CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205580Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`March 30, 2018
`Requesting Office or Division:
`Division of Hematology Products (DHP)
`Application Type and Number: NDA 205580
`Product Name and Strength:
`Bendamustine Hydrochloride Injection, 100 mg/4 mL (25
`mg/mL)
`Eagle Pharmaceuticals
`March 20, 2018
`2018-283-1
`Nicole Garrison, PharmD, BCPS
`Hina Mehta, PharmD
`
`Applicant/Sponsor Name:
`FDA Received Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`PURPOSE OF MEMORANDUM
`1
`The Division of Hematology Products (DHP) requested that we review the revised container
`labels and carton labeling for Bendamustine Hydrochloride (Appendix A) to determine if it is
`acceptable from a medication error perspective. The revisions are in response to
`recommendations that we made during a previous label and labeling review.a We note per
`email response; the Applicant intends to market the product with the established name,
`bendamustine hydrochloride for nowb.
`
` CONCLUSION
`2
`The revised container labels and carton labeling are acceptable from a medication error
`perspective.
`
`a Garrison N. Label and Labeling Review for Bendamustine Hydrochloride (NDA 205580). Silver Spring (MD): FDA,
`CDER, OSE, DMEPA (US); 2018 MAR 13. RCM No.: 2018-283.
`b Information Request Response received on March 30, 2018.
`1
`
`Reference ID: 4242375
`Reference ID: 4266336
`
`

`

`APPENDIX A. IMAGES OF LABEL AND LABELING RECEIVED ON MARCH 20, 2018
`Container labels
`
`Reference ID: 4242375
`Reference ID: 4266336
`
`2
`
`(b) (4)
`
`3 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NICOLE B GARRISON
`03/30/2018
`
`HINA S MEHTA
`03/30/2018
`
`Reference ID: 4242375
`Reference ID: 4266336
`
`

`

`MEMORANDUM
`REVIEW OF REVISED LABEL AND LABELING
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`Date of This Memorandum:
`March 13, 2018
`Requesting Office or Division:
`Division of Hematology Products (DHP)
`Application Type and Number: NDA 205580
`Product Name and Strength:
`Belrapzo (bendamustine hydrochloride) Injection, 100
`mg/4 mL (25 mg/mL)
`Eagle Pharmaceuticals
`January 31, 2018 and February 9, 2018
`2018-283
`Nicole Garrison, PharmD, BCPS
`Hina Mehta, PharmD
`
`Applicant/Sponsor Name:
`FDA Received Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`DMEPA Associate Director
`Mishale Mistry, PharmD, MPH
`(Acting):
`
`PURPOSE OF MEMO
`1
`The Division of Hematology Products (DHP) requested that we review the proposed container
`label, carton labeling, and Prescribing Information (PI) for Bendamustine Injection (NDA
`205580) for areas of vulnerability that may lead to medication errors (Appendix A). DHP
`requested this review as a part of their evaluation of the 505(b)(2) NDA class I resubmission for
`Bendamustine Injection. DMEPA provided recommendations during a previous label and
`labeling review.a,b
`1.1 REGULATORY HISTORY
`
`a Gao. T. Label, Labeling and Packaging Review for Bendamustine (NDA 205580). Silver Spring (MD): FDA, CDER,
`OSE, DMEPA (US); 2013 DEC 24. RCM No.: 2013-1791.
`b Gao. T. Label, Labeling Review Memo for Bendamustine (NDA 205580). Silver Spring (MD): FDA, CDER, OSE,
`DMEPA (US); 2014 APR 09. RCM No.: 2013-1791.
`
`1
`
`Reference ID: 4232855
`Reference ID: 4266336
`
`

