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

`

`Clinical Review
`Division of Hematology Products
`
`205580
`38
`bendamustine
`Eagle
`Alexandria Schwarsin, MD
`January 31, 2018
`
`
`
`
`
`
`NDA #:
`SDN:
`Drug(s):
`Applicant:
`Primary Reviewer:
`Received Date:
`
`This is a 505(b)(2) application. Clinical information for review was not included in the
`application. The clinical team participated in labeling meetings and agreed with the final
`Prescribing Information.
`
`
`
`
`
`Reference ID: 4237221
`Reference ID: 4266336
`
`Page 1
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`

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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.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ALEXANDRIA N SCHWARSIN
`03/21/2018
`
`YVETTE L KASAMON
`03/21/2018
`
`Reference ID: 4237221
`Reference ID: 4266336
`
`

`

`File Memorandum
`
`NDA: 205580
`
`Applicant: Eagle Pharmaceuticals, Inc.
`
`Product: Bendamustine injection 100 mg/4 mL
`
`Submission date: June 30, 2013
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`Review Completion Date: Electronic Stamp
`
`Clinical reviewer: Adam George, PharmD.
`
`Clinical team leader: Virginia Kwitkowski, M.S., R.N., A.C.N.P.-B.C.
`
`Regarding: Clinical review of NBA 205580
`
`Application background
`The Applicant has submitted a 505(b)(2) application for a ready to dilute injection formulation of
`Bendamustine hydrochloride. The listed product Treanda® (bendamustine hydrochloride) is a
`lyophilized powder formulation which requires reconstitution. No clinical data investigating the
`use of the Applicant’s proposed ready to dilute formulation were submitted with this application.
`On January 8, 2014 the Applicant submitted a 120 day safety update.
`M“)
`
`These data are not applicable to NBA 205580
`
`(m4)
`
`During review of the application the biopharmaceutics review identified a potential clinical issue
`with the Applicant’s proposed formulation in that the Applicant’s formulation once diluted for
`administration has a higher osmolality than the listed product. The CMC discipline sent the
`Applicant an Information Request to provide justification for the difference in osmolality
`between the proposed diluted drug product and the reference diluted drug product. In their
`response the Applicant provided Table 1.
`
`Reference ID: 3506008
`Reference ID: 4266336
`
`

`

`
`Table l . Comparison of Treanda and Applicant Proposed Admixtures
`Product
`Eu ~ le
`Treanda
`Eu _le
`Treanda
`En \ le
`Treanda
`Admixture Vehicle
`-
`2.5” ‘o Dextrose!
`-
`.
`0.9% I\aC1
`0.450530
`0.9% .\aCl
`
`BDM HCl
`Concentration
`
`(mg/mL)
`Measured
`Osmolality
`(anSIn/lig).
`Volume of
`admixture after
`
`addition of drug
`product 1mm"
`
`0.2
`
`0.2
`
`_
`
`_
`Estimated Molalitv (moles/k2
`
`\"I \‘U
`
`
`
`
`
`Treanda
`Ea _le
`2.5% Dextrose.”
`().45°1¢Na(‘l
`(W)
`
`(”N“)
`
`BDM HCl
`Manuitol
`Mouotllloflycerol
`PG
`PEG 400
`
`" n=2 per set of vehiclelconcemrauon comomauons
`I’Assumes ideal mixing and volumes are additive
`
`"’"4’
`
`The Applicant addressed the potential of formulation changes (including osmolality) to impact
`the safety profile was addressed in preclinical studies. The hemolytic properties of the
`Applicant’s formulation were assessed in vitro with human whole blood. A comparison to the
`listed drug, Treanda, was also investigated. Additionally, a local irritation study in rabbits was
`conducted to assess potential local irritation that could arise from these admixtures. The results
`of these studies indicate that Bendamustine HCl Injection (Eagle) is not hemolytic at
`bendamustine HCl concentrations of 0.7 to 5.6 mg/mL.
`
`Reviewer comment: It is the opinion of this reviewer that the increased osmolality of the Eagle
`formulation of bendamustine will not result in a clinically meaningful increase in toxicities
`associated with administration of a hyperonotic intravenous solution (i.e., phlebitis and/or
`infusion site reactions). In clinical practice chemotherapy is typically administered to patients
`via central venous access (e.g., peripherally inserted central catheter or Hickman catheter).
`Administration of chemotherapeutic agents through central venous access minimizes the risks of
`phlebitis associated with drugs that are hyperosmolar due the increased venous blood flow with
`central venous access. An article by Gazitua et al evaluated the risk ofphlebitis based upon the
`osmolality of the infusate. The lowest identified risk group was solutions with an osmolarity
`lower than 450 mOsm/L. The upper limit for the range of osmolality with the proposed Eagle
`formulation is (mo mOsm/kg.l
`
`The listed drug Treanda is labeled for phlebitis and infusion site reactions which will also be
`communicated in the prescribing information for this (b)(2) formulation. In addition, it would
`not be feasible to conduct a clinical trial to quantify the possible increased risk of phlebitis with
`the Applicant’s hyperosmolar formulation compared to Treanda as this would require an
`extremely large number ofpatients.
`
`1 Gazitua R. et a1. Factors determining peripheral vein tolerance to amino acid infusions. Arch Surg 1979;114:897-
`900.
`
`Reference ID: 3506008
`Reference ID: 4266336
`
`

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`Conclusion: This reviewer recommends approval of this 505(b)(2) application.
`
`Reference ID: 3506008
`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/
`----------------------------------------------------
`
`ADAM N GEORGE
`05/13/2014
`
`VIRGINIA E KWITKOWSKI
`05/13/2014
`
`Reference ID: 3506008
`Reference ID: 4266336
`
`