
`1.2
`1.3
`
`Introduction .................................................................................................................... 2
`
`Regulatory History ......................................................................................................... 2
`Product Information ....................................................................................................... 2
`
`2 METHODS AND MATERIALS ....................................................................... 3
`
`2.1
`
`2.2
`
`3
`
`ADVERSE EVENT REPORTING SYSTEM ............................................................................... 3
`
`LABELS AND LABELING ...................................................................................................... 4
`
`RESULTS ................................................................................................................................ 4
`
`3.1
`3.2
`
`3.3
`
`Adverse Event Reporting System (AERS) .................................................................... 4
`Container Label .............................................................................................................. 4
`
`Carton Labeling.............................................................................................................. 5
`
`Insert Labeling ............................................................................................................... 5
`3.4
`DISCUSSION .......................................................................................................................... 5
`
`CONCLUSIONS and recommendations ................................................................................. 6
`
`4
`
`5
`
`5.1
`
`Comments To The Division .......p.................................................................................... 6
`
`Comments To The Applicant ......................................................................................... 7
`5.2
`APPENDICES ................................................................................................................................. 8
`
`

`

`EXECUTIVE SUMMARY
`
`DMETS’ analysis of the container, carton and insert labeling noted improvements that should be
`made to the container label and carton labeling to decrease the potential for selection errors,
`mimimize confusion with dosing, and increase readability of information presented on the
`labeling. Such improvements include changing the color of the carton and the proprietary name
`for the 0.075 mg/ 1.5 mL strength to differentiate it from the color on the current 0.25 mg/5 mL
`strength. In addition, the proprietary name should be the same solid color on both the carton and
`container. For full recommendations, we refer you to section 5 of this review.
`
`1
`
`BACKGROUND
`
`1.1
`
`INTRODUCTION
`
`This review was written in response to a request from the Division of Gastroenterology Products
`(DGP) to evaluate the container label and labeling supplement for Aloxi (palonosetron HCL)
`intravenous injection, 0.075 mg/l .5 mL (0.05 mg/mL) for the prevention of postoperative (b) (4)
`(b) (4) nausea and vomiting (PONV/PDNV) for up to t
`(b) (4)
`
`1.2
`
`REGULATORY HISTORY
`
`Aloxi was approved on July 25, 2003 and is currently indicated for: (l) the prevention of acute
`nausea and vomiting associated with initial and repeat courses of moderately and highly
`emetogenic cancer chemotherapy, and (2) the prevention of delayed nausea and vomiting
`associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. Aloxi
`is currently supplied as a 0.25 mg/5 mL (0.05 mg/mL) single-use Vial for intravenous injection.
`
`1.3
`
`PRODUCT INFORMATION
`
`Aloxi (palanosetron HCL) is a 5-HT3 receptor antagonist with a strong binding affinity for this
`receptor and weak affinity for other receptors. Aloxi is currently indicated for the prevention of
`acute and delayed nausea and vomiting associated with initial and repeat courses of moderately
`emetogenic cancer therapy and for acute nausea and vomiting associated with initial and repeat
`courses of highly emetogenic cancer therapy. The recommended dose for adults is a single
`0.25 mg intravenous dose administered over thirty seconds approximately thirty minutes before
`the start of chemotherapy. The safety and effectiveness in patients below the age of 18 years has
`not been established.
`
`The sponsor’s proposed indication for Aloxi is the prevention of postoperative
`nausea and vomiting (PONV (b) (4) up to
`(b) (4) The dosage for adults is
`0.07 5 mg administered as a single dose intravenously over ten seconds immediately before
`induction of anesthesia. Aloxi is not indicated for patients under the age of 18.
`
`(b) (4)
`
`Aloxi will be available as 0.25 mg/5 mL (0.05 mg/mL) and 0.075 mg/l .5 mL (0.05 mg/mL)
`single—use intravenous vials. Aloxi is stored at room temperature (20°C-25°C) and should be
`protected from light.
`-
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`2 METHODS AND MATERIALS
`
`This section describes the methods and materials used by the DMETS medication error staff to
`conduct a label, labeling, and/or packaging risk assessment (see section 3 Results). The primary
`focus of the assessments is to identify and remedy potential sources of medication errors prior to
`drug approval. DMETS 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. 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 carton and
`container labels communicate critical information including the proprietary and established name,
`strength, form, container quantity, expiration date, and so on. The insert labeling is intended to
`communicate to practitioners all the 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 (MERP) may be attributed to the packaging and labeling of drug products,
`including 30 percent of fatal errors.2
`
`DMETS staff analyzes reported misuse of drugs and are able to use their experience to identify
`potential errors with all packaged, labeled and/or prescribed medications. DMETS uses failure
`mode and effects analysis (FMEA) and human factor principles to identify potential sources of
`error with the proposed product labels and insert labeling. DMETS then provides
`recommendations that aim at reducing the risk of medication errors.
`
`2.1
`
`ADVERSE EVENT REPORTING SYSTEM
`
`Because Aloxi has been marketed since 2003, DMETS conducted a search of the Adverse Event
`Reporting System (AERS) database to determine if any medication errors are associated with the
`use of Aloxi. The MedDRA Higher Level Terms (HLT) “Maladministration”, “Medication
`Errors NEC”, “Medication Errors Due to Accidental Exposures”, “Medication Monitoring
`Errors”, and the Preferred Terms (PT) “Overdose”, “Accidental Overdose”, “Multiple Drug
`Overdose”, “Multiple Drug Overdose Accidental”, and verbatim substance names “Alox%” and
`“Palonos”, tradename “Aloxi”, and active ingredient “Palonosetron” were used as search criteria.
`
`The cases were manually reviewed to determine if a medication error occurred. Those cases that
`did not describe a medication error were excluded from further analysis. The cases that did
`describe a medication error were categorized by type of error. DMETS reviewed the cases within
`each category to identify factors that contributed to the medication errors.
`
`I National Coordinating Council for Medication Error Reporting and Prevention.
`http://www.nccmergorgzaboutMedErrors.htm1. Last accessed 10/11/2007.
`
`2 Institute of Medicine. Preventing Medication Errors. The National Academies Press: Washington DC.
`2006. p275.
`
`