`

`Eagle Pharmaceuticals submitted Bendamustine Injection (NDA 205580) on September 6, 2013,
`a 505(b)(2) application which relies upon the listed drug, Treanda (bendamustine
`hydrochloride) for Injection under NDA 022249. Treanda is currently marketed in the following
`dosage forms and strengths: For injection 25 mg per vial and 100 per vial, and Injection 45
`mg/0.5 mL (90 mg/mL) and 180 mg/2 mL (90 mg/mL). The proposed product will be available
`in an injection dosage form with a strength of 100 mg/4 mL (25 mg/mL). The application
`received a Tentative Approval letter on July 2, 2014 due to patent protection of the listed drug,
`Treanda.
`On December 7, 2015, the Applicant received marketing approval for Bendeka (bendamustine
`hydrochloride) Injection 100 mg/4 mL (25 mg/mL) for infusion in a 50-mL admixture, under
`NDA 208194.
`Eagle Pharmaceuticals submitted a request for final approval of Bendamustine Injection (NDA
`205580) on January 31, 2018.
`
` OVERALL ASSESSMENT
`2
`We note that Bendeka is the same formulation, dosage form (injection) and uses the same
`container closure system (multiple-dose vial) as the proposed Bendamustine Hydrochloride
`Injection. However, there are differences in the required diluent as both products can be
`diluted in Sodium 0.9% Chloride Injection and 2.5% Dextrose/0.45% Sodium Chloride Injection;
`however, Bendeka can also be diluted in 5% Dextrose whereas the proposed Bendamustine
`Hydrochloride Injection cannot. Furthermore, Bendeka requires a diluent volume of 50 mL, with
`a resulting final concentration of bendamustine hydrochloride in the infusion bag within 1.85
`mg/mL – 5.6 mg/mL. The proposed Bendamustine Hydrochloride product requires a diluent
`volume of 500 mL, with a resulting final concentration of bendamustine hydrochloride in the
`infusion bag within 0.2 mg/mL– 0.7 mg/mL. The administration time of Bendeka is 10 minutes
`whereas the proposed Bendamustine hydrochloride product has an administration time of 30
`or 60 minutes. Finally, the storage time following dilute also differs (6 hours vs. 3 hours)
`between Bendeka and Bendamustine Hydrochloride, respectively. See Appendix A for product
`characteristics comparison of the listed drug Treanda (NDA 022249), Bendeka (NDA 208194),
`and the proposed Bendamustine hydrochloride injection product (NDA 205580).
`
`From a medication error perspective, the introduction of Bendamustine Hydrochloride diluted
`in a larger volume (500 mL) with a lower resulting final concentration than the currently
`approved, Bendeka, may result in preparation errors if the labeling is overlooked or does not
`sufficiently indicate the proper diluent, required volume for infusion, and final resulting
`concentration. Therefore, it is important to ensure that labels and labeling contain warning
`statements regarding further dilution and include prominent concentration information.
`
`The proposed PI, label, and labeling can be improved to increase readability and prominence of
`proper preparation of the product as well as ensuring that peel-back labels does not get
`detached. Additionally, we note that the labels and labeling contain both term
`
`
`
`Reference ID: 4232855
`Reference ID: 4266336
`
`2
`
`(b) (4)
`
`

`

`and “multiple-dose”, we defer to the Office of Pharmaceutical Quality (OPQ) for determination
`of the appropriate package type and to maintain consistency of terms on labels and labeling.
`
`CONCLUSION & RECOMMENDATIONS
`3
`We determined that the proposed PI, container label and carton labeling is vulnerable to
`confusion that can lead to medication errors. We provide recommendations for the Division in
`Section 3.1 and for the Applicant in Section 3.2 to be implemented prior to approval of NDA
`205580.
`
`3.1 RECOMMENDATIONS FOR THE DIVISION
`A. Prescribing Information
`1. Highlights and Full Prescribing Information
`a. Dangerous abbreviations, symbols, and dose designations that are included on
`the Institute of Safe Medication Practice’s List of Error-Prone Abbreviations,
`Symbols, and Dose Designations appear throughout the package insert. As part
`of a national campaign to avoid the use of dangerous abbreviations and dose
`designations, FDA agreed not to approve such error prone abbreviations in the
`approved labeling of products. Thus, please revise those abbreviations, symbols,
`and dose designations as follows:
`Replace the symbols “≤” and “” with their intended meanings to
`i.
`prevent misinterpretation and confusion.
`2. Highlights of Prescribing Information
`a. General Dosing Considerations
`i.
`Consider removing storage information as this information is
`contained in Section 2.3 Preparation for Intravenous Administration.
`3. Section 2.3 Preparation for Intravenous Administration
`a.
`Intravenous Infusion
`i.
`Bold the statement, “... 500 mL infusion bag”. We recommend this
`revision to increase prominence of this important information and to
`mitigate the risk of preparation errors.
`Bold the statement, “The resulting final concentration of
`bendamustine HCl in the infusion bag should be within 0.2-0.7
`mg/mL.” We recommend this revision to increase prominence of this
`important information and to mitigate the risk of preparation errors.
`In Table A, underline the statement in the heading, “dilution into 500
`mL”. We recommend this revision to increase prominence of this
`important information and to mitigate the risk of preparation errors.
`
`iii.
`
`ii.
`
`3.2 RECOMMENDATIONS FOR EAGLE PHARMACEUTICALS
`We recommend the following be implemented prior to approval of this NDA:
`A. Container label
`
`Reference ID: 4232855
`Reference ID: 4266336
`
`3
`
`

