CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`208194Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
`
`
`
`
`
`

`

`MEMORANDUM
`
`Date:
`From:
`
`November 10, 2015
`Christopher M. Sheth, PhD
`Pharmacology/Toxicology Supervisor
`Division of Hematology Oncology Toxicology (DHOT)
`Office of Hematology and Oncology Products (OHOP)
`Re:
`Approvability for Pharmacology and Toxicology
`NDA:
`208194
`Drug:
`Bendamustine hydrochloride
`Indications: Chronic lymphocytic leukemia and B cell non-Hodgkin lymphoma
`Applicant:
`Eagle Pharmaceuticals, Inc.
`
`I have examined the pharmacology/toxicology supporting review for bendamustine HCl
`conducted by Dr. Manning. I concur with Dr. Manning’s conclusion that bendamustine HCl
`may be approved for the proposed indication.
`
`Reference ID: 3845430
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`11/10/2015
`
`Reference ID: 3845430
`
`

`

`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:
`Supervisor/Team Leader:
`Division Director:
`
`Project Manager:
`
`Disclaimer
`
`NDA 208194
`1
`February 12, 2015
`February 13, 2015
`Bendamustine hydrochloride (HCl)
`Chronic lymphocytic leukemia (CLL)
`B cell non-Hodgkin lymphoma (NHL)
`Eagle Pharmaceuticals, Inc (EPI)
`Division of Hematology Oncology Toxicology
`(DHOT) for Division of Hematology Products
`(DHP)
`Michael L Manning, PhD (DHOT)
`Christopher M Sheth, PhD (DHOT)
`John Leighton, PhD, DABT (DHOT)
`Ann Farrell, MD (DHP)
`Laura Wall, MS, APHN, OCN
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 208194 are owned by EPI or are data for which EPI has
`obtained a written right of reference. Any information or data necessary for approval of
`NDA 208194 that EPI 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
`of a previously approved application is for descriptive purposes only and is not relied
`upon for approval of NDA 208194.
`
`Reference ID: 3827747
`
`1
`
`

`

`NDA 208194
`
` Reviewer: Michael L Manning, PhD
`
`TABLE OF CONTENTS
`
`3
`
`1
`
`EXECUTIVE SUMMARY...........................................................................................4
`1.1
`INTRODUCTION .....................................................................................................4
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS .......................................................4
`1.3
`RECOMMENDATIONS .............................................................................................5
`2 DRUG INFORMATION..............................................................................................5
`2.1
`DRUG ..................................................................................................................5
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS............................................................5
`2.3
`DRUG FORMULATION ............................................................................................6
`2.4
`COMMENTS ON NOVEL EXCIPIENTS........................................................................7
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN..........................................7
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN.......................................8
`2.7
`REGULATORY BACKGROUND .................................................................................8
`STUDIES SUBMITTED.............................................................................................8
`3.1
`STUDIES REVIEWED..............................................................................................8
`3.2
`STUDIES NOT REVIEWED.......................................................................................8
`3.3
`PREVIOUS REVIEWS REFERENCED.........................................................................9
`PHARMACOLOGY ...................................................................................................9
`4
`PHARMACOKINETICS/ADME/TOXICOKINETICS .................................................9
`5
`6 GENERAL TOXICOLOGY........................................................................................9
`7 GENETIC TOXICOLOGY..........................................................................................9
`8 CARCINOGENICITY.................................................................................................9
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY...................................9
`10
`SPECIAL TOXICOLOGY STUDIES......................................................................9
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION..................................12
`12
`APPENDIX/ATTACHMENTS ..............................................................................12
`
`Reference ID: 3827747
`
`2
`
`

`

`NDA 208194
`
` Reviewer: Michael L Manning, PhD
`
`Table of Tables
`
`Table 1: Comparison of Treanda® (lyophilized powder and sterile solution) and EPI’s
`bendamustine HCl formulation .........................................................................................6
`Table 2: Comparison of Treanda® (lyophilized powder and sterile solution) and EPI’s
`bendamustine HCl preparation and final solution properties............................................7
`Table 3: Local tolerance study: summary of experimental design..................................10
`Table 4: Local tolerance study: dermal, macroscopic, and microscopic findings of test
`article and placebo preparations ....................................................................................11
`
`Reference ID: 3827747
`
`3
`
`

