CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`208194Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross-Discipline Team Leader Review
`
`_ See electronic signature stamp
`
`From
`Janice Brown M. S.
`
`Subject
`Cross—Disc1phne Team Leader Review
`NDA #
`NDA 208194
`
`Ea e Pharmaceuticals, Inc.
`
`Date of Submission
`
`PDUFA Goal Date
`
`Feb
`
`.
`
`13, 2015 received Feb .
`
`13, 2013
`
`December 13, 2015
`
`BENDEKA (bendamustine hydrochloride)
`Proprietary Name /
`
`Established (USAN) names
`Dosa_e forms / Stren_ h
`
`In‘ection, 100 m 4 mL 25 In mL
`
`Proposed Indication(s)
`
`For treatment of patients with:
`. Chronic lymphocytic leukemia (CLL).
`-
`Indolent B-cell non-Hodgkin lymphoma (NHL) that
`has progressed during or within six months of
`
`treatment with rituximab or a rituximab-containing Recommended:
`
`Approval, pending an acceptable recommendation from the
`Office of Study Integrity and Surveillance (OSIS) of the
`bioe uivalence clinical site ins ections
`
`Include the following in the action letter:
`
`A shelf life of 24 months is granted for Bendeka (bendamustine hydrochloride) Injection,
`when stored in refrigerator at 2 — 8°C (36 - 46°F), protected from light.
`
`

`

`Cross Discipline Team Leader Review
`NDA 208194
`
`1. Introduction
`
`Bendamustine hydrochloride (HCl) is a small molecule, alkylating agent approved for
`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.
`
`The current application for Bendamustine HCl injection is submitted as a 505(b)(2) NDA. The
`proposed drug product is a ready-to-dilute solution, and does not require reconstitution, as is
`the case for the listed drug product, Treanda (bendamustine) for injection, which is a
`lyophilized powder. The proposed drug product is self-preserving and is intended for
`multiple-uses.
`(hm) the proposed bendamustine HCl injection
`also must be diluted in 500 mL of 0.9% Sodium Chloride Injection, USP, or 2.5%
`Dextrose/0.45% Sodium Chloride Injection, USP prior to intravenous infusion.
`
`2. Background
`
`The subject of the current NDA application is a new formulation for bendamustine HCl. The
`applicant for this NDA is relying upon information in the public domain (labeling for
`approved bendamustine HCl product and published studies about bendamustine HCl) to
`support the safety and efficacy of the proposed product.
`
`(It) (4)
`
`New information in NDA
`
`208194 includes a modification of the dose preparation and administration, allowing
`administration of the product in a smaller volume (50 mL admixture) over a shorter time
`period (10 minutes), three options for admixtures, drug product stability data to support a 24
`month shelf life, a BB study, and a safety and tolerability profile of bendamustine HCl
`injection when infused over 10 minutes in a 50 mL admixture volume.
`
`Eagle received tentative approval for the companion NDA 205580, bendamustine HCl
`injection
`(m4) on July 2, 2014 for
`(mo
`indolent B—cell NHL only.
`
`3. CMC
`
`(mo nonspecific DNA alkylating
`Drug Substance: Bendamustine HCl is a
`agent. It is a bifimctional mechlorethamine derivative containing a purine-like benzimidazole
`ring. Mechlorethamine forms electrophilic alkyl groups that form covalent bonds with
`electron—rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional
`covalent linkage in the DNA leads to cell death.
`
`Page 2 of 14
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`

`Cross Discipline Team Leader Review
`NDA 208 194
`
`The chemical name of bendamustine HCl is lH-benzimidazole-Z-butanoic acid, 5-
`
`chloroeth 1 amino -1 meth l, monoh drochloride. Bendamustine HCl is a
`
`is 2-
`
`
`The CMC information for the drug substance was providedin DMF No.