`

` to
`
`
`
`1. Please indicate where the required lot number and expiration date will appear as
`required per 21 CFR 610.60.
`2. Revise the statement,
`“See prescribing information for dosing and dilution information.”
`3. As the peel-back labels contain important information regarding the preparation of
`the product, we are concerned that the peel-back labels may become detached from
`the product container under actual use. Therefore, we recommend that the peel-
`back label are resealable, able to withstand repeated openings and closings without
`detaching itself from the product container, and able to withstand moisture without
`detaching from the product container.c
`4. On the principal display panel (PDP), revise the cautionary statement, “
`” to the following:
`“Must dilute required dose in a 500 mL admixture prior to administration”.
`We recommend this revision using bold, red font to bring prominence to this
`important information and to mitigate the risk of preparation errors and confusion
`with other formulations of Bendamustine Hydrochloride Injection 100 mg/4 mL (25
`mg/mL), which are diluted in a 50 mL admixture prior to administration with a
`resulting higher concentration.
`5. On the peel-back label, include the diluent solutions (e.g. Sodium 0.9% Chloride
`Injection and 2.5% Dextrose/0.45% Sodium Chloride Injection) that can be used to
`prepare a 500 mL infusion bag of Bendamustine HCl. For example:
`“Aseptically withdraw the volume needed for the required dose based on 25 mg/mL
`concentration as per Table A (see package insert) and immediately transfer to a 500
`mL infusion bag of Sodium 0.9% Chloride Injection or 2.5% Dextrose/0.45% Sodium
`Chloride Injection. We recommend this revision in bold, red font to bring
`prominence to this important information.
`B. Ferrule label
`1. You did not submit a copy of the ferrule label with the resubmission. If you intend
`to have a ferrule label we ask that you resubmit it to the Agency. If you intend to
`have a ferrule label, please ensure the cautionary statement ‘Dilute Before Using”
`also appears on the ferrule in addition to the cap overseal in accordance with United
`States Pharmacopeia (USP) General Chapter <7> Labeling standard. We recommend
`this to minimize the risk of a medication error where the drug is administered
`undiluted, because this is a multi-dose vial and the cap overseal is often discarded
`during the pharmacy dispensing process.
`C. Carton labeling
`1. See A.2 and A.4 and revise the carton labeling accordingly.
`2. On the PDP, revise the cautionary statement,
` to the following:
`
`
`
`c Label Process Series LPS2011-04, Guidance for Designing Peel-Back and Multi-Component Labels of Domestic
`Class Pest Control Products [Internet]. Ottawa (Ontario): Health Canada Pest Management Regulatory Agency.
`2011 [cited 2013 Nov 6]. Available from http://www.hc-sc.gc.ca/cps-spc/pubs/pest/ pol-guide/lps2011-04/index-
`eng.php#a5.
`
`4
`
`Reference ID: 4232855
`Reference ID: 4266336
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`“Must dilute required dose in a 500 mL infusion bag of Sodium 0.9% Chloride
`Injection or 2.5% Dextrose/0.45% Sodium Chloride Injection prior to
`administration”.
`We recommend this revision using bold, red font to bring prominence to this
`important information.
`
`Reference ID: 4232855
`Reference ID: 4266336
`
`5
`
`