`

`2.2
`
`LABELS AND LABELING
`
`For this product, the Sponsor submitted on October 10, 2007, the following labels and insert
`labeling for DMETS review (see Appendices A and B for images):
`
`0 Container Label: 0.075 mg/ 1.5 mL (0.05 mg/mL) vial
`
`o Carton Labeling: 0.075 mg/l.5 mL (0.05 mg/mL) vial
`
`-
`
`Prescribing Information- package insert and patient package insert (no image)
`
`Additionally, the Sponsor provided the current carton labels for comparison (see Appendices C
`and D for images):
`
`0 Current Container Label: 0.25 mg/5 mL (0.05 mg/mL) vial
`
`- Current Carton Labeling: 0.25 mg/5 mL (0.05 mg/mL) vial
`
`3
`
`RESULTS
`
`3.1
`
`ADVERSE EVENT REPORTING SYSTEM (AERS)
`
`The FDA Adverse Event Reporting System (AERS) search conducted on February 26, 2008,
`yielded two cases involving Aloxi. Of the two cases, one was determined to involve a medication
`error in which the patient received an extra dose of Aloxi without any adverse effects as a result
`of the extra dose. No causality was included as to why the patient was administered the second
`dose in error. The second case only listed Aloxi as a concomitant medication but did not involve
`Aloxi in the medication error.
`
`3.2 '
`
`. CONTAINER LABEL
`
`Review of the container labels and carton labeling identified several potential sources of
`medication errors. These concerns are noted below.
`
`The color scheme of the proposed 0.075 mg/1.5 mL vial
`(b) (4) and the currently marketed 0.25 mg/5 mL vial
`(b) (it) appear to be very similar and are virtually indistinguishable.
`b 4
`The product strength
`(
`) ( )however the established name
`
`(b) (4)
`(b) (4)
`
`('0) (4)
`
`(b) (4)in the proprietary name.
`Two different color fonts
`The
`(D) (4)'or the established name and‘product strength does not provide
`ade uate contrast.
`q
`.
`(b) (4)
`The establrshed name appears to be smaller 1
`
`trade name
`
`('0) <4)
`
`(b) (4)
`
`The product strength lacks prominence and is difficult to read.
`The
`(D) (4)uti]ized for the NDC number, distributor statement, and
`storage recommendations makes the information difficult to read.
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`3.3
`
`CARTON LABELING
`
`The product strength is expressed
`('0) (4)
`
`(b) (4) however the established name
`
`(D) (4)in the proprietary name.
`Two diffegent4color fonts
`The large(
`) ( )graphic makes the label difficult to read.
`The
`(D) (4)gray background utilized for the established name and product strength
`does not provide adequate contrast.
`The established name
`
`(b) (4)trade name
`
`(b) (4)
`
`The product strength lacks prominence and is difficult to read.
`
`(b) (4)
`
`(b) (4)has a trailing zero.
`
`The
`presented therein difficult to read.
`
`3.4
`
`INSERT LABELING
`
`(b) (4)
`
`(b) (4) side panels makes the information
`
`The abbreviation “IV” is used for the word intravenous or intravenously throughout the physician
`labeling.
`
`The heading in the Dosage and Administration section of the package insert entitled
`(b) (4)
`
`4
`
`DISCUSSION
`
`Our analysis of the container labels and carton labeling noted areas of vulnerability that could
`lead to medication errors. For example, the proposed color scheme on the container label for the
`0.075 mg/l .5 mL strength
`(b) (4) is verv similar to the
`currently marketed 0.25 mg/5 mL strengtht
`(b) (4). Our
`postmarketing experience demonstrates that product selection errors may occur due to the similar
`appearance of container labels especially when similar colors and trade dress are used. Selection
`errors may be perpetuated during administration leading to overdose and potentially resulting in
`adverse events.
`
`(b) (4)
`
`in the proprietary name on the
`We also noted the use of two different color
`(D) (4)name is distracting and
`container label and carton labeling. The
`(b) (4) The use of two different color fonts mav
`promotional as it appears to be a
`(b) (4)1
`cause the name to be misinterpreted as
`(b) (4)to the proposed carton
`letter. Furthermore, the applicant
`(b) (4)on the grey background utilized for the
`labeling.
`established name, product strength, route of administration, and net quantity does not provide
`adequate contrast. Poor color contrast leads to low legibility and often misinterpretation.
`(b) (4)
`Additionallv. due to the color scheme and font type of the trade name,
`(b) (4)The letters comprising the established
`name should be presented with prominence commensurate to that of the proprietary name. All
`pertinent factors, including, typography, layout, contrast, and other printing features should be
`taken into account in accordance with 21 CFR 201 .10(g)(2).
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`.
`DMETS also noted that the product strength is expressed
