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

`

`Office of Clinical Pharmacology Review
`
`Application Number
`
`NDA 205580 SDN 38
`
`Letter Date of Submission
`
`January 31, 2018
`
`Product Name (Trade and
`generic, code)
`
`Bendamustine Hydrochloride Injection
`100 mg4 mL (25 mgmL!
`
`Route of Administration
`
`Intravenous Injection
`
`
`
`
`Treahnent of Chronic Lymphocytic
`Leukemia (CLL) and Indolent B—Cell
`Proposed Indication
`AM
`
`Submission Type
`Resubmission Class 1
`
`Sponsor
`Eagle Pharmaceuticals, Inc.
`
`Related Applications
`
`NDA205580 SDN 8
`
`Prior Reviews (Application
`number, Submission type, Date)
`
`NDA 205580,
`
`"”“’
`, May 29, 2014
`
`
`
`On September 6, 2013, Eagle Pharmaceuticals, Inc. submitted a 505(b)(2) New Drug Application
`(NDA 205580) for Bendamustine Hydrochloride Injection 100 mg/4 mL (25 mg/mL) in a 500
`mL admixture for the treatment of Chronic Lymphocytic Leukemia (CLL) and Indolent B—Cell
`non-Hodgkin Lymphoma (NHL). The Agency gave a tentative approval on July 2, 2014. The
`approval was tentative due to CMC, labeling and patent rights infringement issues.
`
`Dr. Y-J. Moon reviewed (DARRTS 5/29/2014) the clinical pharmacology information in the
`2013 submission. Dr. Moon’s review states (indented):
`Although the Eagle bendamustine HCl product has a higher concentration (25 mg/mL)
`than the reconstituted listed drug (LD) (5 mg/mL), after dilution in the admixture vehicle
`the concentration is the same between the two products. Therefore, the actual dose that
`will be administered to patients and the infusion time to administer that dose has not
`changed. A request for waiver for requirement to conduct bioequivalence testing is
`included in this NDA.
`
`ONDQA-Biopharmaceutics review stated ODARRTS Communication date: 5/ 13/14) that
`the Applicant provided appropriate information/data justifying that the higher osmolality
`range of their product (when compared to that of the listed product), will not have an
`impact on the clinical safety profile of their proposed bendamustine HCl product. Also it
`was stated that the absence of mannitol and inclusion of monothioglycerol, propylene
`glycol, and PEG 400 in the proposed formulation does not affect the distribution and/or
`elimination of bendamustine HCl (when compared to those of the listed product) and
`that the Applicant’s response included evidence from literature supporting the safety of
`the intravenous infusions of bendamustine HCl solutions containing the proposed
`
`Reference ID: 42371 87
`Reference ID: 4266336
`
`

`

`concentrations of monothioglycerol, propylene glycol, and PEG 400. ONDQA-
`Biopharmaceutics recommended approval and granted a Biowaiver.
`This submission contains no new clinical pharmacology information for review. NDA
`205580 is recommended for approval from the standpoint of clinical pharmacology.
`
`Recommendation
`This submission contains no new clinical pharmacology information for review. Consistent with
`clinical pharmacology’s 2013 recommendation, NDA 205580 is recommended for approval from
`the standpoint of clinical pharmacology.
`
`Signatures
`
`Gene Williams, Ph.D.
`Christy S John, Ph.D.
`Team Leader
`Reviewer
`Division of Clinical Pharmacology V
`Division of Clinical Pharmacology V
`DHP: RPM – L. Wall; MO – A. Schwarsin; MTL – A. de Claro
`Cc:
`DCP-V: DDD – B. Booth; DD – A. Rahman
`
`2
`
`Reference ID: 4237187
`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/
`----------------------------------------------------
`
`CHRISTY S JOHN
`03/20/2018
`
`GENE M WILLIAMS
`03/20/2018
`I concur with the recommendation
`
`Reference ID: 4237187
`Reference ID: 4266336
`
`