`

`APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED
`
`APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION
`
`Table 2 presents relevant product information for Belrapzo received on January 31, 2018 and
`February 9, 2018 from Eagle Pharmaceuticals, in comparison to Treanda and Bendeka.
`Table 2. Relevant Product Information for Belrapzo, Bendeka and Treanda
`Belrapzo
`Treanda
`Bendeka
`Product Name
`(NDA 205580)
`(NDA 022249)
`(NDA 208194)
`
`Conditionally approved K March 20, 2008
`December 7, 2015
`on July 2, 2014
`
`Initial Approval
`Date
`Active Ingredient
`Indication
`
`Route of
`Administration
`Dosage Form
`
`Strength
`
`Dose and
`Frequency
`
`Bendamustine Hydrochloride
`For the treatment of patients with:
`Chronic lymphocytic leukemia (CLL) and Indolent B-cell non-Hodgkin
`lymphoma (NHL) that has progressed during or within six months of treatment
`with rituximab or a rituximab-containing regimen.
`Continuous intravenous infusion
`
`Injection
`
`100 mg/4 mL (25
`mg/mL) in a multiple-
`dose vial
`
`Injection and For
`Injection
`Injection (in a single-
`dose vial)
`45 mg/0.5 mL
`180 mg/2 mL (90
`mg/mL)
`
`Injection
`
`100 mg/4 mL (25 mg/mL)
`in a multiple-dose vial
`
`For Injection
`(lyophilized powder in
`a single-dose vial for
`reconstitution)
`25 mg per vial
`100 mg per vial
`CLL: The recommended dose is 100 mg/m2 administered intravenously over 30
`minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.
`NHL: The recommended dose is 120 mg/m2 administered intravenously over
`60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles.
`
`Preparation
`
`Injection:
`
`Injection:
`
`Injection:
`
`6
`
`Reference ID: 4232855
`Reference ID: 4266336
`
`

`

`Dilute with 500 mL
`infusion bag of
`0.9% Sodium Chloride
`Injection, USP, or 2.5%
`Dextrose/0.45%
`Sodium Chloride
`Injection, USP
`
`Dilute with 500 mL
`infusion bag of
`0.9% Sodium Chloride
`Injection, USP, or 2.5%
`Dextrose/0.45%
`Sodium Chloride
`Injection, USP
`
`Resulting final
`concentration of
`bendamustine HCL in
`the infusion bag should
`be within
`0.2 mg/mL– 0.7 mg/mL
`
`Storage
`
`Bendamustine HCl
`Injection 100 mg/4 mL
`(25 mg/mL) should be
`stored between 2° and
`8°C (36° to 46°F).
`Retain in original
`package until time of
`use to protect from
`light.
`
`For injection:
`Reconstitute with
`SWFI
`25 mg TREANDA for
`Injection vial: Add 5
`mL of only Sterile
`Water for Injection,
`USP.
`100 mg TREANDA for
`Injection vial: Add 20
`mL of only Sterile
`Water for Injection,
`USP
`Dilute with
`0.9% Sodium Chloride
`Injection, USP, or 2.5%
`Dextrose/0.45%
`Sodium Chloride
`Injection, USP
`Treanda Injection
`must be stored
`refrigerated between
`2-8°C (36-46°F).
`Retain in original
`package until time of
`use to protect from
`light.
`
`Dilute with 50 mL infusion
`bag of
`0.9% Sodium Chloride
`Injection, USP; or
`2.5% Dextrose/0.45%
`Sodium Chloride Injection,
`USP; or
`5% Dextrose Injection,
`USP.
`
`Resulting final
`concentration of
`bendamustine
`hydrochloride in the
`infusion bag should be
`within
`1.85 mg/mL – 5.6 mg/mL
`
`Store Bendeka in
`refrigerator, 2°-8°C (36° to
`46°F). Retain in original
`package until time of use
`to protect from light.
`
`After first use, the
` vial should be
`stored in original
`carton at 2 °C to 8 °C,
`
`Treanda for Injection
`may be stored up to
`25°C (77°F) with
`excursions permitted
`up to 30°C (86°F) (see
`
`7
`
`Reference ID: 4232855
`Reference ID: 4266336
`
`(b) (4)
`
`