`
`- The applicant provided adequate reference to their Type H DMF
`
` rtainin to the dru substance, bendamustine HCl. Bendamustine HClis
`
`
`
`
`
`
`The DMF contains the necessary information related to
`manufacturing, characterization, physical properties, manufacture, process controls, analytical
`methods, specification, validation, container closure system, reference standard and stability
`data for bendamustine HCl. DMF- was reviewed and found adequate to support the
`manufacture of a drug product as a solution dosage form by Joyce Crich, Ph.D. on May 6,
`2014. There is no new quality update provided in the Dh/[F since the last review.
`
`Stability data su
`
`orts a retest eriod of months for bendamustine HCl dru substance
`
`
`
`The NDA included minor drug substance updates and the drug substance reviewer found the
`information adequate to support the NDA 208194 (refer to the drug substance section of the
`integrated quality assessment signed by Nina Ni on September 21, 2015).
`
`Drug Product: Bendeka (bendamustine HCl) injection is a ready-to-dilute non-aqueous
`solution formulation of Bendamustine HCl intended for intravenous administration after
`
`further dilution in 50 mL of either 0.9% Sodium Chloride Injection, USP, 2.5%
`Dextrose/0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.
`
`
`
`formulation to adjust the pH of PEG 400. The excipient levels, in terms of maximum daily
`dose in the drug product and the admixture are below the levels used in currently approved
`parenteral drug products.
`
`A shelf life of 24 months is granted for Bendeka (bendamustine HCl) Injection, when stored
`refrigerated at 2 - 8°C (36 - 46°F), protected fiom light. Storage precautions are required as the
`
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`Cross Discipline Team Leader Review
`NDA 208194
`
`drug product is light sensitive. The primary container must be kept in the secondary
`packaging in order to protect the drug product from light. Accordingly, the following
`statement was put on the vial and carton labels: “Retain in originalpackage until time ofuse.
`Protectfrom light.”
`
`At the request of the CDTL, the drug product reviewer included the following information on
`the compatibility of the drug product and admixes in the infusion bags. The drug product
`review included the following information,
`
`“However, in the NDA 208194, the applicant did not provide compatibility study in terms
`of leachable/extractables for the diluted products which contain
`”(0
`monothioglycerol, PG, and PEG 400 while prepared and stored in infusion bags. The in-
`use stability studies provided in the NDA 208194 mamly focused on the stability in terms
`of assay and degradation products of diluted bendamustine solutions while stored in
`infilsion bags.
`
`Lack of compatibility study is deemed acceptable based on the following risk assessments:
`
`El PG and monothioglycerol are present in the drug product at very low concentrations
`(
`(b)(n%’ respectively).
`omPEG 400 is very
`hydrophilic and is present at no more than"""% in the admixture solutions. Thus, both
`formulation and admixtures are considered low risk in terms of extraction power.
`
`[I According to USP <88>, extraction in PEG 400 is not required for Class IV plastics.
`
`Therefore, the risk associated with presence of PEG 400 for Class IV plastics which is
`the proposed admixture bags is expected to be low given that USP <88> does not
`require PEG 400 extraction for Class IV plastics.
`
`CI The contact time for admixture solutions in the infusion bags is considered short which
`
`is no more than 6 hours at room temperature or no more than 24 hours at refrigerator.
`The total infusion time is only 10 minutes. Therefore, as a summary, the drug product
`is considered compatible with the proposed infusion bags as well as all the other
`commercially available transfer devices, including adaptor, syringe, filter, and tubing.’
`
`‘)
`
`The CDTL agrees with this risk assessment.
`
`No drug product issues which preclude approval were found and the drug product reviewer
`found the information adequate to support the approval of NDA 208194 (refer to the drug
`product section of the integrated quality assessment signed by Nina Ni on September 21,
`2015).
