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

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`
`Applicant:
`Review Division:
`
`Reviewer:
`Secondary Reviewer:
`Division Director:
`
`Project Manager:
`
`NDA 205580
`1 (original) and 8 (resubmission after refuse to
`file)
`September 6, 2013
`September 6, 2013
`Bendamustine HCl
`Chronic Lymphocytic Leukemia (CLL)
`Non-Hodgkin’s lymphoma (NHL)
`Eagle Pharmaceuticals, Inc. (EPI)
`Division of Hematology Oncology Toxicology
`(DHOT) for Division of Hematology Products
`(DHP)
`Christopher M. Sheth, Ph.D. (DHOT)
`Todd Palmby, Ph.D. (DHOT)
`John Leighton, Ph.D., DABT (DHOT)
`Ann Farrell, M.D. (DHP)
`Modupe Fagbami
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 205580 are owned by Eagle Pharmaceuticals, Inc. or
`are data for which Eagle Pharmaceuticals, Inc. has obtained a written right of reference.
`Any information or data necessary for approval of NDA 205580 that Eagle
`Pharmaceuticals, Inc. does not own or have a written right to reference constitutes one
`of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`1
`
`

`

`of a previously approved application is for descriptive purposes only and is not relied
`upon for approval of NDA 205580.
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`2
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`TABLE OF CONTENTS
`
`1
`
`EXECUTIVE SUMMARY ......................................................................................... 5
`1.1
`INTRODUCTION.................................................................................................... 5
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 5
`1.3
`RECOMMENDATIONS............................................................................................ 6
`2 DRUG INFORMATION ............................................................................................ 6
`2.1
`DRUG................................................................................................................. 6
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 6
`2.3
`DRUG FORMULATION ........................................................................................... 7
`2.4
`COMMENTS ON NOVEL EXCIPIENTS....................................................................... 9
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 10
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 10
`2.7
`REGULATORY BACKGROUND .............................................................................. 10
`STUDIES SUBMITTED.......................................................................................... 11
`3.1
`STUDIES REVIEWED........................................................................................... 11
`3.2
`STUDIES NOT REVIEWED ................................................................................... 11
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 11
`PHARMACOLOGY................................................................................................ 11
`
`3
`
`4
`
`5
`
`PHARMACOKINETICS/ADME.............................................................................. 11
`
`6 GENERAL TOXICOLOGY..................................................................................... 11
`
`7 GENETIC TOXICOLOGY ...................................................................................... 11
`
`8 CARCINOGENICITY ............................................................................................. 12
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 12
`
`10
`
`11
`
`12
`
`SPECIAL TOXICOLOGY STUDIES................................................................... 12
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 16
`
`APPENDIX/ATTACHMENTS............................................................................. 16
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`3
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`Table of Tables
`
`Table 1 Comparison of Treanda 100 mg Vial and EPI’s Bendamustine HCl................... 7
`Table 2 Comparison of Preparation and Final Solution for Infusion ................................ 7
`Table 3 Proposed Specifications for EPI’s Drug Product ................................................ 8
`Table 4 Administered Concentration and Maximum Daily Dose of Excipients in Eagle’s
`Bendamustine HCl Product............................................................................................. 9
`Table 5 Test and Comparator Article Preparations in Diluent, and Placebos, Combined
`with Human Whole Blood and Plasma .......................................................................... 13
`Table 6 Dermal, Macroscopic, and Microscopic Findings in Local Tolerance Study of
`Test and Comparator Article Preparations .................................................................... 16
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`4
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`1
`
`Executive Summary
`
`Introduction
`1.1
`Treanda® (bendamustine HCl) is an alkylating drug that was approved in 2008 (NDA
`022249) for the treatment of CLL and Indolent NHL that has progressed during or within
`6 months of treatment with rituximab or a rituximab-containing regimen. Bendamustine
`HCl is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole
`ring. Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups
`form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand
`DNA crosslinks. The bifunctional covalent linkage produced can lead to cell death via
`several pathways (including DNA, RNA and protein synthesis inhibition, leading to
`subsequent apoptosis).