`

`and then discarded
`after 28 days.
`
`USP Controlled Room
`Temperature). Retain
`in original package
`until time of use to
`protect from light.
`
`Reference ID: 4232855
`Reference ID: 4266336
`
`8
`
`

`

`APPENDIX B. IMAGES OF LABEL AND LABELING RECEIVED ON FEBRUARY 9, 2018
`
`Container labels
`
`
`
`Carton labeling
`
`Reference ID: 4232855
`Reference ID: 4266336
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NICOLE B GARRISON
`03/13/2018
`
`HINA S MEHTA
`03/13/2018
`
`MISHALE P MISTRY
`03/13/2018
`
`Reference ID: 4232855
`Reference ID: 4266336
`
`

`

`LABEL AND LABELING REVIEW - MEMO
`Division of Medication Error Prevention and Analysis (DMEPA)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`*** This document contains proprietary information that cannot be released to the public***
`
`Date of This Review:
`April 9, 2014
`Requesting Office or Division:
`Division of Hematology Products (DHP)
`Application Type and Number: NDA 205580
`Product Name and Strength:
`Bendamustine Hydrochloride for Injection,
`100 mg/4 mL (25 mg/mL)
`Single Ingredient
`Rx
`Eagle Pharmaceuticals, Inc.
`March 31, 2014
`2013-1791
`Tingting Gao, PharmD
`Yelena Maslov, PharmD
`
`Product Type:
`Rx or OTC:
`Applicant/Sponsor Name:
`Submission Date:
`OSE RCM #:
`DMEPA Primary Reviewer:
`DMEPA Team Leader:
`
`Reference ID: 3486259
`Reference ID: 4266336
`
`1
`
`

`

`1
`
`REASON FOR REVIEW
`
`This review evaluates the revised container label and carton labeling for Bendamustine
`
`hydrochloride for Injection, NDA 205580, submitted by Eagle Pharmaceuticals, Inc. on February
`
`28, 2014 for areas of vulnerability that could lead to medication errors. DMEPA previously
`
`reviewed the proposed labels and labeling under OSE Review # 2013-1791 dated December 24,
`2013 for NBA 205580.
`
`2 MATERIALS REVIEWED
`
`We considered the materials listed in Table 1 for this review. The Appendices provide the
`methods and results for each material reviewed.
`
`Table 1. Materials Considered for this Label and labeling Review
`
`Material Reviewed
`
`Appendix Section (for Methods
`
`and Results)
`
`for Use or Medication Guide (if applicable)
`
`Product Information/Prescribing Information
`
`FDA Adverse Event Reporting System (FAERS)
`
`B — N/A
`
`Previous DMEPA Reviews
`
`Human Factors Study (if applicable)
`
`ISMP Newsletters
`
`D — N/A
`
`E - N/A
`
`
`
`Other (if applicable) F — N/A
`
`Container Label, Carton Labeling, and Instructions
`
`G
`
`N/A=not applicable for this review
`
`3
`
`OVERALL ASSESSMENT OF THE MATERIALS REVIEWED
`
`We reviewed the revised labels and labeling submitted by the Applicant on February 28, 2014
`
`and compared the revised labels and labeling against the recommendations contained in OSE
`
`Review #2013—2126 dated November 6, 2013. We identified the following areas of vulnerability
`
`to error in the container label and carton labeling:
`
`o The ”hydrochloride" part of the established name is in a different font size and does not
`
`appear to be part of the drug name.
`
`0 The barcode appears to be a
`
`(ram) instead of a linear
`
`barcode. This is not in accordance with 21 CFR 201.25(c) and 2004 FDA Barcode Rule.
`
`Reference ID: 3486259
`Reference ID: 4266336
`
`