`

`
`
`NDA
`
`Clinical Phannacolgx Memorandum
`205580 SDN 8
`
`6 September 2013
`Submission Date:
`Bendamustine HCL, 100 mg/4 mL (25 mg/mL)
`Drug Name:
`Eagle Pharmaceuticals, Inc.
`Sponsor:
`Young Jin Moon, Ph.D.
`OCP Reviewers:
`
`OCP Team Leader: Julie M. Bullock Pharm.D.—
`
`This 505(b)(2) applicafion relies on the FDA's finding of safety and effectiveness for the listed drug,
`TREANDA® (bendamustine HCI) marketed by Teva Pharmaceuticals under the approved NDA 22249.
`Bendamustine HCI, an alkylating agent, is approved for the treatment of chronic lymphocyfic leukemia
`(CLL) and indolent Non-Hodgkin Lymphoma (NHL). Dosing regimen is 100 mg/m2 infused intravenously
`over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles for CLL and 120 mg/m2 infused
`intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles for NHL.
`
`Eagle's Bendamustine HCI is intended for the same indications and by the same dosing regimen. The
`difference and similarity of the two products are detailed as follows.
`
`TREANDA (bendamustine HCI) for Injection has two vial sizes, 100 mg of bendamustine HCI Iyophilized
`powder in a 20 mL amber glass vial and 25 mg of bendamustine HCI Iyophilized powder in a 8 mL amber
`glass vial. Both have the exact same compositions. Eagle’s Bendamustine HCI Injection, 25 mg/mL has
`only one presentation as 100 mg of bendamustine HCI in 4 mL solution in a 5 mL clear glass vial. A
`comparison between the TREANDA 100 mg presentation and Eagle Bendamustine HCI, 25 mg/mL is
`provided in Table 1 below.
`
`Table 1. Comparison of Treanda 100 mg Vial and Eagle’s Bendamustine HCI Injection, 25 mg/mL (100
`mg/_4 mL)
`Product
`
`Treanda (bendamustine HCI) for Injection
`100 I 1 vial)
`
`Bendamustine HCI Injection, 25 mg/mL
`100 Ini4 mL)
`
`
`
`Dosage Form
`
`Composition
`
`Lyophilized powder
`
`Ingredients
`
`Amount per vial
`
`Bendamustine HC]
`
`100 mg
`
`
`
`Sten'le Solution
`
`Ingredient
`
`Amount per rial
`
`Bendamustine HCI
`
`100 mg
`
`
`Mannitol. USP
`[70 mg
`Monotllioglycerol. NF
`20 mg
`
`Polyethylene Glycol 400
`QS to 4 mL
`(PEG 400). NF*
`(m4)
`
`
`
`Propylene Glycol. USP 0.4 mL
`
`
`
`The preparation of the product solutions for infusion is different as follows.
`
`Reference ID: 3515092
`Reference ID: 4266336
`
`

`

`.
`.
`.
`Reconstitution
`
`
`
`Final
`Solution
`
`Infusion"
`
`
`
`
`Table 2. Comparison of Preparation and Final Solufion for Infusion
`
`
`Bendamustine HCI Injection, 25
`
`Treanda (bendamustine HCI) for
`
`.
`.
`.
`Product
`mg/mL
`
`
`Injection (100 mg Vlal)
`(100
`M l )
`
`
`
`
`
`Reconstituted with sterile water for
`No reconstitution is needed (A ready to
`injection to yield a solution of 5 tug/niL
`dilute solution of 25 mg/niL)
`
`
`
`
`Withdraw require dose and dilute into
`Withdraw require dose and dilute into
`
`500 ml. bag of 0.9% Sodium Chloride
`500 mL bag of0.9% Soditun Chloride
`Further Dilution prior to
`Injection. USP or 0.45% Sodium
`Injection. USP or 0.45% Soditnn
`Infusion
`
`ClllOl‘ide.'2.59’o Dextrose Injection. USP. Chloride’25% Dextrose Injection. USP.
`Admixture
`
`
`C°"‘°"“'afi°“
`02
`lmL
`06
`lmL
`02
`lmL
`Covering Dose
`' mg
`' mg
`' mg
`Ran-e
`
`
`
`Osmolarity
`
`(m05m/kg)
`
`
`Although the Eagle bendamustine HCI product has a higher concentration (25 mg/mL) than the
`reconstituted listed drug (LD) (5 mg/mL), after dilution in the admixture vehicle the concentrafion is me
`same between fire two products. Therefore, the actual dose that will be administered to patients and the
`infusion time to administer that dose has not changed. A request for waiver for requirement to conduct
`bioequivalence testing is included in this NDA.
`
`ONDQA—Biopharmaceuties review stated (DARRTS Communication date: 5/13/14) that the Applicant
`provided appropriate information/data justifying that the higher osmolality range of their product (when
`compared to that of the listed product), will not have an impact on the clinical safety profile of their
`proposed bendamustine HCI product. Also it was stated that the absence of mannitol and inclusion of
`monothioglycerol, propylene glycol, and PEG 400 in the proposed formulation does not affect the
`distribution and/or elimination of bendamustine HCI (when compared to those of the listed product) and
`that the Applicant's response included evidence from literature supporting the safety of the intravenous
`infusions of bendamustine HCI solutions containing the proposed concentrations of monothioglycerol,
`propylene glycol, and PEG 400. 0NDQA—Biopharmaceutirs recommended approval and granted a
`Biowaiver.
`
`This submission contains no new clinical pharmacology information for review. NDA 205580 is
`recommended for approval from the standpoint of clinical pharmacology.
`
`Reference ID: 351 5092
`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/
`----------------------------------------------------
`
`YOUNG J MOON
`05/29/2014
`
`JULIE M BULLOCK
`05/29/2014
`
`Reference ID: 3515092
`Reference ID: 4266336
`
`