`

`NDA 208194
`
`Reviewer: Michael L Manning, PhD
`
`1
`
`Executive Summary
`
`1.1
`
`Introduction
`
`Treanda® (bendamustine HCI) is an alkylating agent approved in 2008 for the treatment
`of two indications: 1) indolent B cell non-Hodgkin lymphoma (NHL) that has progressed
`during or within 6 months of treatment with rituximab or a rituximab-containing regimen,
`and 2) chronic lymphocytic leukemia (CLL). The Applicant, EPI, is seeking marketing
`approval for a liquid formulation of bendamustine HCI which can be administered as a
`50 mL admixture over an infusion time of 10 minutes, whereas Treanda® must be
`administered as a 500 mL admixture over a 30-60 minute infusion time. Also unlike
`
`Treanda®, EPl’s bendamustine HCI formulation may be diluted in a 5% dextrose
`solution. EPl’s bendamustine HCI formulation is intended to be administered via the
`
`same route, at the same dose levels, and for the same indications as Treanda®.
`
`In 2014 EPI received tentative marketing approval for
`bendamustine HC
`
`“"0
`
`“m
`
`EPI has not submitted any new nonclinical studies since their previous NDA
`submission and subsequent tentative marketing approval. The nonclinical aspects of
`EPl’s liquid formulation of bendamustine HCI was reviewed by Christopher M Sheth,
`PhD under NDA 205580. The current review examines the findings of high
`concentrations of bendamustine HCI but otherwise relies on the conclusions of Dr.
`
`Sheth's review.
`
`1.2
`
`Brief Discussion of Nonclinical Findings
`
`"'"" . In the
`EPl’s liquid formulation of bendamustine HCI is
`current application, EPI is relying in part upon the Agency’s previous findings of safety
`and efficacy for Treanda® as described in the drug’s approved labeling. EPl’s nonclinical
`testing strategy was designed in accordance with FDA/CDER 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). EPI
`submitted reports to assess the hemolytic and irritant potential of bendamustine HCI at
`a concentration of up to 5.6 mg/mL, the highest final admixture concentration covering
`the clinical dose range. These reports were previously reviewed by Dr. Sheth during the
`review of NDA 205580.
`
`EPI conducted a GLP-compliant local tolerance study in rabbits evaluating the irritation
`potential of bendamustine HCI administered by intended (intravenous, IV) and
`unintended (perivascular, PV) routes of administration. IV administration of EPl's
`bendamustine HCI, Treanda®, and their respective placebos were associated with a
`similar degree of minor trauma and do not represent a toxicologically significant
`concern. PV administration of EPl’s bendamustine HCI was associated with local
`
`macroscopic and microscopic irritation that was not observed with Treanda® or either
`placebo. The irritation extended up to 2 cm from the injection site and was followed by
`
`Reference ID: 3827747
`
`

`

`NDA 208194
`
`Reviewer: Michael L Manning, PhD
`
`epidermal hyperplasia, consistent with normal tissue repair processes. The clinical
`relevance of findings limited to the PV route of administration is uncertain.
`
`The hemolytic potential of EPl’s bendamustine HCI was assessed alongside Treanda®
`and their respective placebos in a GLP-compliant study. Human whole blood was
`incubated with test articles at a 1:1 ratio for 30 minutes at 37°C. No hemolysis was
`observed in any of the samples tested, except for the positive control.
`
`1.3 Recommendations
`
`1 .3.1 Approvability
`
`From the Phamlacologyfroxicology perspective, bendamustine HCI, administered as a
`50mL admixture over an infusion time of 10 minutes, may be approved for the proposed
`indications.
`
`1.3.2 Additional Non Clinical Recommendations
`
`None
`
`1 .3.3 Labeling
`
`The nonclinical sections of the label will be comparable to the label of the listed drug
`Treanda®.
`
`3543-75-7
`Bendamustine HCI
`
`Not applicable
`1H-Benzimidazole-2-butanoic acid, 5-[bis(2-
`chloroethyl)amino]-methyI-,hydrochloride (1 :1 )
`C16H21C|2N302 - HCI -
`"M
`"m g/mol
`
`O
`H N
`# CKWOH
`
`\C
`
`H3
`
`'HC‘I
`
`(m4)
`
`Cl
`
`Cl
`
`2
`
`Drug Information
`
`2.1
`
`Drug
`
`CAS Registry Number:
`Generic Name:
`
`Code Name:
`Chemical Name:
`
`Molecular Formula:
`Molecular Weight:
`Structure:
`
`Pharmacologic Class:
`
`Alkylating drug
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`
`— IND 116448 (bendamustine HCI concentrate for injection): nonclinical information
`contained in the current NDA was previously submitted to IND 116448.
`
`Reference ID: 3827747
`
`