`
`Process Review — Drug Product: The manufacturing and packaging process of Bendamustine
`HCl Injection consists of the following unit operations:
`
`Page 4 of 14
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`Cross Discipline Team Leader Review
`NDA 208194
`
`The commercial batch size '
`
`. Bendamustine HCl In'ection is 1i
`
`t sensitiv
`
`The drug product manufacturing process was reviewed and found acceptable and the process
`reviewer recommended approval of the NDA (refer to the process section of the integrated
`quality assessment signed by Vidya Pai on October 5, 2015).
`
`Facilities review andmtion: There are no significant, outstanding manufacturing risks and
`the Office of Process and Facilities find the facilities acceptable. Based on the firm’s
`inspectional history and district file review, the manufacturing facilities as listed below for
`NDA 208194 are acceptable.
`
`Drug Substance Facilities
`1.
`
`2.
`
`A
`
`
`
`table Based on District Recommendation
`
`Acceptable Based on Profile
`
`Drug Product Facilities
`
`1.— Acceptable Based on District
`Recommen tron
`2.— Acceptable Based on Profile
`
`Microbiolo Review: The
`
`
`The
`
`an operated
`e equipment an container c osure is appropriate y q
`tron o
`st
`using validated loading patterns. Microbiological attributes, container-closure, package
`integrity, and the preservative efl'ectiveness and bacterial endotoxin testing are adequate to
`support the microbiological quality for this drug product.
`
`Bendamustine HCl is a multi—use vial. Although it does not contain any antimicrobial
`preservative, bendamustine HCl is bacteriostatic and does not support bacterial growth. The
`partially used vials are stable for up to 28 days when stored in its original carton Imder
`refiigeration (2°C — 8°C or 36°F - 46°F). Each vial is not recommended for more than six (6)
`dose withdrawals (see drug product review for the companion NDA by Erika A. Pfeiler on
`May 14, 2014). Afier first use, the partially used vial should be stored in original carton at 2
`°C to 8 °C, and then discarded after 28 days. The in-use stability for the 50 mL diluted
`
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`Cross Discipline Team Leader Review
`NDA 208194
`
`product in 5% Dextrose Injection is 3 hours at room temperature and 24 hours at refrigerated
`conditions.
`
`The microbiology section was reviewed and found acceptable (refer to the microbiology
`section of the integrated quality assessment signed by Vinayak Pawar, Ph.D. on October 14,
`201 5).
`
`4. Nonclinical Pharmacology/Toxicology
`
`('mfonnulation of
`According to the nonclinical review, “The nonclinical aspects of EPI’s
`bendamustine HCl were reviewed by Christopher M. Sheth, Ph.D. under NDA 205580. The
`current review examines the findings of high concentrations of bendamustine HCl but
`otherwise relies on the conclusions of Dr. Sheth’s review.”
`
`The nonclinical review concluded that the “GLP-compliant local tolerance study in rabbits
`evaluating the irritation potential of bendamustine HCl administered by intended (intravenous,
`IV) and unintended (peiivascular, PW routes of administration. IV administration of EPI’s
`bendamustine HCl, 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 EPI’s bendamustine HCl was associated with local macroscopic and
`microscopic imitation that was not observed with Treanda® or either placebo.” The imitation
`extended up to 2 cm from the injection site and was followed by epidermal hyperplasia,
`consistent with normal tissue repair processes. The clinical relevance of findings limited to the
`PV route of administration is uncertain.”
`
`An additional study evaluating the hemolytic potential of EPI’s bendamustine HCl 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.
`
`The nonclinical reviewer recommended approval of the NDA for bendamustine HCL injection
`administered as a 50mL admixture over an infusion time of 10 minutes, for the proposed
`indications (see review by Michael Manning, Ph.D., final signature October 1, 2015).
`
`Pharmacology/Toxicology has no concerns with the nonclinical findings and the excipients
`used for Eagle’s bendamustine HCl injection at the defined level
`m4)
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`Clinical Pharmacology: The bioequivalence study was reviewed by the OPQ
`biopharmaceutics team, therefore, there is no Clinical Pharmacology review for this NDA.