`

`Application No.:
`Submission Date:
`
`BIOPHARMACEUTICS REVIEW
`Office of New Drug Quality Assessment
`NDA 205580
`September 6, 2013
`
`Reviewer: Elsbeth Chikhale, PhD
`Team Leader:
`Angelica Dorantes, PhD
`
`Acting Supervisor:
`Richard Lostritto, PhD
`
`Date
`Assigned: September 6, 2013
`Date of
`May13, 2014
`Review:
`Type of Submission: Resubmission
`of original New Drug Application –
`505(b)(2)
`
`Division:
`
`Division of Hematology Products
`
`Applicant:
`
`Eagle Pharmaceuticals, Inc.
`
`Trade Name:
`
`TBD
`
`Established Name: Bendamustine HCl concentrate for
`Injection
`For the treatment of patients with:
`Indication:
`• 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 regimen.
`Concentrated solution for IV
`infusion/
`25 mg/mL
`IV infusion
`Biowaiver Request
`
`Route of
`Administration
`Type of Review:
`
`Dosage form/
`strengths
`
`SUBMISSION:
`
`The Applicant is seeking approval of a New Drug Application (NDA) for Bendamustine HCl
`concentrate for Injection under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act.
`This 505(b)(2) application relies on the FDA’s previous findings of safety and efficacy for the
`listed drug, Treanda® for Injection (bendamustine hydrochloride for injection) marketed by
`Cephalon (a subsidiary of Teva Pharmaceutical) under the approved NDA 22249 and NDA
`22303. The proposed formulation is a ready-to-dilute solution, and will not require
`reconstitution as is the case for the listed drug, Treanda®, which is a lyophilized powder. The
`proposed product is a self-preserving, multiple-use drug containing vial.
`
`BIOPHARMACEUTICS INFORMATION:
`
`The proposed bendamustine HCl Injection has a different presentation from the listed
`Treanda® product and was designed as a concentrated liquid to eliminate the reconstitution
`
`1
`
`Reference ID: 3506088
`Reference ID: 4266336
`
`