`
`The Applicant, EPI, has submitted this 505(b)(2) NDA for a bendamustine HCl product
`that is intended to be used via the same (IV) route, at the same dose levels and for the
`same indications as the listed drug (LD), Treanda. EPI’s to-be-marketed formulation
`that is the subject of this NDA is different from the Treanda® formulation, in that it will
`be supplied as a ready-to-dilute concentrated sterile solution containing bendamustine
`HCl (100 mg), monothioglycerol (20 mg), propylene glycol (0.4 mL), and polyethylene
`glycol 400 (QS to 4 mL), rather than a lyophilized powder of bendamustine HCl (100
`mg) and mannitol (170 mg). Prior to IV administration, both reconstituted Treanda (5
`mg/mL in sterile water) and EPI’s ready-to-dilute (25 mg/mL) formulation of
`bendamustine HCl require further dilution into 500 mL of 0.9% Sodium Chloride
`Injection or, alternatively, 500 mL of 2.5% Dextrose / 0.45% Sodium Chloride Injection.
`The final concentrations of both Treanda- and EPI-bendamustine HCl will be 0.2-
`mg/mL.
`
`EPI has included in this NDA a request for waiver for pharmacokinetic bioequivalency
`studies (Supporting Document #1, eCTD Module 1, Section 1.12.15) for bendamustine
`HCl. Inclusion of the biowaiver request was based on End-of-Phase 2 meeting
`discussions (December 12, 2012), in which the Agency indicated that such a waiver
`may be granted provided EPI submit a side-by-side comparison of the physiochemical
`properties of the LD and EPI’s product, including comparative characterizations of the
`product in the vial and the final solution to be administered to patients after dilution. EPI
`submitted GLP-compliant nonclinical “special toxicology” studies (i.e., single dose local
`tolerance in rabbits and hemolytic potential in human whole blood) of their product
`compared with Treanda. No additional toxicology, pharmacology or PK/PD study
`results were submitted by EPI for this NDA.
`1.2 Brief Discussion of Nonclinical Findings
`EPI relies upon the FDA’s previous findings of safety and effectiveness for Treanda®,
`as described in the drug’s approved labeling. The Applicant has not performed any
`animal pharmacology studies in support of the NDA approval for bendamustine HCl.
`EPI conducted GLP-compliant local tolerance studies in rabbits, in addition to in vitro
`hemolytic potential studies in human whole blood, comparing their bendamustine HCl
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`5
`
`(b) (4)
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`product with the LD (Treanda®). There was no indication of hemolysis in human blood
`exposed to EPI’s bendamustine HCl. Intravenous administration of EPI’s bendamustine
`HCl was well tolerated in the rabbit local tolerance study, as exemplified by results
`typical of minor trauma associated with injection procedures. Pharmacology/Toxicology
`has no concerns with the nonclinical findings and the excipients used for EPI’s
`bendamustine HCl at the defined levels.
`1.3 Recommendations
`
`1.3.1 Approvability
`From the Pharmacology/Toxicology perspective, bendamustine HCl may be approved
`for the proposed indications.
`1.3.2 Additional Non Clinical Recommendations
`None
`Labeling
`1.3.3
`The nonclinical sections of the label will be comparable to the label of the LD.
`2
`Drug Information
`
`2.1 Drug
`CAS Registry Number:
`Generic Name:
`Code Name:
`Chemical Name:
`Molecular Formula:
`Molecular Weight:
`
`Structure or Biochemical Description:
`
`3543-75-7
`Bendamustine HCl
`Not Applicable
`1H-Benzimidazole-2-butanoic acid, 5-[bis(2-
`chloroethyl)amino]-methyl-,hydrochloride (1:1)
`C16H21Cl2N3O2 · HCl · H2O
`412.72
`
`Alkylating drug
`Pharmacologic Class:
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`NDA 022249 (Treanda); IND 109789 (bendamustine HCl injection concentrate); DMF
` (bendamustine HCl)
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`6
`
`(b) (4)
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`2.3 Drug Formulation
`
`Table 1 Comparison of Treanda 100 mg Vial and EPl’s Bendamustine HCI
`
`(Excerpted from Applicant’s Submission)
`Bendamustine HCI Injection, 25 mg/mL
`‘ Treanda (bendamustine HCI) for Injection
`Product
`
`(100 mg/4 mL)
`(100 mg vial)
`Sterile Solution
`Dosage Form
`Lyophilized powder
`
`
`Ingredients
`Amount per vial
`Ingredient
`Amountper vial
`
`
`
`Composition
`
`‘ Bendamustine HCI
`‘
`Mannitol, USP
`
`‘
`‘
`
`100 mg
`170 mg
`
`100 mg
`‘
`Bendamustine HCI
`20 mg
`‘
`l\«lon0thioglycerol, NF
`0.4 mL
`‘
`Propylene Glycol, USP
`
`Polyethylene Glycol 400 QS to 4 m1.