`

`NDA 208194
`
`Reviewer: Michael L Manning, PhD
`
`— NDA 205580 (bendamustine HCI
`tentative marketing approval for
`2, 2014.
`— NDA 022249 (Treanda®): Cephalon Inc received marketing approval for the
`lyophilized powder formulation of bendamustine HCI on March 20, 2008.
`— DMF
`“""(bendamustine HCI)
`
`W" for injection): EPI received
`“m bendamustine HCI on July
`
`2.3 Drug Formulation
`
`EPl’s bendamustine HCI drug formulation (see Table 1)
`
`(W)
`EPI is seeking
`approval of bendamustine HCI when administered as a 50 mL admixture over an
`infusion time of 10 minutes (see Table 2), whereas Treanda® is administered as a 500
`mL admixture over an infusion time of 30 minutes (CLL) or 60 minutes (NHL). EPI is
`proposing bendamustine HCI to be diluted in 50 mL of one of the following diluents:
`— 0.9% Sodium Chloride Injection, USP; or
`
`— 2.5% Dextrose/0.45% Sodium Chloride Injection, USP; or
`
`— 5% Dextrose Injection, USP.
`
`In contrast, Treanda® is to be diluted in 500 mL of one of the following diluents:
`— 0.9% Sodium Chloride Injection, USP; or
`
`— 2.5% Dextrose/0.45% Sodium Chloride Injection, USP.
`
`Table 1: Comparison of Treanda®(lyophilized powder and sterile solution) and
`EPI’s bendamustine HCI formulation
`
`Treandao (bendamustine
`HCI) for injection
`(100 mg vial“)
`
`Treandao (bendamustine HCI)
`injection, 90 mgImL
`(180 mgl2 mL”)
`
`EPI bendamustine HCI
`
`(100 mgl4 mL)
`
`
`Lyophilized powder
`Sterile solution
`Sterile solution
`
`injection, 25 mglmL
`
`
`.
`.
`Single use VIaI
`
`.
`.
`Single use Vial
`
`Multi-use vial (up to 28 days
`after initial use)
`
`
`
`
`
`How
`supplied
`
`
`
`
`Ingredients
`
`Ingredients
`
`Ingredients
`
`BDM HCI
`
`100 mg
`
`BDM HCI
`
`180 mg
`
`BDM HCI
`
`Composition
`
`Mfliggol,
`170 mg
`Propyle’nsePGlycol,
`648 mg
`Monothfilglycerol,
`
`N N
`Dimethylacetamide
`(DMA). EP
`
`PropyltLe’nSePGchol,
`
`Polyethylene Glycol
`400 (PEG 400).
`NFc
`
`BDM = bendamustine; DMA = N,N-Dimethylacetamide; EP = European Pharrnacopeia; HCI = hydrochloride: NF =
`National Formulary; PEG = polyethylene glycol; USP = United States Phannacopeia
`a Treanda“ (bendamustine HCI) for injection (Lyophilized) is also available in a 25 mg vial which has the same
`product composition.
`b Treandao (bendamustine HCI) injection (Sterile Solution) is also available in a 45 mgl0.5 mL vial, which has the
`same product composition.
`0 PEG 400 acidity may be modified using sodium hydroxide (NaOH) in water-for-injection solution.
`
`Reference ID: 3827747
`
`