`
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`Cross Discipline Team Leader Review
`NDA 208194
`
`Biopharmaceutics: The applicant conducted a Phase 1, open-label, crossover, randomized,
`bioequivalence study (# EGL-BDM-C-1301) to evaluate Eagle’s Bendamustine (BDM)
`Hydrochloride (HCl) injection and Treanda for injection (Teva- BDM) administered to
`patients with a histologically confirmed diagnosis of cancer (solid tumors and hematologic
`malignancies excluding chronic lymphocytic leukemia [CLL]) who had progressed or relapsed
`on standard therapy, or for whom no curative or standard therapy was appropriate. The
`primary objective of Study EGL-BDM-C-1301 was to demonstrate that the Eagle-BDM
`formulation is bioequivalent to the currently marketed Teva- BDM with respect to total
`bendamustine systemic exposure (AUC). The maximum peak plasma concentration (Cmax)
`value for Eagle-BDM is higher than Teva-BDM due to the 6-fold increase in administration
`rate for the Eagle-BDM (10 minutes versus 60 minutes).
`The reference product (Teva-BDM; 120 mg/m2) was replicated across 2 periods and the test
`product (Eagle-BDM; 120 mg/m2) was administered once over the 2 treatment cycles for PK
`evaluation (allowing for 3 treatments per patient) to determine whether the two BDM HCl
`formulations were bioequivalent: (1) Eagle-BDM was given IV over 10 minutes, and (2) Teva-
`BDM was given IV over 60 minutes (see figure 2.5.1 for the study design reproduced below).
`A total of 102 patients were screened, of which 83 were randomized into 3 study cohorts based
`on treatment sequences. Of the 83 patients randomized into a treatment sequence, two patients
`were not dosed; therefore, a total of 81 patients received at least one dose of study drug. Of
`these 81 patients, 60 patients completed all 3 study treatment doses.
`
`Page 7 of 14
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`Cross Discipline Team Leader Review
`NDA 208194
`
`According to the biopharmaceutics review, four (4) PK Evaluable (PKE) sub-populations were
`evaluated:
`(cid:16) FDA-requested population for primary BE analysis: n=60, who received 3 doses of
`BDM, which included 22 patients who completed 3 doses but had major infusion-
`related deviations or PK sample collection deviations;
`(cid:16) FDA-requested population for secondary BE sensitivity analysis: n=57, who received 3
`doses of BDM, but excluding the 2 patients with major PK sample collection
`deviations and 1 patient with a major infusion-related deviation;
`(cid:16) Eagle original proposed population for primary BE analysis: n=44, who received 3
`doses of BDM without deviations, plus 6 patients with PK sampling deviation but used
`for interim analysis;
`(cid:16) Eagle original proposed population for secondary BE sensitivity analysis: n=38, who
`received 3 doses of BDM without deviations.
`
`The biopharmaceutics review concluded, “Study EGL-BDM-C-1301 demonstrated that the
`EAGLE-bendamustine (Eagle-BDM) product given over a 10 minutes infusion interval is
`bioequivalent to the reference product (Teva-BDM) given over 60 minutes. The results
`showed the Eagle-BDM is bioequivalent to Teva-BDM for BDM AUC0-t and AUC0-(cid:146) for the 2
`Primary PKE populations (FDA requested [n=60] and Eagle proposed [n=44]), as well as for
`
`Page 8 of 14
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`Cross Discipline Team Leader Review
`NDA 208194
`
`the 2 Secondary Sensitivity populations (FDA requested [n=57] and Eagle proposed [n=38]),
`respectively, by using the RSABE method as well as the unscaled- ABE method.
`
`Based on FDA recommendations in a meeting held on 1/15/2013, BE was based only on the
`AUCs for BDM, because the proposed product was intentionally formulated to exhibit
`different Cmax and Tmax compared to the Listed Drug (due to the difference in concentration
`and duration of administration). Bioequivalence was determined based on comparison of the
`bendamustine AUCs (AUC0-t & AUC0-(cid:146)) between the Test product and the Listed Drug.”