`(PEG 400), NF“
`(5N4)
`
`Table 2 Comparison of Preparation and Final Solution for Infusion
`
`(Excerpted from Applicant’s Submission)
`Bendamustine HCI Injection, 25
`mg/mL
`
`(100 m - /4 mL
`
`
`
`
`(b) «F
`
`Treanda (bendamustine HCI) for
`Product
`Injection (100 mg vial)
`Reconstituted with sterile water for
`No reconstitution is needed (A ready to
`Re constitution
`
`injection to yield a solution of 5 mg,i”mL
`dilute solution of 25 mgme)
`
`
`
`Withdraw re quire dose and dilute into Withdraw require dose and dilute into
`
`
`500 mL bag of 0.9% Sodium Chloride
`500 mL bag of 0.9% Sodium Chloride
`Injection, USP or 0.45% Sodium
`Injection, USP or 0.45% Sodium
`
`Chloride/2.5% Dextrose Injection, USP4 Chloridef2.59="o Dextrose Injection, USP.
`
`Admixture
`
`Concentration
`
`
`
` 0.2 mg/mL
`
`Covering Dose
`Ra n . e
`
`
`
`Further Dilution prior to
`Infusion
`
`Final
`Solution
`for
`Infusion"
`
`
`O smola rity
`
`(mOSm/kg)
`
`
`
`
`0.6 mg/mL
`
`0.2 mg/mL
`
`mg/mL
`
`(b) (4)
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`Table 3 Proposed Specifications for EPI’s Drug Product
`
`(Excerpted from Applicant’s Submission)
`
`Description
`
`Release: Clear colorless to slight yellow
`solution, essentially free from visible
`articulates
`
`Based on the qap ea'a'ice ofnewly
`f ctur d
`d ct
`menu a
`e pro u '
`
`essentiall- free from visible . articulates
`
`batches over time
`
`Identi ficaion: HPLC
`
`Identi ficaion:
`HPLC/UV
`
`Bendamustine HCl
`Assay (By HPLC)
`Related Substances:
`
`By HPLC: The retention time ofthe major
`peak in the sample solution corresponds to
`that in the standard solution as obtained in the
`Assay.
`
`By HPLC: In the HPLC assay, the UV
`spectrum of the analyte peak in the sample
`solution exhibits the same maxima as those in
`
`the UV spectrum of the standard.
`
`Based on the retention time of the reference
`standard.
`
`Based on the UV spectrum of the reference
`standard.
`
`Shelf—/3
`
`Based on typicd USP drug product assay
`limits.
`
`further details.
`
`.
`e
`r
`case see Section
`3.2.P.5.6.2 fior further details
`
`Total i u urities:
`
`NM’I‘ 2.0%
`
`.
`2 10 “mi NMT-paticles
`a 25 pm: NMT-Iarticles
`
`Based on the Particulate Matter in [medians
`USP <788> requirements for smdl volume
`pa'enteral products tested by the microscopic
`particle count test, Method II.