`

`NDA 208194
`
`Reviewer: Michael L Manning, PhD
`
`Table 2: Comparison of Treanda®(lyophilized powder and sterile solution) and
`EPI’s bendamustine HCI preparation and final solution properties
`
`
`
`Treanda" (bendamustine
`HCI) for injection (100 mg
`vial)a
`
`Treanda‘D (bendamustine
`HCI) injection 90 mglmL
`(180 mgl2 mL vial )h
`
`EPI bendamustine HCI
`injection 25 mglmL (100
`mgl4 mL vial)
`
`Reconstitution
`
`Reconstitute with sterile
`
`water for injection to yield a
`solution of 5 mglmL
`
`No reconstitution needed
`
`No reconstitution needed
`
`Further dilution
`
`before infusion
`
`Withdraw required dose and Withdraw required close and
`dilute into 500 mL bag of:
`dilute into 500 mL bag of.
`0.9% Sodium Chloride
`0.9% Sodium Chloride
`
`Withdraw required dose and
`dilute into 50 mL bag of:
`0.9% Sodium Chloride
`
`Injection, USP, or 0.45%
`Injection. USP, or 0.45%
`Injection, USP, or 0.45%
`Sodium Chloride [2.5%
`.
`.
`Sodium Chloride [2.5%
`Sodium Chloride [2.5%
`Dextrose Injection, USP, or
`.
`.
`.
`.
`
`Dextrose Injection, USP
`Dextrose Injection, USP
`5% Dextrose Injection, USP
`
`Infusion duration
`
`30—60 minutes
`
`30—60 minutes
`
`10 minutes
`
`Final admixture
`concentration
`
`covering
`dose range
`
`1.85 mglmL to 5.6 mglmL
`0.2 mglmL to 0.7 mglmL
`0.2 mglmL to 0.6 mg/mL
`
`
`pH of final admixture 3.4 to 3.9c
`
`(Not measured)
`
`3.2d
`24 hours when stored
`
`
`
`
`
`
`
`
`
`refrigerated 2-8°C [36-46°F])
`
`
`
`or 3 hours [5% dextrose,
`24 hours when stored
`24 hours when stored
`
`
`USP] when stored at room
`
`
`refrigerated (2-8°C [36-46"Fj)
`refrigerated (2-8°C [36-46°Fj)
`temperature (1 5-30°C [59-
`
`
`
`
`86°F]) and room light
`
`
`
`
`Admixture stability
`or 3 hours when stored at
`or 2 hours when stored at
`
`room temperature (15-30°C
`room temperature (15-30°C
`or 6 hours [0.9% Sodium
`
`
`
`Chloride Injection, USP, or
`[59—86°F]) and room light
`[59-86°F]) and room light
`
`
`
`0.45% Sodium Chloride/2.5%
`Dextrose Injection, USP]
`
`when stored at room
`
`temperature (15—30°C [59-
`
`
`86°F]) and room light
`
`HCI = hydrochloride; USP = United States Pharmacopeia
`‘1 Treandao lyophilized product, also available in 25 mg vial
`b Treandao liquid product, also available in 45 mg vial
`(“"9
`° Reference:
`0 Reference: Toxicology Rabbit Local Tolerance Study No.13-2342
`
`2.4 Comments on Novel Excipients
`
`The excipients contained in EPl’s current bendamustine HCI drug formulation (for 50 mL
`admixture)
`“"0
`
`2.5 Comments on Impurities/Degradants of Concern
`
`The impurities contained in EPl’s current bendamustine HCI drug formulation (for 50 mL
`admixture)
`m"
`
`Reference ID: 3827747
`
`