`

`step during preparation of the product for administration. The proposed product is intended for
`the same indications and has the same active ingredient, final admixture bendamustine HCl
`concentration, dose, dosing regimen, and route of administration as the reference drug. The
`differences and similarities of the two products are summarized as follows:
`
`Comparison of the Formulations for the Listed and Proposed Drug Products
`Listed Product
`Proposed Product
`Treanda (bendamustine HCl) for Injection
`Bendamustine HCl Injection,
`25 mg/mL (100 mg/4 mL)
`(100 mg vial)
`Lyophilized powder
`Sterile
`Solution
`
`Ingredients
`
`Amount per vial
`
`Ingredient
`
`Amount per vial
`
`Product
`
`Dosage Form
`
`Composition
`
`Bendamustine HCl
`
`Mannitol, USP
`
`100 mg
`
`170 mg
`
`Bendamustine HCl
`
`Monothioglycerol, NF
`
`Propylene Glycol, USP
`Polyethylene Glycol 400
`(PEG 400), NF*
`
`100 mg
`
`20 mg
`
`0.4 mL
`
`QS to 4 mL
`
`Product
`
`Reconstitution
`
`Comparison of the preparation, stability and final solution for infusion
`Listed Product
`Proposed Product
`Treanda (bendamustine HCl) for
`Bendamustine HCl Injection,
`Injection (100 mg vial)
`25 mg/mL (100 mg/4 mL)
`Reconstituted in 20 mL sterile water for
`No reconstitution is needed (A ready
`injection to yield a solution of 5 mg/mL
`to dilute solution of 25 mg/mL)
`A partially used vial is proposed to be
`The reconstituted solution must be
`stable for up to 28 days when stored in
`transferred to the infusion bag within 30
`its original carton at refrigeration (2-8°C
`minutes of reconstitution.
`or 36-46°F).
`
`
`Withdraw require dose and dilute into
`500 mL bag of 0.9% Sodium Chloride
`Injection, USP or 0.45% Sodium
`Chloride/2.5% Dextrose Injection, USP.
`Proposed to be stable for 24 hours when
`stored refrigerated (2-8°C or 36-47°F)
`or for 3 hours when stored at room
`temperature (15-30°C or 59-86°F) and
`room light.
`
`Storage Condition before
`dilution
`
`Further Dilution prior to
`Infusion
`
`Storage Condition after
`dilution
`
`Withdraw require dose and dilute into
`500 mL bag of 0.9% Sodium Chloride
`Injection, USP or 0.45% Sodium
`Chloride/2.5% Dextrose Injection, USP.
`Stable for 24 hours when stored
`refrigerated (2-8°C or 36-47°F) or for
`hours when stored at room temperature
`(15-30°C or 59-86°F) and room light
`(per approved label).
`
`0.2 mg/mL
`
`0.6 mg/mL
`
`0.2 mg/mL
`
`mg/mL
`
`Final
`Solution
`for
`Infusion*
`
`Admixture
`Concentration
`Covering Dose
`Range
`
`pH
`
`Osmolarity
`(mOsm/kg)
`
`Reference ID: 3506088
`Reference ID: 4266336
`
`2
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Despite the formulation differences with regards to the inactive ingredients between the listed
`drug, Treanda for Injection and the proposed product, the Applicant claims that both products
`as administered to the patient (i.e. final admixture) are similar in terms of the physicochemical
`properties, pH and osmolality.
`
`The difference in inactive ingredients in terms of concentration, for a maximum dose of
`324 mg (based upon a 2.7 m2 patient) is shown in the following table:
`
`Listed Product
`Treanda for Injection
`(after Reconstitution, 5 mg/mL)
`
`Formulation Volume to deliver
`324 mg bendamustine HCl: 65 mL
`
`Proposed Product
`Eagle Bendamustine HCl
`(concentrate 25 mg/mL)
`
`Formulation Volume to deliver
`324 mg bendamustine HCl: 13 mL
`
`Final Admixture Volume: 565 mL
`
`Final Admixture Volume: 513 mL
`
`Ingredients
`
`Bendamustine
`HCl
`
`Mannitol, USP
`
`Concentration in 500 mL
`admixture
`
`0.6 mg/mL
`
`1.0 mg/mL
`
`Ingredient
`
`Bendamustine HCl
`
`Monothioglycerol,
`NF
`Propylene Glycol,
`USP
`Polyethylene Glycol
`400 (PEG 400), NF
`
`Concentration in 500 mL
`admixture
`mg/mL
`
`0.13 mg/mL
`
`0.0025 mL/mL
`
`0.023 mL/mL
`
`BIOWAIVER REQUEST:
`
`The NDA includes a request for a waiver of the CFR requirement to submit data from an in vivo
`bioequivalence study, based on the similarity between the proposed product and the listed
`product.
`
`Based on 21 CFR 320.22(b)(1) such a waiver can be granted if the drug product:
`i)
`Is a parenteral solution intended solely for administration by injection, and
`ii) Contains the same active and inactive ingredients in the same concentration as a drug
`product that is the subject of an approved full new drug application or abbreviated new drug
`application.
`
`In further support of the Biowaiver, the solubility of bendamustine HCl was determined in
`normal saline (0.9% NaCl). For the bendamustine HCl salt, normal saline was chosen since it
`is a poor solvent relative to 0.45% saline/2.5% dextrose due to the potential for a common ion
`(Cl-) effect. The solubility of bendamustine at 25°C was determined to be 3.97 mg/mL. The
`solubility increases further due to the addition of propylene glycol in the proposed admixture
`(> 4 mg/mL). These results show that the proposed drug product admixture (up to and
`including the maximum dose) is a true solution of bendamustine HCl (no precipitation).
`
`Reference ID: 3506088
`Reference ID: 4266336
`
`3
`
`(b) (4)
`
`