`
`Volume in Container
`
`Release only: NL'i'nL
`
`fifzgnfifigegmiysp <1> requtrements
`
`Sterility
`
`Bacterial Endotoxin
`
`NMT-EU/mg
`
`Based on Sterility Test USP <71 >
`
`Based on Bacterial Endaton‘ns Test USP
`
`<85>. Please see Section 3.2.P.5.6.4 for
`
`Reference ID: 342591 8
`Reference ID: 4266336
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`2.4 Comments on Novel Excipients
`
`“m solution of bendamustine HCI as an alternative
`EPI developed their
`formulation to the lyophilized listed drug; by substituting polyethylene glycol 400
`mu), propylene glycol
`mm, and monothioglycerol W"
`for mannitol. The components, their respective strengths in the vial,
`concentrations as IV administered, and maximum daily doses are presented below
`(Table 4).
`
`Table 4 Administered Concentration and Maximum Daily Dose of Excipients in
`Eagle’s Bendamustine HCI Product
`
`(Excerpted from Applicant’s Submission)
`
`Concentratio-
`
`ns Administered Dilly Dose
`
`7
`
`Polyethylene glycol 400. NF
`
`
`Strength
` 25 mg/mL
`
`120 mg/m2
`
`Maximum [)3in
`Dose for 2.0 m1 BSA
`('1) (4)
`
`1!:
`
`0)“)
`
`
`Propylene glycol. USP
`
`Monolhioglycerol.NF
`
`l
`
`5mgjml.
`
`According to the Agency’s database of inactive ingredients (IIG), there are several FDA
`approved IV products containing one or more of the excipients used in EPl’s product.
`The maximum daily doses of the excipients (and concentrations as administered) are
`higher in the previously approved drugs when compared to the maximum daily doses
`associated with EPl’s bendamustine HCI. Some examples are provided below:
`
`Busulfex® contains polyethylene glycol 400 at 67% (v/v):
`Dose = 0.8 mg/kg Busulfex x 70 kg (adult body weight) = 56 mg
`Vials are 6 mg/mL
`56 mg + 6 mg/mL = 9.3 mL (every six hours for 4 days)
`9.3 mL x 4 (# of doses in 24 hours) = 37.3 mL Busulfex/day
`37.3 mL x 67% polyethylene glycol 400 = 25 mL polyethylene glycol 400lday
`
`Ativan® for infection contains propylene glycol at =82%:
`Dose (maximum for status epilepticus in adults) = 4 mg + 4 mg (10 to 15 minutes later)
`Each mL contains 2 mg or 4 mg Ativan
`8 mg (max dose) + 2 mg/mL = 4 mL
`4 mL x 82% propylene glycol = 3.2 mL propylene glycol
`
`Methyldopate HCI Iniection contains monothioglycerol at 2 ngmL:
`Dose (maximum in adults) = 1000 mg every 6 hours = 4000 mg/day
`Each mL contains 50 mg methyldopate HCI
`4000 mg (max dose) + 50 mg/mL = 80 mL
`80 mL x 2 mg monothioglycerol/mL = 160 mg monothioglycerol/day
`
`Reference ID: 342591 8
`Reference ID: 4266336
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`2.5 Comments on Impurities/Degradants of Concern
`
`The specifications for impurities in the drug substance are acceptable from a
`Pharmacology/Toxicology perspective as they comply with the qualification threshold in
`ICH Q3A. The impurities in this product do not need to be controlled to lower levels due
`to any genotoxic potential based on the genotoxic activity of the active pharmaceutical
`ingredient (API) and the indication.
`
`The impurities identified in EPl’s bendamustine HCI drug product include
`
`“m
`
`(Table 3). The specifications for
`“N" are qualified as per ICH
`"’"". The
`Q3B(R2)
`%) is also acceptable as it
`specification for any single unidentified impurity (NMT
`complies with the Q3B qualification threshold based on the maximum daily dose of
`EPl’s bendamustine HCI injection being "’m’ mg/day. The Applicant provided a
`justification for the proposed specifications for
`W"
`m”. This justification was based on a side-by—side
`comparison of the stability of reconstituted solutions of EPl’s bendamustine HCI and the
`listed drug (LD) at pre-defined temperatures using 0.9% Sodium Chloride Injection and
`0.45% Sodium Chloride/2.5 % Dextrose Injection. This stability comparison showed that
`higher levels of
`W" and
`M“) were detected in the LD
`reconstituted solutions, as compared to the respective reconstituted solutions of EPl’s
`product (admixture study report
`"’“"-P1268—13—R001-0).