`

`NDA 208194
`
` Reviewer: Michael L Manning, PhD
`
`Proposed Clinical Population and Dosing Regimen
`2.6
`The proposed clinical population for EPI’s bendamustine HCl is identical to that of
`Treanda®. EPI is proposing bendamustine HCl to be administered as a 50 mL admixture
`over an infusion time of 10 minutes, whereas Treanda® is to be administered as a 500
`mL admixture over an infusion time of 30 minutes (CLL) or 60 minutes (NHL).
`Otherwise, the proposed dosing regimen for EPI’s bendamustine HCl
` Treanda®.
`2.7 Regulatory Background
`Treanda® is marketed by Cephalon Inc and first received FDA approval on March 20,
`2008 for the lyophilized powder formulation of bendamustine HCl (NDA 022249). On
`September 13, 2013, Cephalon Inc received FDA approval for the liquid formulation of
`Treanda®. On July 2, 2014 EPI received tentative approval for
`
`bendamustine HCl under NDA 205580.
`
`
`
`A pre-NDA meeting was held with EPI on December 17, 2014 at which the Agency
`instructed EPI to submit a new NDA to obtain approval of the low-volume admixture of
`bendamustine HCl. No non-clinical issues were discussed at this meeting.
`
`EPI’s low-volume admixture of bendamustine HCl received Orphan Drug Designation
`for both chronic lymphocytic leukemia (CLL) and NHL indications on July 2, 2014 [NHL-
`ODD#14-4303 and CLL-ODD#14-4318].
`3
`Studies Submitted
`3.1
`Studies Reviewed
`
`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)
`
`eCTD Module
`
`4.2.3.7
`
`4.2.3.6
`
`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)
`
`eCTD Module
`
`4.2.3.7
`
`4.2.3.6
`
`4.2.3.6
`
`Reference ID: 3827747
`
`8
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 208194
`
`Reviewer: Michael L Manning, PhD
`
`3.3
`
`Previous Reviews Referenced
`
`The nonclinical aspects of EPl's current liquid formulation of bendamustine HCI were
`reviewed by Christopher M Sheth, PhD under NDA 205580 (Reference ID: 3425918).
`No new nonclinical studies have been submitted since Dr. Sheth’s review. This review
`
`examines the findings of high concentrations of bendamustine HCI but otherwise relies
`on the conclusions of Dr. Sheth’s review.
`
`4
`
`Pharmacology
`
`No pharmacology studies were submitted.
`
`5
`
`PharmacokineticslADME/Toxicokinetics
`
`No pharmacokinetic/ADME/toxicokinetic studies were submitted.
`
`6
`
`General Toxicology
`
`No general toxicology studies were submitted.
`
`7
`
`Genetic Toxicology
`
`No genetic toxicology studies were submitted.
`
`8
`
`Carcinogenicity
`
`No carcinogenicity studies were submitted.
`
`9
`
`Reproductive and Developmental Toxicology
`
`No reproductive and developmental toxicology studies were submitted.
`
`10 Special Toxicology Studies
`
`0”“) approved drug substance with a
`EPl’s bendamustine HCI
`"m the listed drug. EPl’s nonclinical
`proposed route of administration
`testing strategy was designed in accordance with FDA/CDER 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). EPI
`submitted reports to assess the hemolytic and irritant potential of bendamustine HCI at
`a concentration of up to 5.6 mg/mL, the highest final admixture concentration covering
`the clinical dose range.
`
`Hemolysis study:
`
`The hemolytic potential of EPI’s bendamustine HCI was compared to that of Treanda®
`using human whole blood as a substrate. Test samples were prepared as follows:
`— EPl’s bendamustine HCI (25 mg/mL) was diluted with saline across a range from
`0.7 to 5.6 mg/mL;
`— Treanda®was diluted with saline to 0.61 mg/mL;
`— Human plasma was used for negative control;
`
`Reference ID: 3827747
`
`

