CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 022249/S-19
`
`TREANDA
`
`Cephalon, Inc.
`
`03/10/2015
`
`
`Trade Name:
`
`Bendamustine Hydrchloride
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
` TREANDA is an alkylating drug indicated 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 regimen.
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 022249/S-19
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
`
`X
`
`
`
`
`
`
`
`
`
`
`
`
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 022249/S-19
`NDA 022249/8-19
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
` NDA 022249/S-019
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`
` Silver Spring MD 20993
`
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
`
`
` Cephalon, Inc. (a wholly owned subsidiary of Teva Pharmaceuticals, Ltd.)
`
`
` Attention: Michael J. McGraw, PharmD, MS
`
` Director, Regulatory Affairs
`
` 41 Moores Road
`
` P.O. Box 4011
` Frazer, PA 19355
`
`
`
`
`Dear Dr. McGraw:
`
`
`
`
`
`
`Please refer to your Supplemental New Drug Application (sNDA) dated March 6, 2015, received
`
`
`
`March 6, 2015, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
` (FDCA) for TREANDA® (bendamustine hydrochloride) Injection (solution) 45mg/0.5mL or
`
`
`
`
`
` 180mg/2mL, and TREANDA® (bendamustine hydrochloride) for Injection (lyophilized powder),
`
`
`
`
`
`
` 25 mg/vial or 100mg/vial.
`
`
`
`
` We acknowledge receipt of your submissions related to this NDA dated February 26, March 2, 3,
` 4, and 6, 2015. We also acknowledge receipt of your amendments to this supplement on March
`
`
`
`
`
`
`
` 9 and 10, 2015.
`
`
`
`
` This “Changes Being Effected” supplemental new drug application provides for updates to the
` Unites States Prescribing Information (USPI) to include both formulations, Treanda Injection
`
`
`
` (Solution) and Treanda for Injection (lyophilized powder). In addition, the label provides for
`
`
`additional information on the use of Treanda liquid formulation and incompatibilities with
`
` Closed System Transfer Devices (CSTD) that contains polycarbonate or acrylonitrile-butadiene­
`
` styrene (ABS).
`
`We also have the following comments regarding this sNDA approval:
`
`
`
`1. Submit quarterly reports until March 2017 of complaints about preparation and use of
`
`
`
`Treanda injection (solution) and Treanda for injection (lyophilized powder).
`
`
`
`2. We remind you of your commitment to continue conducting device compatibility studies
`
`
`
`with Treanda injection (solution) to ensure safe preparation and use of Treanda injection
`(solution).
`
`
`
`
`
`
`Reference ID: 3713848
`
`

`

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`
` NDA 022249/S-019
`
` Page 2
`
`
`
` APPROVAL & LABELING
`
` We have completed our review of this supplemental application, as amended. It is approved,
`
`
` effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`
` text.
`
`
`CONTENT OF LABELING
`
` As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`
`
`
`
`
`
` labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
` automated drug registration and listing system (eLIST), as described at
`
` http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`
`of labeling must be identical to the enclosed labeling (text for the package insert), with the
`
`addition of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as
`
`
`well as annual reportable changes not included in the enclosed labeling.
`
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled
`
`
`
`“SPL Standard for Content of Labeling Technical Qs and As at
`
`
`
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`
`CM072392.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`
`
`Also within 14 days, amend all pending supplemental applications that includes labeling changes
`
`
`
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`
`
`
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`
`
`
`
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`
`should provide appropriate annotations, including supplement number(s) and annual report
`
`
`date(s).
`
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`
` Until carton labeling and vial changes are implemented, as an interim measure for the Treanda
`
`
`
`liquid product that has already been distributed to pharmacies, hospitals, etc., you need to
`provide stickers/labels that can adhere to the carton labeling with the Treanda liquid product.
`
`FDA recommends the following statement on the sticker: “Not for use with devices that
`
`
`
` accompanied with the Dear Healthcare Provider (DHCP) letter. Furthermore, the same sticker
`
`
`
`
`
`
` should be attached to carton and any other appropriate labeling of already existing and ready for
` shipment product supply at the manufacturers and distributors sites.
`
`
`
`
`
`contain polycarbonate or acrylonitrile‐butadiene‐styrene (ABS)”. The sticker should be
`
`
`
`
`Reference ID: 3713848
`
`