`established name
`.
`(b) (4)
`
`(b) (4)
`(b) (4)
`.
`.
`Additionally, the product strength is small making it difficult to locate. Since there will be two
`Aloxi products on the market, it is important that the strengths are readily distinguishable in order
`to minimize the potential for selection errors.
`
`(b) (4)
`
`however; the
`
`,
`
`,
`
`We also noted the heading in the Dosage and Administration section of the package insert entitled
`V
`,
`.
`_,
`_
`<p>(4)
`(b) (4)
`(b) (4) We are also concerned with the use of a trailing zero on
`the carton labeling and the abbreviation “IV” in the package insert. Trailing zeros are considered
`dangerous abbreviations and are listed on the Institute for Safe Medication Practices (ISMP) “List
`of Error-Prone Abbreviations, Symbols. and Dose Designations”. The decimal place is often not
`seen when trailing zeros are used.
`.
`,
`7
`(b) (4)
`(b) (4) We also noted the use of the abbreviation “IV”. “IV”
`could potentially be misinterpreted for another route of administration (e.g. IM) or a dosage unit
`(e.g. IU) and lead to medication errors. In June 2006, FDA launched a campaign in conjunction
`with ISMP to prevent the use of error-prone abbreviations such as “IV” and trailing zeros in
`prescribing. As part of this campaign, FDA agreed not to approve such abbreviations in their
`labeling because these abbreviations are carried on to the prescribing practice.
`
`The approval of this application will allow for one additional strength of Aloxi (0.075 mg/
`1.5 mL). It does not appear that this additional strength poses any dosing problems but the labels
`and labeling for this new strength should be adequately distinguished from the currently marketed
`product to avoid selection errors.
`
`5
`
`CONCLUSIONS AND RECOMMENDATIONS
`
`The approval of the new 0.075 mg/1.5 mL strength does not appear to increase the risk of
`medication errors. However, efforts need to be made to adequately differentiate the visual
`similarity of this new strength from the currently marketed strength.
`
`DMETS recommends the label and labeling recommendations outlined below be implemented to
`improve differentiation between the differing strengths and to increase readability of the labels
`and labeling,
`
`DMETS would appreciate feedback on the final outcome of this review. We would be willing to
`meet with the Division for further discussion, if needed. Please copy DMETS on any
`communication to the Applicant with regard to this review. If you have further questions or need
`clarifications, please contact Cherye Milburn, Project Manager, at 301-796-2084.
`
`5.]
`
`COMMENTS TO THE DIVISION
`
`This hpnrlino in the Dosage and Administration section of the package insert entitled
`
`(b) (4)
`
`The comments below should be forwarded to the applicant so that these recommendations can be
`implemented prior to approval of this supplement.
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Based upon our assessment of the labels and labeling, DMETS has identified areas of needed
`improvement. We have provided recommendations in section 5.2 below and request this
`information be forwarded to the applicant.
`
`5.2
`
`COMMENTS TO THE APPLICANT
`
`A. Container Label
`1.
`
`Revise the established name and product strength so that they are in accordance
`(b) (4) Consult Rik Lostritto, chair of the CDER
`Labeling and Nomenclature Committee for further guidance.
`
`Revise the color scheme for the 0.075 mg/1.5 mL strength to ensure it is adequately
`differentiated from the 0.25 mg/5 mL strength.
`
`Revise the color scheme for the proprietary name so that the entire name is
`presented in one color font.
`
`Revise the color of the font utilized for the established name and product strength
`so that it provides adequate contrast against the grey backround.
`
`5.
`
`Increase the prominence of the established name and product strength.
`
`B. Carton Labeling
`l. Revise the established name and product strength so that they are in accordance
`with
`(b) (4) Consult Rik Lostritto, chair of the CDER
`Labeling and Nomenclature Committee for further guidance.
`
`Revise the color scheme of the proprietary name so that the entire name is
`presented in one color font.
`
`Revise the color of the font utilized or the established name and product strength so
`that it provides adequate contrast against the grey backround.
`
`Increase the prominence of the established name and product strength.
`
`Eliminate the use of trailing zeroes.
`
`Include a “New Strength” banner on the principal display panel for a period not to
`exceed six months.
`
`C.
`
`Insert Labeling
`1. Eliminate the use of the abbreviation “IV”. Revise all references to read
`“intravenously” or “intravenous”.
`
`(b) (4)
`
`(b) (4)
`
`