`The biopharmaceutics reviewer concluded that the safety profiles of the two products are
`similar based on the clinical safety review in DARRTs, despite the higher Cmax achieved by
`the Eagle-BDM product. No biopharmaceutics issues which preclude approval were identified
`and the biopharmaceutics reviewer found the information adequate to support the approval of
`NDA 208194 (refer to the biopharmaceutics section of the integrated quality assessment
`signed by Jing Li, Ph.D.).
`6. Clinical Microbiology
`
`No Clinical Microbiology review was required for this NDA.
`7. Clinical/Statistical- Efficacy
`
`The clinical recommendation for the approval of Bendeka is based on the safety and efficacy
`of the marketed bendamustine (Treanda) lyophilized powder for injection product (NDA
`22249), supportive safety and efficacy information from the marketed bendamustine (Treanda)
`products and the available Bendeka supportive safety information from the bioequivalence
`study EGL-BDM-C-1301.
`According to the clinical review, “From a clinical perspective NDA 208194 should be granted
`approval for the following indications which are the same indications as the reference drug.
`
`(cid:120) Bendamustine hydrochloride is an alkylating drug indicated for treatment of patients
`with:
`o Chronic lymphocytic leukemia (CLL).
`o Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or
`within six months of treatment with rituximab or a rituximab-containing
`regimen.”
`
`No clinical issues which preclude approval were found and the clinical reviewer found the
`information adequate to support the approval of NDA 208194 for the proposed indications (see
`review by Andrew Dmytrijuk M.D., final signature November 19, 2015).
`
`No Statistical Review was done for this NDA.
`
`Page 9 of 14
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`Cross Discipline Team Leader Review
`NDA 208194
`
`8. Safety
`
`The clinical review concluded that “From a clinical perspective the pharmacokinetic results,
`the proportion of patients with adverse events and severity of adverse events in the
`bioequivalence study EGL—BDM—C-l301 were similar for Bendeka infusion over 10 minutes
`compared to Treanda infusion over 60 minutes.
`
`Review of safety in study EGL—BDM—C—l301 supporting the Bendeka application NDA
`208194 does not raise new or additional safety concerns for the Bendeka formulation and
`faster infusion rate compared to the marketed Treanda lyophilized powder product. This study
`was conducted in patients with a histologically confirmed diagnosis of any malignant disease
`for which no curative or standard therapy is appropriate. Most patients 38/81 (47%) in this
`study had stage IV solid tumor malignancies at the time of enrollment in which disease
`progression and a high mortality rate is expected. In this study 6 patients died. All 6 patients
`had stage IV disease and a poor prognosis (AJCC Cancer Staging Handbook, 2002). There
`was no clear difference between Bendeka and Treanda in the proportion of patients with
`CTCAE grade 2 3 AEs or SAEs. Exclusion of patients with CLL from study EGL-BDM-
`1301-C is acceptable, as is also stated in the Reviewer Comment for section 5 in this review,
`because the recommended dose of Treanda for patients with CLL is lower than the
`recommended dose of Treanda for patients with indolent NHL which would make it difficult
`to compare phannacokinetic results for patients with CLL to those with solid tumor
`malignancies or NHL.”
`
`The increased osmolality of the proposed drug product once diluted into either 0.9% Sodium
`Chloride Injection, USP or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP one
`
`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 hyperosmotic 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. 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 of patients. I agree with Dr.
`George’s assessment of the potential for these adverse reactions and his conclusion. In NDA
`208194, there were no reported adverse reactions of phlebitis or hemolysis. Skin adverse
`events were generally reported infrequently and were considered to be to be of mild severity.