`

`ASSESSNIENT OF THE BIOWAIVER REQUEST:
`
`According to CFR 320.22(b), for certain drug products the in vivo bioavailability (BA) or
`bioequivalence (BE) of the drug product may be self-evident and FDA can waive the
`requirement for the submission of in vivo BA or BE data of these drug products. A drug
`product's in vivo bioavailability or bioequivalence may be considered self—evident if the drug
`product meets the following:
`
`Is a parenteral solution intended solely for administration by injection, and
`Contains the same active and inactive ingredients in the same concentration as a drug product
`that is the subject of an approved full new drug application or abbreviated new drug
`application.
`
`The proposed bendamustine HCl for injection product, when diluted, contains the same
`concentration of active ingredient but different inactive ingredients compared to the diluted
`listed product, Treanda.
`In support of the Biowaiver request, the pH and osmolality
`comparison data were provided. These data showed very similar pH values for the diluted
`solutions of the proposed and the listed drug products; but with respect to osmolarity, the data
`showed a lower osmolality range
`W" mOsm/kg) for the diluted listed product when
`compared to the proposed diluted product
`(m4) mOsm/kg). With regards to the diluted
`drug product stability, both the listed and the proposed diluted drug products appear to be
`unstable and show degradation of the active ingredient, bendamustine HCl. This degradation
`occurs regardless of the difference in the inactive ingredients.
`
`Since a justification/information was needed to support that; 1) the observed difference in the
`osmolality range of the proposed drug product when compared to that of the listed product did
`not have any clinical impact, and 2) the differences in the inactive ingredients (i.e., absence of
`mannitol and inclusion of monothioglycerol, propylene glycol, and PEG 400 in the proposed
`formulation) did not affect the distribution and/0r elimination of bendamustine HCl, the
`following Information Request was conveyed to the Applicant in the NDA’s filing letter
`dated 9/16/13:
`
`
`
`1. Provide a justification for the difference in osmolality between your proposed diluted drug
`product and the reference diluted drug product. Include information demonstrating that
`the observed difference in osmolality does NOT affect the safety profile of your
`bendamustine HCl product.
`
`. Provide information indicating whether the absence of mannitol and inclusion of
`monothioglycerol, propylene glycol, and PEG 400 in your proposed formulation affect or
`NOT the distribution and/or elimination of bendamustine HCl (when compared to those of
`the RLD product). Also, submit evidence from literature supporting the safety of the
`intravenous infusions of bendamustine HCl solutions containing the proposed
`concentrations of monothioglycerol, propylene glycol, and PEG 400.
`
`On 10/15/13, the Applicant addressed the IR comments and submitted the following
`information:
`
`Reference ID: 3506088
`Reference ID: 4266336
`
`