`

`
`
` NDA 022249/S-019
`
` Page 3
`
`
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`
`
`
` Carton Labeling
`
` 1. In the proposed statement “Do not use with devices that contain polycarbonate or
`
`
`
`acrylonitrile butadiene-styrene (ABS)” increase the prominence of negation “NOT,”
`by using all capital letters or bolding as negative sentences containing NOT can be
`
`misinterpreted as the opposite since NOT can be overlooked”.
`
`2. Increase the prominence of the storage information on the side panel by bolding the
`
`
`
`entire statement “Store refrigerated at….” As storage for Treanda Injection differs
`
`
`
`from the storage of Treanda for Injection and this information should be easily
`
`
`identified by healthcare providers.
`
`
`
`
`
` Vial Container
`
`1. We recommend addition of a flag to the actual vial containing a statement “Do not
`
`
`
`
`
`
`use with devices that contain polycarbonate or acrylonitrile butadiene-styrene (ABS)”
`
`on the container. Increase the prominence of negation “NOT,” by using all capital
`
`letters or bolding as negative sentences containing NOT can be misinterpreted as the
`
`
`
`opposite since NOT can be overlooked.
`
`
`Submit final printed carton and immediate container labels that are identical to the submitted
`
`carton and immediate container labels dated March 6, 2015, except with the revisions listed
`
`
`
`above, as soon as they are available, but no more than 7 days after they are printed. Please
`
`submit these labels electronically according to the guidance for industry Providing Regulatory
`
`
`
`Submissions in Electronic Format – Human Pharmaceutical Product Applications and Related
`
`Submissions Using the eCTD Specifications (June 2008). Alternatively, you may submit 12
`
`paper copies, with 6 of the copies individually mounted on heavy-weight paper or similar
`
`material. For administrative purposes, designate this submission “Final Printed Carton and
`Container Labels for approved NDA 022249/S-019.” Approval of this submission by FDA is
`
`
`
`not required before the labeling is used.
`
`
`Marketing the product with FPL that is not identical to the approved labeling text may render the
`
`product misbranded and an unapproved new drug.
`
`
`PROPRIETARY NAME
`
`
`To prevent medication errors related to confusion between the two formulations of bendamustine
`
`hydrochloride due to different products’ concentrations, we recommend you consider one of the
`
`following options regarding proprietary name:
`
`
`1. Propose a modifier to be added to the proprietary name Treanda for the injection
`
`
`
`
`dosage form to help differentiate the product from the lyophilized powder
`
`
`formulation and submit to the Agency for evaluation. We continue to recommend
`
`
`
`
`Reference ID: 3713848
`
`

`

`
`
` NDA 022249/S-019
`
` Page 4
`
`
`
`
`
` against the
`
`
` as stated in proprietary name request unacceptable
`letter sent to you on June 13, 2013 (see attached).
`
`
`2. Alternatively, you can propose a dual proprietary name for the injection dosage form.
`
`
`However, if choosing this option, consider retaining a portion of the original Treanda
`name in the new name (e.g. TreanXXXX) so health care practitioners recognize that
`
`
`this product is associated with, (or an extension of) Treanda.
`
`
`
`Please submit a request for review of your proposed proprietary name. The content requirements
`
`
`for such a submission can be found in the draft Guidance for Industry entitled, Contents of a
`
`Complete Submission for the Evaluation of Proprietary Names
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/.
`UCM075068.pdf). Further information about how FDA evaluates propriety names for drug
`
`products is available in the following guidance, Best Practices in Developing Proprietary Names
`
`
`
`for Drugs
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM398997.pdf.
`
`
`If you intend to have a proprietary name for this product, the name and its use in the labels must
`
`
`
`conform to the specifications under 21 CFR 201.10 and 201.15. We recommend that you submit
`
`
`a request for a proposed proprietary name review. (See the guidance for industry titled,
`
`
`“Contents of a Complete Submission for the Evaluation of Proprietary Names”, at
`
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/u
`cm075068.pdf and “PDUFA Reauthorization Performance Goals and Procedures Fiscal Years
`
`
`
`2008 through 2012”.)
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`
`
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`
`
`
`administration are required to contain an assessment of the safety and effectiveness of the
`
`
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`
`
`
`deferred, or inapplicable.
`
`Because none of these criteria apply to your application, you are exempt from this requirement.
`
`
`PROMOTIONAL MATERIALS
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`
`
`
`
`
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`
`
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`
`(3) the package insert(s) to:
`
`
`Reference ID: 3713848
`
`(b) (4)
`
`