`
`and
`
`The amounts of the classified (class 2 and 3) residual solvents in the drug substance
`and the excipients comprising EPl’s product are acceptable based on ICH Q3C limits for
`solvents under option 1; for doses that do not exceed 10 g/day.
`“m is an
`unclassified residual solvent detectable in the
`“m" however the
`
`levels are acceptable based on the Applicant’s calculation that the daily exposure from
`their product (
`"M" mg/day) will be lower than the permitted daily exposure ( “m"
`mg/day).
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`EPI proposed dosing recommendations consistent with current Treanda® labeling for
`the treatment of CLL and NHL. The recommended dose for treatment of CLL is 100
`mg/m2 infused intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle (up to
`8 cycles). The recommended dose for treatment of NHL is 120 mg/m2 infused
`intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle (up to 8 cycles).
`
`2.7 Regulatory Background
`
`The Applicant submitted NDA 205580 on July 1, 2013, and resubmitted on September
`6, 2013 after addressing items cited in a refuse to file letter dated August 28, 2013. The
`listed drug is Treanda (NDA 022249). A pre-IND meeting was held with EPI on
`November 9, 2010 to obtain agreement with the Agency on the proposed type of NDA
`(b) (4)
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`10
`
`

`

`eCTD Module
`4.2.3.7
`
`4.2.3.6
`
`4.2.3.6
`
`Previous Reviews Referenced
`
`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`filing and development program. An End-of-Phase 2 meeting was held with EPI on
`December 12, 2012, to discuss their plans to submit a 505(b)(2) NDA for bendamustine
`HCl.
`3
`
`Studies Submitted
`
`eCTD Module
`4.2.3.7
`
`4.2.3.6
`
`Studies Reviewed
`3.1
`Study Title
`Hemolytic Properties of Test and Reference Formulations of
`Bendamustine Hydrochloride in Human Whole Blood (# 8280095)
`Single Dose Intravenous and Perivascular Tolerance Study of
`Bendamustine Containing Formulations in Male Rabbits (# 13-2342)
`3.2
`Studies Not Reviewed
`Study Title
`Hemolytic Properties of Test and Reference Formulations of
`Bendamustine Hydrochloride in Human Whole Blood (# 8264313)
`Single Dose Intravenous and Perivascular Tolerance of
`Bendamustine-Containing Formulations in Male Rabbits (# 12-2298)
`Single Dose Perivascular Tolerance of Bendamustine-Containing
`Formulations in Male Rabbits with a 21-Day Recovery Period (# 12-
`2311)
`3.3
`None
`Pharmacology
`4
`No new pharmacology studies were submitted.
`5
`Pharmacokinetics/ADME
`No PK or ADME study reports were submitted. EPI submitted a request for waiver for
`pharmacokinetic bioequivalency studies (Module 1.12.15) of bendamustine HCl based
`on discussions with the Agency at the December 12, 2013 End-of-Phase 2 meeting.
`EPI submitted a side-by-side comparison of their product and the listed drug (Treanda
`for Injection), including comparative characterizations of the products in the vial and the
`final reconstituted solutions (Tables 1 and 2, and admixture study repor
`-P1268-
`13-R001-0).
`6
`General Toxicology
`Not submitted
`7
`Genetic Toxicology
`Not submitted
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`11
`
`(b) (4)
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`Carcinogenicity
`8
`Not submitted
`9
`Reproductive and Developmental Toxicology
`Not submitted
`10 Special Toxicology Studies
`The Applicant submitted data from nonclinical studies designed to comply with Agency
`Draft Guidance for Industry and Review Staff: Nonclinical Safety Evaluation of
`Reformulated Drug Products and Products Intended for Administration by an Alternate
`Route (March 2008). As EPI’s bendamustine HCl is a reformulation of an approved
`drug substance and is to be administered in an identical manner (IV) to the listed drug,
`EPI submitted reports for studies of local toxic effects in addition to studies evaluating
`the compatibility of their product with blood.