`

`CONCLUSION & RECOMMENDATIONS
`4
`DMEPA concludes that the proposed container label, carton and insert labeling can be
`improved to increase the readability and prominence of important information on the label to
`promote the safe use of the product to mitigate any confusion. DMEPA provides the following
`comments for consideration by the review Division prior to the approval of this NDA.
`
`4.1
`
`COMMENTS TO THE APPLICANT
`A. All container labels and carton labeling
`
`a. The “Hydrochloride” part of the established name is in a different font size and
`does not appear to be part of the drug name. Revise the drug name so that the
`entire drug name, “Bendamustine hydrochloride” is presented in the same font
`size and boldness.
`
`B. Container label
`
`
`a. The barcode on the vial label appears to be a
` instead of a linear barcode. Revise this barcode to a linear barcode that
`contains, at a minimum, the appropriate National Drug Code (NDC) number in
`accordance with 21 CFR 201.25(c).
`
`C. Ferrule Label
`
`a. Ensure the cautionary statement “Dilute Before Using” also appears on the
`ferrule in addition to the cap overseal in accordance with United States
`Pharmacopeia (USP) General Chapter <1> Injections labeling standard. We
`recommend this to minimize the risk of a medication error where the drug is
`administered undiluted, because this is a multi-dose vial and the cap overseal is
`often discarded during the pharmacy dispensing process.
`
`Reference ID: 3486259
`Reference ID: 4266336
`
`3
`
`(b) (4)
`
`

`

`APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED
`
`APPENDIX A. PRODUCI' lNFORMATION/PRESCRIBING INFORMATION
`
`Table 2 presents relevant product information for bendamustine hydrochloride that Eagel
`
`Pharmaceuticals, Inc. submitted on September 6, 2013.
`
`505(b)(2)
`
`RLD
`
`Bendamustine HCI Injection (100
`
`Treanda’ (bendamustine
`
`mg/4 mL (25 mg/mL)
`
`hydrochloride) for Injection
`
`Active
`
`Ingredient
`
`Bendamustine Hydrochloride
`
`Indication of
`
`o Indolent B-cell non—Hodgkin
`
`0 Chronic lymphocytic
`
`Use
`
`lymphoma (NHL) that has
`
`leukemia (CLL). Efficacy
`
`progressed during or within
`six months of treatment with
`
`relative to first line therapies
`other than chlorambucil has
`
`rituximab or a rituximab-
`
`not been established.1
`
`containing regimen.
`
`Indolent B-cell non-Hodgkin
`lymphoma (NHL) that has
`
`progressed during or within
`six months of treatment with
`
`rituximab or a rituximab-
`
`containing regimen.
`
`
`
`Route of
`_
`.
`_
`Administration
`
`_
`_
`_
`_
`Continuous Intravenous Infu5Ion
`
`Dosage Form
`
`Concentrated solution for dilution
`
`Injection, powder for
`
`(ready-to-dilute solution)
`m cums/4mm mg...
`Dose and
`NHL: 120 mg/m2 infused
`
`reconstitution
`
`CLL: 100 mg/m2 infused
`
`Frequency
`
`intravenously over 60 minutes on
`
`intravenously over 30 minutes on
`
`Days 1 and 2 of a 21-day cycle, up Days 1 and 2 of a 28—day cycle, up
`
`to 8 cycles.
`
`to 6 cycles.
`
`NHL: 120 mg/m2 infused
`
`1 The CLL indication is not included in the Applicant’s proposed prescribing information because it is covered by an
`Orphan Drug Exclusivity (ODE) that expires on September 20, 2015 (with PED extension). Therefore, this indication
`must be excluded from the proposed labeling until the expiration of the associated ODE and its associated PED
`extension.
`
`Reference ID: 3486259
`Reference ID: 4266336
`
`