`There were two patients who developed adverse skin reactions (mild macular rash and mild
`urticaria) during the study drug administration or within 1 hour after the end of study drug
`administration. The faster infusion rate of Bendeka, i.e., 10 minutes, compared to the infusion
`rate of Treanda, i.e., 60 minutes, does not appear to increase the risk for hemolysis, phlebitis,
`or infusion site reactions. Also, the current proposed Warnings and Precautions section
`
`Page 10 of14
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`Cross Discipline Team Leader Review
`NDA 208194
`
`labeling for Bendeka is the same as that of Treanda and states that there is a potential risk for
`skin reactions including SJS and TEN and extravasation.” The clinical team leader agrees
`with Dr. Dmytrijuk’ s conclusion.
`9. Advisory Committee Meeting
`
`There was no Advisory Committee meeting held for this application.
`10. Pediatrics
`
`The labeling for the listed drug contains information in the Pediatric Use section based upon a
`study conducted by the listed drug applicant. Information from the study regarding pediatric
`experience was placed into the label based on safety concerns that could arise should the
`product be used off label in pediatric patients. Consequently, this information was retained in
`the label for the new Eagle bendamustine product.
`
`Also, as noted in the Clinical Review, on July 2, 2014 Office of Orphan Products granted
`orphan drug designation to Eagle’s Bendamustine HCl 50 mL admixture. Therefore, PREA
`requirements do not apply.
`
`11. Other Relevant Regulatory Issues
`
`(cid:120) Application Integrity Policy (AIP): No issues were identified.
`
`(cid:120) Exclusivity or patent issues of concern: The following exclusivities are listed in the
`orange book:
`
`Exclusivity Data
`Application Number
`
`Product Number
`
`Exclusivity Code
`
`N022249
`N022249
`N022249
`N022249
`
`001
`001
`001
`001
`
`ODE
`PED
`ODE
`PED
`
`Exclusivity
`Expiration
`
`(cid:120) Financial disclosures: In accordance with 21 CFR 54.4, the applicant submitted the
`required financial disclosure requirement and certification.
`
`(cid:120) Other GCP issues: None
`
`
`(cid:120) Office of Study Integrity and Surveillance (OSIS) Audits: FDA Office of Scientific
`Investigations performed inspections of the following clinical sites:
`
`Page 11 of 14
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`11
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`NDA 208194
`
`- Oncology Institute of Hope and Innovation, Long Beach, CA
`-
`Innovative Clinical Research Institute, Whittier, CA
`-
`Evergreen Hematology & Oncology, Spokane, WA
`- Greenville Hospital System University Medical Center, Greenville, SC
`- Cancer Center of Kansas, Wichita, KS
`-
`
`site where analytical testing in support of the
`The inspection of the
`bioequivalence study was conducted from
`. A 1-item Form FDA 483 was
`issued at the conclusion of the inspection. OSIS concluded that this observation does not
`affect the data integrity of the study.
`
`The status of the remaining clinical sites are pending.
`
`(cid:120) Other discipline consults: None
`
`
`(cid:120) Any other outstanding regulatory issues: None
`
`12. Labeling
`
`General: Final labeling was found acceptable for all the review disciplines.
`
`(cid:120) Proprietary name: Bendeka. The DMEPA review of the proprietary name, Bendeka,
`was found acceptable (see review by Michelle Rutledge, PharmD on June 15, 2015).
`
`(cid:120) Division of Medication Error Prevention and Analysis (DMEPA): Labeling
`recommendations were provided by the (DMEPA). Recommendations included the
`removal of trailing zeros after the decimal point in Section 2.3 - Preparation for
`Intravenous Administration in the full prescribing information. The review also
`recommendation to increase the font size, reduce size of company logo, bolding
`important information and including a resealable peel-back label for the container
`carton label (see review by Michelle Rutledge, PharmD on September 16, 2015).
`
`(cid:120) Office of Prescription Drug Promotion (OPDP): OPDP did not have any labeling
`comments to the draft prescribing information (see review by Nisha Patel on August
`12, 2015).
`
`(cid:120) Prescribing Information: The wording of the labeling in the PLR format has been
`reviewed and comments from all disciplines (including DMEPA) were conveyed to the
`applicant.