`

`
`
` NDA 022249/S-019
`
` Page 5
`
`
`
`
` Food and Drug Administration
`
` Center for Drug Evaluation and Research
`
` Office of Prescription Drug Promotion (OPDP)
`
`
` 5901-B Ammendale Road
` Beltsville, MD 20705-1266
`
`
`
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`
`
`
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`
`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`
`
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`
`more information about submission of promotional materials to the Office of Prescription Drug
`
`
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`
`
`
`(21 CFR 314.80 and 314.81).
`
`
`
`If you have any questions, please call Kimberly Scott, Regulatory Project Manager, at
`
`
`
`
`
`
`(240) 402-4560.
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`Ann T. Farrell, MD
`
`Director
`
`Division of Hematology Products
`
`
`Office of Hematology and Oncology Products
`
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURES:
`
`Content of Labeling
`
`
`Carton and Container Labeling
`
`
`
`
`Reference ID: 3713848
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ANN T FARRELL
`03/10/2015
`
`Reference ID: 3713848
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 022249/S-19
`NDA 022249/8-19
`
`APPLICA TION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`TREANDA safely and effectively. See full prescribing information for
`TREANDA.
`
`TREANDA® (bendamustine hydrochloride) injection, for intravenous use
`TREANDA® (bendamustine hydrochloride) for injection, for intravenous
`use
`Initial U.S. Approval: 2008
`
`------------------------RECENT MAJOR CHANGES------------------------
`Dosage and Administration (2)
`03/2015
`Selection of TREANDA Formulation to Administer (2.1)
` 03/2015
`Preparation for Intravenous Administration (2.4)
` 03/2015
`Admixture Stability (2.5)
` 03/2015
`
`-------------------INDICATIONS AND USAGE------------------------------
`TREANDA is an alkylating drug indicated for treatment of patients with:
`• Chronic lymphocytic leukemia (CLL). Efficacy relative to first line
`therapies other than chlorambucil has not been established. (1.1)
`• Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during
`or within six months of treatment with rituximab or a rituximab-containing
`regimen. (1.2)
`
`--------------------DOSAGE AND ADMINISTRATION-----------------------
`TREANDA is available in two formulations, a solution (TREANDA
`Injection) and a lyophilized powder (TREANDA for Injection). (2.1)
`Do not use TREANDA injection with devices that contain polycarbonate
`or acrylonitrile-butadiene-styrene (ABS), including most Closed System
`Transfer Devices (CSTDs). (2 1, 2.4)
`For CLL:
`• 100 mg/m2 infused intravenously over 30 minutes on Days 1 and 2 of a 28-
`day cycle, up to 6 cycles (2.2)
`• Dose modifications for hematologic toxicity: for Grade 3 or greater
`toxicity, reduce dose to 50 mg/m2 on Days 1 and 2; if Grade 3 or greater
`toxicity recurs, reduce dose to 25 mg/m2 on Days 1 and 2. (2.2)
`• Dose modifications for non-hematologic toxicity: for clinically significant
`Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of
`each cycle. (2.2)
`• Dose re-escalation may be considered. (2.2)
` For NHL:
`• 120 mg/m2 infused intravenously over 60 minutes on Days 1 and 2 of a 21-
`day cycle, up to 8 cycles (2.3)
`• Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce
`the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity
`recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. (2.3)
`• Dose modifications for non-hematologic toxicity: for Grade 3 or greater
`toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if
`Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1
`and 2 of each cycle. (2.3)
`General Dosing Considerations:
`• Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥
`Grade 2 non-hematologic toxicity. (2.2, 2.3)
`
`
`
`
`---------------------DOSAGE FORMS AND STRENGTHS--------------------
`Injection: solution-45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial. (3)
`For Injection: 25 mg or 100 mg lyophilized powder in a single-dose vial for
`reconstitution. (3)
`
`
`------------------CONTRAINDICATIONS------------------
`TREANDA is contraindicated in patients with a history of a hypersensitivity
`reaction to bendamustine. Reactions have included anaphylaxis and
`anaphylactoid reactions. (5 3)
`
`
`----------------WARNINGS AND PRECAUTIONS------------
`• Myelosuppression: Delay or reduce dose. Restart treatment based on ANC
`and platelet count recovery. (2.2) Complications of myelosuppression may
`lead to death. (5.1)
`• Infections: Monitor for fever and other signs of infection and treat
`promptly. (5.2)
`• Anaphylaxis and Infusion Reactions: Severe and anaphylactic reactions
`have occurred; monitor clinically and discontinue TREANDA. Pre-
`medicate in subsequent cycles for milder reactions. (5.3)
`• Tumor Lysis Syndrome: Acute renal failure and death; anticipate and use
`supportive measures. (5.4)
`• Skin Reactions: Discontinue for severe skin reactions. Cases of SJS and
`TEN, some fatal, have been reported when TREANDA was administered
`concomitantly with allopurinol and other medications known to cause these
`syndromes. (5.5)
`• Other Malignancies: Pre-malignant and malignant diseases have been
`reported. (5.6)
`• Extravasation: Assure good venous access and monitor infusion site during
`and after administration. (5.7)
`• Embryo-fetal toxicity: Fetal harm can occur when administered to a
`pregnant woman. Women should be advised to avoid becoming pregnant
`when receiving TREANDA. (5.8, 8.1)
`
`
`-------------------ADVERSE REACTIONS--------------------
`• Most common non-hematologic adverse reactions for CLL (frequency
`≥15%) are pyrexia, nausea, and vomiting. (6.1)
`• Most common non-hematologic adverse reactions for NHL (frequency
`≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation,
`anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis.
`(6.2)
`• Most common hematologic abnormalities for both indications (frequency
`≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and
`neutropenia. (6.1, 6 2)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Teva
`Pharmaceuticals at 1-800-896-5855 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`
`------------------------DRUG INTERACTIONS----------------------
`Concomitant CYP1A2 inducers or inhibitors have the potential to affect the
`exposure of bendamustine. (7)
`
`---------------USE IN SPECIFIC POPULATIONS-------------------
`• Renal impairment: Do not use if CrCL is <40 mL/min. Use with caution in
`lesser degrees of renal impairment. (8.6)
`• Hepatic impairment: Do not use in moderate or severe hepatic impairment.
`Use with caution in mild hepatic impairment. (8.7)
`
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`Revised: 03/2015
`
`
`
`
`
`