`

`12.3 Pharmacokinetics
`
`,
`
`(b) (4)
`
`We suggest revising this sentence slightly for clarity. We recommend,
`
`After intravenous dosing of palonosetron in patients undergoing surgery
`(abdominal surgery or vaginal hysterectomy), the pharmacokinetic
`characteristics. .
`
`lndenting
`. We suggest that the subsections for Distribution, Metabolism, etc. not be indented.
`makes them appear that they belong under the PONV paragraph that precedes them.
`
`14 Clinical Studies
`
`0 Because this drug will now have two distinct indications, we suggest that section 14.1 be for
`the ClNV studies and 14.2 for PONV.
`
`. We will defer comments on the PONV clinical study description until an updated version of the
`label is available.
`
`17 Patient Counseling Information
`
`0 The first line, “See FDA—approved Patient Labeling (17.2)” should not
`remain italicized).
`
`(b) (4)(but should
`
`17.2 FDA-Approved Patient Labeling
`
`. Although the patient labeling is not the subject of this review, please ensure that all mention of
`(b) (4)is deleted.
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`2 Page(s) Withheld
`
`§ 552(b)(4) Trade Secret / Confidential
`
`__/_ § 552(b)(4) Draft Labeling
`
`§ 552(b)(5) Deliberative Process
`
`

`

`Appendix C: Currently Marketed Container Label 0.25 mg/mL
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`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`William Bender
`
`2/29/2008 10:39:40 AM
`CSO
`
`Kristina Arnwine
`
`2/29/2008 10:43:03 AM
`DRUG SAFETY OFFICE REVIEWER
`
`Denise Toyer
`2/29/2008 01:03:00 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Carol Holquist
`2/29/2008 03:21:43 PM
`DRUG SAFETY OFFICE REVIEWER
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