`

`l. The osmolality values reported in the admixture study are summarized here:
`
`Comparison of Treanda 100 mg Vial and Eagle’s Bendamustine HCl Injection, 25 mg/mL
`(100 mg/4 mL) Admixtures:
`
`2.5% Dextrose“
`2.5% Dextrose“
`Adlnixture Vehicle
`0
`‘
`0
`
`0.9 oNaCI 0.45°o.\TaCl 0.45°o.\TaCl 0.9 oNaCl
`
`
`BDM HCI
`(h) (4)
`Concentration
`
`0.2
`
`0.2
`
`
`
`m_z“lnL
`Measured
`
`Osmolality
`(m05mx’k_ )‘
`Volume of
`admixture after
`
`addition of drug
`product (mL)"
`
`BDM HCI
`)Iannitol
`.\lonothio~ Ivcerol
`
`PEG 400
`
`Estimated Molalitx‘ (molesv'kg
`
`' n=2 per set of vehicle/concentration combinations
`bAssumes ideal mixing and volumes are additive
`
`As a point of reference, the osmolality of normal saline is approximately 300
`mOSmol/kg. The osmolality of sermn (human) normally ranges from 287 to 300
`mOsmol/kg. The proposed admixture drug product’s osmolality is hypertonic and always
`higher than that of Treanda which is consistently hypotonic.
`
`The potential of formulation changes (including osmolality) to impact the safety profile
`was addressed in preclinical studies. The hemolytic properties of Eagle Bendamustine
`HCl Concentration for Injection 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.
`
`These concentrations exceed the approved clinical administration concentration of
`Treanda (admixture: up to {'3 mg/mL). There was no evidence of venous irritation after
`intravenous administration of Bendamustine HCl Injection at concentrations up to 5.6
`mg/mL (for a total dose of 5 mg/kg). Perivenous administration of Bendamustine HCl
`Injection (diluted in saline) at 3.2 to 5.6 mg/mL resulted in observations of local irritation
`(with evidence of reversibility). The severity of the irritation observed was more notable
`than that seen with Treanda. This observation is consistent with a dose and/or
`
`concentration relationship for the perivascular tolerance of bendamustine HCl as
`illustrated b an increase in erivascular irritation 0 otential seen with hi :er doses/
`
`Reference ID: 3506088
`Reference ID: 4266336
`
`

`

`concentrations of bendamustine HCl administered in pilot studies, and is unlikely due to
`the osmolarity of treatments as administered. Finally, the range of osmolality values
`noted for the final admixtures of Eagle’s bendamustine HCL injection product (
`mOsm/kg) are well within the range observed for commonly administered IV products,
`and are also within the range for which the risk of injection/infusion related complication
`(such as phlebitis) would be considered low. Gazitua et.al., classified three risk levels for
`phlebitis caused by infusate osmolarity, in which the lowest risk was observed for
`solutions less than 450 mOsm/L. The Infusion Nursing Society (INS) recormnends an
`upper limit of 500 mOsm/L for peripheral vein tolerance (with higher values permissible
`when administration is into fast-flowing major vessels).
`
`0» (4)
`
`Pharmacokinetic Parameters of Bendamustine in Cynomolgus Monkeys after 3
`1 IV Bendamustine H drochloride:
`Formulation m4)
`Parameter
`TREANDA
`
`
`(‘0. rig/1111.
`8664 i 3841
`10716 i 2033
`Cm 1122/1111.
`6037 i 2456
`7380 i 1170
`
`2314 i 800
`
`
`CL. L’llr/kg
`[.27 d: 0.40
`0.96 i 0.14
`V2. L/kg
`[.04 i 0.36
`0.74 :t 0.05
`V5,. L/k2
`0.34 :1: 0.11
`0.26 i 0.05
`
`. Recently, a new version of Treanda (bendamustine HCl) Injection, a liquid formulation
`(as a nonaqueous solution) for intravenous infusion (afier dilution in saline or dextrose
`saline), was approved for marketing in the US. This new liquid formulation contains 90
`mg/mL of bendamustine HCl, 324 mg/mL propylene glycol and 586 mg/mL N,N,
`dimethylacetamide (DMA). Mannitol, which is in the lyophilized Treanda formulation,
`has been eliminated in the new version. The pharmacokinetic profile relating to
`distribution and elimination for bendamustine remains the same between the two products.
`Nonclinical evidence also suggests that the absence of mannitol and presence of propylene
`glycol does not impact the distribution and/or elimination of bendamustine:
`
`
`
`NIRTO—m. 111‘
`
`0.26 i 0.02
`
`0.27 i 0.02
`
`Based upon the reported information, the elimination of mannitol and the addition of
`propylene glycol did not cause a change in the reported distribution nor elimination of
`bendamustine or its metabolites. The amount of propylene glycol administered at the
`maximum bendamustine HCl dose at a concentration of 0.7 mg/mL from Treanda
`(bendamustine HCl) Injection is 1166 mg. This value is comparable to the maximum
`amount of propylene glycol to be administered via the Eagle product, 1238 mgs.
`Therefore, a change in distribution or elimination of bendamustine would not be expected
`from such a small difference in the amount of propylene glycol (as no change was evident
`'
`inclusion of PG in the Treanda 1i uid roduct .
`
`Reference ID: 3506088
`Reference ID: 4266336
`
`