`

`NDA 208194
`
` Reviewer: Michael L Manning, PhD
`
` 1% Saponin was used for positive control.
`
`Human whole blood was collected on the day of testing from a fasted volunteer and
`incubated with test articles at a 1:1 ratio for 30 minutes at 37ºC. Samples were
`centrifuged and hemolysis was evaluated by spectrophotometric analysis for
`hemoglobin in the supernatant. No hemolysis was observed in any of the samples
`tested, except for the positive control (see Table 5 in Dr. Sheth’s review).
`
`Local tolerance study:
`
`The single dose IV and PV tolerance of EPI’s bendamustine HCl was compared to that
`of Treanda® in rabbits. The study was intended to assess the irritation potential for
`intended (IV) and unintended (PV) routes of administration.
`
`Male albino New Zealand white rabbits were 4.5 to 5.5 months of age and weighed 2.8
`to 3.2 kg at the initiation of dosing. Three rabbits/group received a single dose of IV or
`PV administered test article and corresponding placebo in the left and right ear,
`respectively. EPI’s bendamustine HCl and Treanda® were administered at a
`concentration of 5.6 mg/mL and 0.6 mg/mL, respectively (see Table 3). EPI’s
`bendamustine HCl was administered as an IV infusion over 10 minutes in accordance
`with the proposed label while Treanda® was administered as an IV infusion over 30
`minutes in accordance with the currently approved label. To evaluate the unintended
`route of administration, test articles and corresponding placebos (250 μL) were injected
`PV to simulate extravasation. Rabbits were observed for 96-hours post-dose, after
`which animals were sacrificed for further macroscopic and microscopic examination of
`both ears.
`
`Table 3: Local tolerance study: summary of experimental design
`
`Dose
`
`Number of male animals
`
`Group
`
`Route Dosea (mg/kg
`IV or mg PV)
`
`Volume (mL
`per dose)
`
`BDM conc.a
`(mg/mL)
`
`1 = Treanda® / Treanda®
`placebo
`
`2 = BDM in saline / BDM
`placebo
`
`3 = Treanda® / Treanda®
`placebo
`
`IV
`
`IV
`
`PV
`
`5
`
`5
`
`25
`
`2.7
`
`0.15
`
`0.25
`
`0.6
`
`5.6
`
`0.6
`
`Infusion
`duration
`minute/rate
`(mL/min)
`
`30/0.83b, c
`
`10/0.27b, c
`
`NA
`
`Total
`
`Left eara
`
`Right
`eara
`
`96-hour
`necropsy
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`3
`
`4 = BDM in saline / BDM
`placebo
`BDM = bendamustine hydrochloride
`aDoses represent active pharmaceutical ingredient as administered to the left ear. Placebo formulations (0 mg; 0
`mg/mL) were administered to the right ear. For the IV groups the dose was presented as mg/kg, for the PV groups
`the dose was presented as mg administered.
`bThese rates assumed a rabbit body weight of 3 kg. The rate/minute was adjusted in accordance with the actual body
`weight to reach the 5 mg/kg target in the specified infusion duration (of either 10 or 30 minutes)
`
`NA
`
`3
`
`3
`
`3
`
`3
`
`PV
`
`1.4
`
`0.25
`
`5.6
`
`Reference ID: 3827747
`
`10
`
`

`

`NDA 208194
`
` Reviewer: Michael L Manning, PhD
`
`cAs the volumes and infusion rates changed based on the body weights, the following dose volumes were used: 8.3
`mL/kg (5 mg/kg ÷ 0.6 mg/mL) for Group 1; 0.89 mL/kg (5 mg/kg ÷ 5.6 mg/mL) for Group 2. For consistency, the same
`dose volumes were used for the placebos.
`The first day of dosing was defined as Day 1 of the study.
`
`IV administration of EPI’s bendamustine HCl, Treanda®, and their respective placebos
`were well tolerated at all concentrations. The types and degree of findings were typical
`of the trauma associated with injection procedures and do not represent a
`toxicologically significant concern (see Table 4).
`
`PV administration of EPI’s bendamustine HCl was associated with local irritation that
`was not observed with Treanda® or either placebo. The irritation extended up to 2 cm
`from the injection site and was characterized by macroscopic scabs and red
`discoloration, and microscopic findings of moderate to marked edema/collagen
`degeneration, slight mixed inflammation, minimal to slight hemorrhage and slight to
`moderate epidermal pustules and erosion/ulceration of the overlying epidermis. During
`the 96-hour post-dose observation period epidermal hyperplasia was noted, consistent
`with normal tissue repair processes.
`
`Table 4: Local tolerance study: dermal, macroscopic, and microscopic findings of
`test article and placebo preparations
`Treanda
`Treanda
`® in
`®
`saline
`placebo
`in
`(0.6
`saline
`mg/mL)
`5 mg/kg (IV)
`
`BDM
`BDM in
`placebo
`saline
`(5.6
`in
`mg/mL)
`saline
`5 mg/kg (IV)
`
`Treanda
`Treanda
`®
`® in
`placebo
`saline
`in
`(0.6
`saline
`mg/mL)
`0.15 mg (PV)
`
`BDM
`BDM in
`placebo
`saline
`(5.6
`in
`mg/mL)
`saline
`1.4 mg (PV)
`
`Dose (route)
`Number of
`animals
`Noteworthy
`findings
`Died/euthanized
`moribund
`Body weight (%)
`Dermal
`evaluation
`Erythema slight
`Erythema
`moderate
`Bruising
`Eschar
`
`Gross
`pathology
`Discolored
`Scab
`Histopathology
`(injection site)
`Edema/collagen
`degeneration
`Mixed
`inflammation
`Hemorrhage
`Hyperplasia,
`epithelial
`
`Reference ID: 3827747
`
`3
`
`3
`
`3
`
`3
`
`0
`-
`
`1
`1
`0
`0
`
`0
`2
`
`1
`
`0
`1
`0
`
`0
`-
`
`0
`1
`0
`0
`
`0
`1
`
`2
`
`0
`1
`0
`
`0
`-
`
`1
`1
`0
`0
`
`2
`0
`
`0
`
`0
`1
`0
`
`0
`-
`
`1
`0
`0
`0
`
`1
`0
`
`0
`
`1
`0
`0
`
`11
`
`0
`-
`
`0
`0
`0
`0
`
`0
`0
`
`1
`
`0
`0
`0
`
`0
`-
`
`0
`0
`0
`0
`
`0
`0
`
`1
`
`1
`1
`0
`
`0
`-
`
`1
`1
`1
`0
`
`2
`1
`
`3
`
`2
`2
`2
`
`0
`-
`
`2
`0
`0
`1
`
`2
`2
`
`2
`
`0
`1
`0
`
`