`

`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`1.1 Chronic Lymphocytic Leukemia (CLL)
`1.2 Non-Hodgkin Lymphoma (NHL)
`2 DOSAGE AND ADMINISTRATION
`2.1 Selection of TREANDA Formulation to Administer
`2.2 Dosing Instructions for CLL
`2.3 Dosing Instructions for NHL
`2.4 Preparation for Intravenous Administration
`2.5 Admixture Stability
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Myelosuppression
`5.2 Infections
`5.3 Anaphylaxis and Infusion Reactions
`5.4 Tumor Lysis Syndrome
`5.5 Skin Reactions
`5.6 Other Malignancies
`5.7 Extravasation Injury
`5.8 Embryo-fetal Toxicity
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience in CLL
`6.2 Clinical Trials Experience in NHL
`6.3 Postmarketing Experience
`
`
`*Sections or subsections omitted from the full prescribing information are not listed
`
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`8.8 Effect of Gender
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Chronic Lymphocytic Leukemia (CLL)
`14.2 Non-Hodgkin Lymphoma (NHL)
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 Safe Handling and Disposal
`16.2 How Supplied
`16.3 Storage
`17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`

`

`
`
` 1
`
`
`
`FULL PRESCRIBING INFORMATION
`
` INDICATIONS AND USAGE
`1.1 Chronic Lymphocytic Leukemia (CLL)
`TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line
`therapies other than chlorambucil has not been established.
`
`1.2 Non-Hodgkin Lymphoma (NHL)
`TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed
`during or within six months of treatment with rituximab or a rituximab-containing regimen.
`
` 2
`
` DOSAGE AND ADMINISTRATION
`
`
`2.1 Selection of TREANDA Formulation to Administer
`TREANDA is available in two formulations, a solution (TREANDA Injection) and a lyophilized powder (TREANDA for
`Injection).
`
`Do not use TREANDA Injection with devices containing polycarbonate or acrylonitrile-butadiene-styrene (ABS)
`including closed system transfer devices (CSTDs), adapters, and syringes.
`
`Only use a polypropylene syringe with a metal needle and polypropylene hub to withdraw and transfer TREANDA
`Injection. Polypropylene syringes are translucent in appearance.
`
`
`TREANDA Injection and the reconstituted TREANDA for Injection have different concentrations of bendamustine
`hydrochloride. The concentration of bendamustine hydrochloride in the solution is 90 mg/mL and the concentration of
`bendamustine hydrochloride in the reconstituted solution of lyophilized powder is 5 mg/mL. Do not mix or combine the
`two formulations.
`
`TREANDA Injection must be withdrawn and transferred for dilution in a biosafety cabinet (BSC) or containment isolator
`using a polypropylene syringe with a metal needle and a polypropylene hub.
`
`If a closed system transfer device or adaptor is used as supplemental protection during preparation1, only use TREANDA
`for Injection, the lyophilized powder formulation.
`
`
` 2.2 Dosing Instructions for CLL
`Recommended Dosage:
`The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up
`to 6 cycles.
`
`Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL :
`TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥
`Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts
`have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at
`the discretion of the treating physician. In addition, dose reduction may be warranted. [see Warnings and Precautions
`(5.1)]
`
`
`
`
`
`