`

`
`
`505(b)(2)
`
`RLD
`
`Bendamustine HCI Injection (100
`
`Treanda“ (bendamustine
`
`mg/4 mL (25 mg/ml.)
`
`hydrochloride) for Injection
`
`intravenously over 60 minutes on
`
`Days 1 and 2 of a 21-day cycle, up
`
`How Supplied
`
`o 100 mg/4 mL (25 mg/mL) in 5
`mL
`M“) vial
`
`to 8 cycles.
`
`o 25 mg in 8 mL single—use vial
`o 100 mg in 20 mL single-use
`vial
`
`Storage
`
`Store at 2° to 8°C (36° to 46°F).
`
`Stored up to 25°C (77°F) with
`
`Retain in original package until
`
`excursions permitted up to 30°C
`
`time of use to protect from light.
`
`(86°F)
`
`Partially used vials are stable for
`
`Protect from light.
`
`up to 28 days when stored in its
`
`Discard unused portion.
`
`original carton at 2—8°C (BS-46°F).
`
`Container and
`
`Closure System
`
`mm) vial in an individual
`
`Amber single-use vial in an
`
`carton
`
`individual carton
`
`Instructions for
`
`Not applicable
`
`Instructions for reconstitution:
`
`
`
`reconstitution
`
`25 mglvial: Add 5 mL Sterile
`
`Water for Injection
`
`100 ngvial: Add 20 mL Sterile
`
`Water for Injection
`
`Concentration after
`
`reconstitution: 5 mg/mL
`
`Instructions for
`
`Aseptically withdraw the volume
`
`Aseptically withdraw the volume
`
`dilution
`
`needed (see Table 1) for the
`
`needed for the required close
`
`required close (based on 25
`
`(based on 5 mg/mL
`
`mg/mL concentration)
`
`concentration)
`
`and immediately transfer to a 500 mL infusion bag of 0.9% NaCl or
`
`2.5% Dextrose/0.45% NaCL
`
`Reference ID: 3486259
`Reference ID: 4266336
`
`

`

`APPENDIX C. PREVIOUS DMEPA REVIEWS
`C.1 Methods
`We searched the L:Drive on April 7, 2014 using the terms, bendamustine to identify reviews
`previously performed by DMEPA.
`
`Results
`C.2
`DMEPA had previously reviewed bendamustine Labels and Labeling under the following OSE
`Reviews:
` OSE Review #2013-1791 dated December 24, 2013
`We looked at all reviews to ensure all our recommendations were implemented.
`
`Reference ID: 3486259
`Reference ID: 4266336
`
`6
`
`

`

`APPENDIX G. CONTAINER LABEL, CARTON LABELING, INSTRUCTIONS FOR USE, MEDICATION
`GUIDE
`List of Label and Labeling Reviewed
`G.1
`We reviewed the following bendamustine labels and labeling submitted by Eagle
`Pharmaceuticals, Inc. on March 31, 2014.
`
` Container label
` Carton labeling
`
`G.2
`
`Label and Labeling Images
`
`Container Labels
`
`Reference ID: 3486259
`Reference ID: 4266336
`
`7
`
`(b) (4)
`
`2 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`TINGTING N GAO
`04/09/2014
`
`YELENA L MASLOV
`04/10/2014
`
`Reference ID: 3486259
`Reference ID: 4266336
`
`

`

`FOOD AND DRUG ADMINISTRATION
`
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`
`****Pre-decisi0nal Agency Information****
`
`Memorandum
`
`Date:
`
`March 17, 2014
`
`To:
`
`From:
`
`Laura Wall — Regulatory Project Manager
`Division of Hematology Products (DHP)
`
`Richard Lyght, Pharm.D. — Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`CC:
`
`Karen Rulli, Ph.D, Team Leader,OPDP
`
`Subject:
`
`OPDP comments on draft Prescribing Information (PI) for bendamustine hydrochloride
`injection for intravenous infusion
`
`This consult is in response to DHP’s October 10, 2013 request for OPDP review of the draft
`bendamustine hydrochloride Prescribing Information. OPDP comments are based on the proposed
`draft marked-up labeling revised by the review division and received by OPDP on March 12, 2014
`
`If you have any questions, please contact
`OPDP appreciates the opportunity to provide comments.
`Richard Lyght at 301-796-2874 or at richard.Iyght@fda.hhs.gov.
`
`Statement from draft
`
`Highlights—-Warnings &
`Precautions
`
`In the Highlights, consider
`changing “Anaphylaxis and
`Infusion Reactions” to
`
`“Infusion Reactions and
`
`Anaphylaxis” to be consistent
`with 5.3 of the FPI
`
`
`
`12.1 Mechanism of
`
`The bifunctional covalent
`
`The term “via several
`
`Action
`
`linkage can lead to cell death
`via several pathways
`
`pathways” is vague and
`overly promotional. This
`phrase could be used
`to overstate the efficacy of
`bendamustine associated with
`
`its MOA compared to
`
`Reference ID: 3472462
`Reference ID: 4266336
`
`