`

`NDA 208194
`
` Reviewer: Michael L Manning, PhD
`
`Treanda
`Treanda
`®
`® in
`placebo
`saline
`in
`(0.6
`saline
`mg/mL)
`5 mg/kg (IV)
`
`BDM
`BDM in
`placebo
`saline
`in
`(5.6
`saline
`mg/mL)
`5 mg/kg (IV)
`
`Treanda
`Treanda
`®
`® in
`placebo
`saline
`in
`(0.6
`saline
`mg/mL)
`0.15 mg (PV)
`
`BDM
`BDM in
`placebo
`saline
`in
`(5.6
`saline
`mg/mL)
`1.4 mg (PV)
`
`2
`
`2
`0
`
`3
`
`2
`2
`2
`
`1
`
`1
`
`2
`
`1
`1
`
`0
`
`0
`0
`
`0
`
`0
`0
`0
`
`0
`
`0
`
`1
`
`0
`0
`
`0
`
`0
`0
`
`0
`
`0
`0
`0
`
`0
`
`0
`
`0
`
`0
`1
`
`0
`
`0
`0
`
`0
`
`0
`0
`0
`
`0
`
`0
`
`0
`
`0
`0
`
`Dose (route)
`Epidermal
`pustule,
`erosion/ulcerati
`on
`Scab
`Thrombus
`Histopathology
`(2 cm d stal to
`injection site)
`Edema/collagen
`degeneration
`Mixed
`inflammation
`Hemorrhage
`Hyperplasia,
`epithelial
`Epidermal
`pustule,
`erosion/ulcerati
`on
`Scab
`Histopathology
`(4 cm d stal to
`injection site)
`Edema/collagen
`degeneration
`Mixed
`0
`0
`inflammation
`Hemorrhage
`2
`0
`BDM = bendamustine hydrochloride
`11
`Integrated Summary and Safety Evaluation
`See Executive Summary
`12 Appendix/Attachments
`None
`
`0
`
`0
`0
`
`1
`
`0
`0
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`0
`
`1
`
`0
`0
`0
`
`0
`
`0
`
`0
`
`0
`
`1
`0
`
`0
`
`0
`0
`0
`
`0
`
`0
`
`0
`
`0
`1
`
`0
`
`0
`1
`
`0
`
`0
`0
`0
`
`0
`
`0
`
`0
`
`0
`0
`
`Reference ID: 3827747
`
`12
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MICHAEL L MANNING
`10/01/2015
`
`CHRISTOPHER M SHETH
`10/01/2015
`
`Reference ID: 3827747
`
`