`

`
`
`Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2
`of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle.
`Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to
`50 mg/m2 on Days 1 and 2 of each cycle.
`Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician.
`
`2.3 Dosing Instructions for NHL
`Recommended Dosage:
`The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up
`to 8 cycles.
`Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL:
`TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥
`Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts
`have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at
`the discretion of the treating physician. In addition, dose reduction may be warranted. [see Warnings and Precautions
`(5.1)]
`Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each
`cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.
`Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1
`and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.
`
`2.4 Preparation for Intravenous Administration
`TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution)
`TREANDA Injection must be diluted in a biosafety cabinet (BSC) or containment isolator.
`• Do not use with devices that contain polycarbonate or acrylonitrile-butadiene-styrene (ABS), including most
`Closed System Transfer Devices (CSTDs). TREANDA Injection contains N,N-dimethylacetamide (DMA), which is
`incompatible with devices that contain polycarbonate or ABS. Devices, including CSTDs, adaptors, and syringes that
`contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA which is present in
`the product. This incompatibility leads to device failure (e.g., leaking, breaking, or operational failure of CSTD
`components), possible product contamination, and potential serious adverse health consequences to the practitioner,
`including skin reactions; or to the patient, including but not limited to, the risk of small blood vessel blockage if they
`receive product contaminated with dissolved ABS or polycarbonate.
`
` •
`
` Only use a polypropylene syringe with a metal needle and a polypropylene hub to withdraw and transfer
`TREANDA Injection.
`
` Each vial of TREANDA Injection is intended for single dose only.
`
` •
`
` •
`
` Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution using a polypropylene
`syringe with a metal needle and a polypropylene hub.
`
` •
`
`
`
`Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline).
`As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5%
`Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of
`bendamustine HCl in the infusion bag should be within 0.2 – 0.7 mg/mL.
`
` •
`
`
`
`
`
`
`
` Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to
`administration. The admixture should be a clear colorless to yellow solution.
`
`

`

`
`Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution,
`as outlined above. No other diluents have been shown to be compatible.
`
`TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder)
`If a closed system transfer device or adaptor is to be used as supplemental protection during preparation1, only use
`TREANDA for Injection, the lyophilized formulation.
`
` •
`
` Each vial of TREANDA for Injection is intended for single dose only.
`
` •
`
` Aseptically reconstitute each TREANDA for Injection vial as follows:
`o 25 mg TREANDA for Injection vial: Add 5 mL of only Sterile Water for Injection, USP.
`o 100 mg TREANDA for Injection vial: Add 20 mL of only Sterile Water for Injection, USP.
`
`• Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL.
`The lyophilized powder should completely dissolve in 5 minutes. The reconstituted solution must be transferred to the
`infusion bag within 30 minutes of reconstitution. If particulate matter is observed, the reconstituted product should not
`be used.
`
`
`
` •
`
` Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately
`transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9%
`Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride
`Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should
`be within 0.2 – 0.6 mg/mL. After transferring, thoroughly mix the contents of the infusion bag.
`
` •
`
` Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to
`administration. The admixture should be a clear and colorless to slightly yellow solution.
`
`
`Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5%
`Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be
`compatible.
`
`General Information
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration
`whenever solution and container permit. Any unused solution should be discarded according to institutional procedures
`for antineoplastics.
`
`2.5 Admixture Stability
`TREANDA Injection and TREANDA for Injection contain no antimicrobial preservative. The admixture should be
`prepared as close as possible to the time of patient administration.
`
`TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution)
`Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection,
`USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for
`2 hours when stored at room temperature (15°-30°C or 59°-86°F) and room light. Administration of diluted TREANDA
`Injection must be completed within this period.
`
`TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder)
`Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection,
`USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36-47°F) or for
`3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of reconstituted and
`diluted TREANDA for Injection must be completed within this period.
`
`
`
`
`
`

`

`
`
` 3
`
` DOSAGE FORMS AND STRENGTHS
`
`• TREANDA Injection: 45 mg/0.5 mL or 180 mg/2 mL in a single-dose vial.
`• TREANDA for Injection: 25 mg or 100 mg white to off-white lyophilized powder in a single-dose vial for
`reconstitution.
`
` 4
`
` CONTRAINDICATIONS
`TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions)
`to bendamustine. [see Warnings and Precautions (5.3)]
`
` 5
`
` WARNINGS AND PRECAUTIONS
`5.1 Myelosuppression
`TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 4). Three
`patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar
`hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).
`In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils
`frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed
`predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions
`if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation
`of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [see Dosage
`and Administrati