`

`
`
`other drugs. Please consider
`revising this statement to
`either delete “via several
`
`
`
`pathways” or to include the
`actual pathways.
`
`(b) (4) '
`
`
`16.1 Safe Handling and
`The phrase
`Disposal
`
`
`
`
`
`handling and preparation of
`promotionally to minimize the
`
`
`risks associated with
`solutions prepared from
`
`
`bendamustine. Please
`
`bendamustine hydrochloride
`
`
`
`consider deleting this
`Injection
`
`
`statement
`
`
`,
`care should be exercised in the
`
`could be used
`
`Reference ID: 3472462
`Reference ID: 4266336
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD A LYGHT
`03/19/2014
`
`Reference ID: 3472462
`Reference ID: 4266336
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`
`Label, Labeling and Packaging Review
`
`Date:
`
`
`
`December 24, 2013
`
`
`
`
`
`
`
`
`
`
`
`Tingting Gao, PharmD
`Division of Medication Error Prevention and Analysis
`Yelena Maslov, PharmD
`Division of Medication Error Prevention and Analysis
`Bendamustine Hydrochloride for Injection,
`100 mg/4 mL (25 mg/mL)
`NDA 205580
`Eagle Pharmaceuticals, Inc.
`2013-1791
`
`Reviewer:
`
`Team Leader:
`
`Drug Name and Strength:
`
`Application Type/Number:
`Applicant:
`OSE RCM #:
`
`*** This document contains proprietary and confidential information that should not be
`released to the public.***
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3427474
`Reference ID: 4266336
`
`

`

`Contents
`
`1 
`
`Introduction ................................................................................................................. 1 
`1.1  Regulatory History ............................................................................................... 1 
`1.2 
`Product Information ............................................................................................. 1 
`2  Methods and Materials Reviewed ............................................................................... 3 
`2.1 
`Selection of Medication Error Cases .................................................................... 3 
`2.2 
`Labels and Labeling ............................................................................................. 3 
`2.3 
`Previously Completed Reviews ........................................................................... 3 
`Integrated Summary of Medication Error Risk Assesment ......................................... 4 
`3 
`4  Conclusions ................................................................................................................. 4 
`5  Recommendations ....................................................................................................... 4 
`5.1  Comments to the Division .................................................................................... 4 
`5.2  Comments to the Applicant .................................................................................. 5 
`Appendices .......................................................................................................................... 7 
`Appendix A. Database Descriptions ............................................................................... 7 
`Appendix B: Bendamustine HCl Injection Container Label ........................................... 8 
`Appendix C: Bendamustine HCl Injection Carton Label ................................................ 9 
`Appendix D: Bendamustine HCl Injection Ferrule Label ............................................... 9 
`
`
`
`
`Reference ID: 3427474
`Reference ID: 4266336
`
`

`

`1
`
`INTRODUCTION
`
`This review evaluates the proposed container label, carton and insert labeling for
`Bendamustine Hydrochloride Injection, NDA 205580, for areas of vulnerability that could
`lead to medication errors.
`
`1.1
`
`REGULATORY HISTORY
`
`This NDA is a 505(b)(2) application. The Reference Listed Drug (RLD), Treanda
`(bendamustine hydrochloride) for Injection, was approved on March 20, 2008 under
`NDA 022249, and is marketed as 25 mg per vial and 100 mg per vial. No other
`bendamustine products are available on the market.
`
`The Applicant proposes introducing a new dosage formation for Bendamustine
`Hydrochloride Injection, 100 mg/4 mL (25 mg/mL) in a
`M“) vial.
`
`1.2
`
`PRODUCT INFORMATION
`
`The Applicant provided the following product information in the draft insert labeling for
`the proposed Bendamustine Hydrochloride Injection, submitted on September 6, 2013.
`
`505(b)(2)
`
`RLD
`
`Bendamustine HCl In