`Hemolysis study:
`The hemolytic potential of EPI’s bendamustine HCl was tested in human whole blood in
`comparison with the listed drug, Treanda. Human whole blood (1mL) was incubated at
`37°C for 30 minutes with 10 different solutions, including: EPI’s bendamustine HCl
`injection placebo [5 mg/mL monothioglycerol and
` propylene glycol in
`polyethylene glycol 400] diluted with saline (1:34 v/v) and (4.32:15 v/v); EPI’s
`bendamustine HCl at 0.47, 1.1, 2.0, or 2.8 mg/mL; listed drug (Treanda) placebo
`
`mg/mL mannitol in sterile water); listed drug (Treanda) at 0.41 mg/mL; negative control
`(human plasma); and positive control (1% Saponin). Human plasma (1 mL) was also
`incubated at 37°C for 30 minutes with EPI’s bendamustine HCl injection placebo [5
`mg/mL monothioglycerol and
` propylene glycol in polyethylene glycol 400]
`diluted with saline (4.32:15 v/v) and EPI’s bendamustine HCl at 2.8 mg/mL. Following
`incubation and centrifugation, plasma was harvested and hemolysis was evaluated by
`spectrophotometric analysis for hemoglobin in the supernatant. The results from the
`evaluation are presented below (Table 5). No hemolysis was observed in any of the
`samples tested, except for the positive control.
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`12
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`Table 5 Test and Comparator Article Preparations in Diluent, and Placebos, Combined with Human Whole Blood
`and Plasma
`
`Calculated
`Bendamustine
`HCl
`Concentration
`in Total
`Sample
`Volume
`(mg/mL)
`
`Volume
`of
`Plasma,
`Diluted
`Solution,
`Total
`or
`Sample
`Ratio of
`Calculated
`Saponin
`Dilution
`Volume
`Plasma,
`Bendamustine
`added to
`of Article
`[solution
`Diluted
`HCl
`1 mL
`or
`+ whole
`Solution, or
`Concentration
`Whole
`Placebo
`blood
`Saponin:Whole
`after Dilution
`Blood
`to Saline
`Tube
`(mL)]
`Blood
`(mg/mL)
`(mL)
`(volume)
`Numbers
`Solution 1: EPI bendamustine HCl Placebo (diluted with saline), pH = 3.23
`NA
`3
`1-4
`1:34
`NA
`2
`20:10
`Solution 2: EPI bendamustine HCl (25 mg/mL, diluted to 0.7 mg/mL with saline), pH = 3.20
`5-8
`1:34
`0.7
`2
`20:10
`3
`0.47
`Solution 3: Treanda Placebo (dilutes with saline), pH = 3.27
`9-12
`14.0:100
`NA
`2
`20:10
`Solution 4: Treanda (5 mg/mL, diluted to 0.6 mg/mL with saline), pH = 3.21
`13-16
`14.0:100
`0.61
`2
`20:10
`Solution 5: EPI bendamustine HCl Placebo (diluted with saline), pH = 3.18
`17-20
`4.32:15
`NA
`1
`10:10
`
`Hemoglobin
`Indexa
`(mg/dL)
`
`Test
`Result
`
`Supernatant
`Colorb
`
`1 to 4
`
`Negative
`
`3 to 5
`
`Negative
`
`3 to 4
`
`Negative
`
`2 to 9
`
`Negative
`
`0 to 9
`
`0 to 1
`
`Negative
`
`Negative
`
`2 to 7
`
`Negative
`
`3 to 5
`
`Negative
`
`6 to 26
`
`Negative
`
`Clear
`
`Clear
`
`Clear
`
`Clear
`
`Clear
`Yellow,
`Slightly
`Cloudy
`
`Clear
`
`Clear
`
`Clear
`
`3
`
`3
`
`2
`
`NA
`
`0.41
`
`NA
`
`21-24
`
`4.32:15
`
`NA
`
`1c
`
`10:10
`
`2
`
`NA
`
`Solution 6: EPI bendamustine HCl (25 mg/mL, diluted to 2.2 mg/mL with saline), pH = 2.94
`25-28
`1.44:15
`2.2
`1
`10:10
`2
`1.1
`Solution 7: EPI bendamustine HCl (25 mg/mL, diluted to 4.0 mg/mL with saline), pH = 3.05
`29-32
`2.88:15
`4.0
`1
`10:10
`2
`2.0
`Solution 8: EPI bendamustine HCl (25 mg/mL, diluted to 5.6 mg/mL with saline), pH = 3.09
`33-36
`4.32:15
`5.6
`1
`10:10
`2
`2.8
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`13
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`Volume