`

`PEG 400 has been reported to affect renal elimination of drugs at intravenous doses of
`1000 to 2000 mg/kg. The dose of PEG 400 from the Eagle product (in a 120 mg/m2
`bendamustine HCl dose) is well below these values, ~173 mg/kg for a 70 kg patient. As
`noted in the Treanda package insert, there was no “meaningful” effect of renal impairment
`on the pharmacokinetics of a high dose of bendamustine HCl (120 mg/m2). Further,
`Dubbelmen and coworkers found that renal clearance of bendamustine ranged from 6.6 to
`29.9 mL/min and renal excretion was minor (3% of dose), concluding that accumulation
`was not likely in cancer patients with renal impairment due to dose administration
`schedule and short half-life of bendamustine. This would suggest that even if PEG 400
`negatively impacted renal elimination of drugs at 173 mg/kg, bendamustine elimination
`would not be affected. Furthermore, Johnson and coworkers studied the effects of PEG
`400 on P-glycoprotein mediated efflux of digoxin and the cytochrome P450 (CYP3A)
`mediated metabolism of verapamil. The results of that work indicated that although PEG
`400 does affect these enzyme systems it lacks the potency of typical enzyme inhibitors.
`Egger-Heigold examined the potential of PEG 200 to modify the blood distribution and
`protein binding of model compounds in vitro. PEG 200 did not modulate the blood
`distribution or protein binding of the compounds studied. Based upon the available
`information, PEG 400 impact on bendamustine metabolism, distribution or elimination
`would not be expected. A literature search on the effects of monothioglycerol on the
`pharmacokinetics of drugs, specifically disposition and elimination, has been performed.
`Relevant references were not found. Monothioglycerol is a commonly used antioxidant in
`parenteral products. Monothioglycerol as with the other excipients in the Eagle product,
`PG and PEG 400, are listed in the FDA CDER database on Inactive Ingredients (IIG) for
`Approved Drug Products for parenteral administration.
`
`Reviewer’s Assessment of Applicant’s Responses: SATISFACTORY
`
`1. The Applicant provided appropriate information/data justifying that the higher osmolality
`range of their product (when compared to that of the listed product), will not have an
`impact on the clinical safety profile of their proposed bendamustine HCl product. The
`Medical Reviewer, Dr. Adam George, has indicated that he agrees with this
`conclusion.(see his review in DARRTS dated 5/13/14).
`
`2. The provided information adequately supports the Applicant’s response stating that the
`absence of mannitol and inclusion of monothioglycerol, propylene glycol, and PEG 400 in
`the proposed formulation does not affect the distribution and/or elimination of
`bendamustine HCl (when compared to those of the listed product). Also, the response
`included evidence from literature supporting the safety of the intravenous infusions of
`bendamustine HCl solutions containing the proposed concentrations of monothioglycerol,
`propylene glycol, and PEG 400.
`
`Reference ID: 3506088
`Reference ID: 4266336
`
`7
`
`

`

`RECOMMENDATION:
`
`ONDQA-Biopharmaceutics had reviewed the overall information/data supporting the approval
`of the Biowaiver request and considers that the provided information is adequate and
`acceptable.
`
`A waiver from the CFR’s requirement to provide data from an in vivo bioequivalence study for
`the IV route of administration is granted. From the Biopharmaceutics perspective, NDA
`205580 for Bendamustine HCl for Injection (25 mg/mL) is recommended for APPROVAL.
`
`Signature Signature
`Elsbeth Chikhale, Ph.D. Angelica Dorantes, Ph.D.
`Biopharmaceutics Reviewer Biopharmaceutics Team Leader
`Office of New Drug Quality Assessment Office of New Drug Quality Assessment
`
`Reference ID: 3506088
`Reference ID: 4266336
`
`8
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ELSBETH G CHIKHALE
`05/13/2014
`
`ANGELICA DORANTES
`05/13/2014
`
`Reference ID: 3506088
`Reference ID: 4266336
`
`