`
`Page 12 of 14
`
`12
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Cross Discipline Team Leader Review
`NDA 208194
`
`0 Carton and Immediate container label: The drug product and DMEPA reviewers
`made suggested edits to the carton and immediate container label. All revisions were
`accepted by the applicant.
`
`0 Patient labeling/Medication guide: This is not required for this product.
`
`13. Recommendations/Risk Benefit Assessment
`
`0 Recommended Regulatory Action: Approval
`
`0 Risk Benefit Assessment
`
`According to the clinical review, “Overall, the risk benefit assessment favors the approval of
`the Bendeka formulation for the same indications as that of the Treanda formulation. Bendeka
`
`offers patients a more rapid intravenous infusion of bendamustine hydrochloride (10 minutes
`for Bendeka compared to 60 minutes for Treanda) and does contain DMA which is compatible
`with closed system transfer devices (CSTDs), adaptors, and syringes containing polycarbonate
`or acrylonitlile-butadiene-styrene (ABS). Overall the proportion of patients with adverse
`events and severity of adverse events were similar for Bendeka infusion over 10 minutes
`compared to Treanda infusion over 60 minutes in study EGL-BDM-C-1301.”
`
`The clinical reviewers for
`
`(on) 208194
`
`m4)
`
`concluded that 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 hyperosmotic intravenous solution, i.e., phlebitis and/or infusion site
`reactions. Additionally, In NDA 208194 there were no reported adverse reactions of phlebitis
`or hemolysis-
`
`A bioequivalence study (EGL-BDM—C—l301) demonstrated the bioequivalence of Eagle
`bendamustine product given over a 10 minutes infilsion interval compared to the listed drug
`Treanda (bendamustine hydrochloride) for injection given over 60 minutes. The safety profile
`of Eagle’s bendamustine drug product is consistent with known effects of bendamustine.
`
`Nonclinical and clinical studies performed with Eagle’s BDM HCl Injection demonstrated an
`acceptable safety and tolerability profile, with no increased toxicity risk compared to the
`existing Treanda formulation.
`
`The drug product reviewer determined that the lack of compatibility data was acceptable based
`on a risk assessment. The PG and monothioglycerol are present in the drug product at very
`low concentrations (
`1”(9%, respectively).
`”(4’ PEG 400
`is very hydrophilic and is present at no more than 3% in the admixture solutions. Thus, both
`formulation and admixtures are considered low risk in terms of extraction power. The contact
`time for admixture solutions in the infusion bags is considered short which is no more than 6
`hours at room temperature or no more than 24 hours at refiigerator. The total infusion time is
`only 10 minutes. Therefore, as a summary, the drug product is considered compatible with the
`
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`Cross Discipline Team Leader Review
`NDA 208194
`
`proposed infusion bags as well as all the other commercially available transfer devices,
`including adaptor, syringe, filter, and tubing.”
`
`Pharmacology/Toxicology has no concerns with the nonclinical findings and the excipients
`used for Eagle’s bendamustine HCl injection at the defined levels. The Applicant has
`satisfactorily responded to the identified CMC and biopharmaceutics deficiencies, and the
`application has received an overall acceptable recommendation from the Office of
`Compliance.
`
`(cid:3878) Recommendation for Postmarketing Risk and Management Activities
` (cid:3878) Recommendation for other Postmarketing Study Commitments
`
`No post-marketing risk evaluation and mitigation strategy (REMS) is recommended for
`the Bendeka formulation.
`
`No Postmarketing Requirements (PMRs) or Postmarketing Commitments (PMCs) for
`this NDA submission are recommended.
`
`On July 2, 2014 Office of Orphan Products granted orphan drug designation to Eagle’s
`Bendamustine HCl 50 mL admixture. Therefore, PREA requirements do not apply.
`
`(cid:3878) Recommended Comments to Applicant
`
`None.
`
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