`of
`Plasma,
`Diluted
`Solution,
`or
`Saponin
`added to
`1 mL
`Whole
`Blood
`(mL)
`
`Dilution
`of Article
`or
`Placebo
`to Saline
`(volume)
`
`Calculated
`Bendamustine
`HCl
`Concentration
`after Dilution
`(mg/mL)
`
`Tube
`Numbers
`
`Ratio of
`Plasma,
`Diluted
`Solution, or
`Saponin:Whole
`Blood
`
`Total
`Sample
`Volume
`[solution
`+ whole
`blood
`(mL)]
`
`Calculated
`Bendamustine
`HCl
`Concentration
`in Total
`Sample
`Volume
`(mg/mL)
`
`Hemoglobin
`Indexa
`(mg/dL)
`
`Test
`Result
`
`37-40
`
`4.32:15
`
`5.6
`
`1c
`
`10:10
`
`2
`
`2.8
`
`0 to 1
`
`Negative
`
`Negative Control
`41-44
`NA
`Positive Control
`45-48
`NA
`NA = Not applicable
`Negative = No hemolysis (relative to negative control)
`Positive = Hemolysis (concentration of hemoglobin is greater than or equal to 500 mg/dL more than that of the negative control).
`a = Hemoglobin concentration of the mixture supernatants.
`b = A description of clear indicates no change from the color of plasma alone.
`c = Plasma separated from whole blood sample.
`d = 1% Saponin added to 1 mL whole blood. Saponin is a hemolytic agent used to lyse erythrocytes.
`
`2
`
`2
`
`NA
`
`NA
`
`3 to 4
`
`Negative
`
`5571 to
`5934
`
`Positive
`
`NA
`
`NA
`
`1c
`
`1d
`
`1:1
`
`1:1
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`14
`
`Supernatant
`Colorb
`Yellow,
`Slightly
`Cloudy
`
`Clear
`
`Red
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`Local tolerance study:
`A stand-alone single-dose IV and perivascular (PV) tolerance study of bendamustine
`containing formulations (EPI’s bendamustine HCl compared with the listed drug,
`Treanda) was conducted in male albino New Zealand White rabbits to assess for
`potential local toxic effects. The rabbits were approximately 4.5 to 5.5 months of age
`and weighed 2.8 to 3.2 kg at the initiation of dosing. Three males/group (IV) and 3
`males/group (PV) received a single dose of bendamustine formulation and
`corresponding placebo in the left and right ear, respectively; according to the outline
`below. Animals were held for a 96-hour (post-dose) observation period. Following the
`observation period, all animals were sacrificed and a macroscopic and microscopic
`examination of both ears was performed.
`
`Experimental outline
`
`(Excerpted from Applicant’s Submission)
`
`IV administration (the intended clinical route of EPI’s bendamustine HCl and the listed
`drug) of both bendamustine formulations and their respective placebos (i.e., vehicle
`controls) were well tolerated under the conditions of this study. The results of the
`dermal evaluations, gross pathology, and histopathology were typical of the minor
`trauma associated with injection procedures and do not represent a toxicologically
`significant concern (Table 6).
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`15
`
`

`

`NDA 205580
`
`Reviewer: Christopher M. Sheth, Ph.D.
`
`Table 6 Dermal, Macroscopic, and Microscopic Findings in Local Tolerance Study
`of Test and Comparator Article Preparations
`(Excerpted from Applicant’s Submission)
`
`Integrated Summary and Safety Evaluation
`11
`See Executive Summary
`12 Appendix/Attachments
`None
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`16
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CHRISTOPHER M SHETH
`12/20/2013
`
`TODD R PALMBY
`12/20/2013
`
`Reference ID: 3425918
`Reference ID: 4266336
`
`