`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`Application Number:
`NDA 22249/S-015
`
`
`TREANDA Injection, for intravenous infusion,
`90 mg/mL, available in 45 mg/0.5 mL single-use vial
`and 180 mg/2 mL single-use vial
`
`bendamustine hydrochloride
`
`Trade Name:
`
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`
`
`Cephalon, Inc. (a wholly owned subsidiary of
`Teva Pharmaceuticals, Ltd.)
`
`September 13, 2013
`
`
`This supplemental new drug application provides for
`a new liquid formulation of TREANDA that is
`intended to replace the existing lyophilized powder
`formulation of TREANDA.
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICATION NUMBER:
`NDA 22249/S-015
`
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Division 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)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`X
`X
`
`
`
`
`
`
`X
`
`
`
`X
`X
`X
`
`
`X
`
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 22249/S-015
`NDA 22249/8-015
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`NDA 22249/S-015
`
`
`APPROVAL LETTER
`
`
`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 8, 2013, received
`March 8, 2013, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for TREANDA (bendamustine hydrochloride) lyophilized solid for injection, 25
`mg/vial; 100mg/vial.
`
`We acknowledge receipt of your amendments dated April 26, May 6, May 10, May 21, May 30,
`June 3, June 7, June 12, June 21, June 27, June 28, August 29, and September 5, 2013.
`
`The July 26, 2013, submission constituted a complete response to our July 2, 2013, action letter.
`
`This supplemental new drug application provides for a new liquid formulation of TREANDA
`that is intended to replace the existing lyophilized powder formulation of TREANDA.
`
`We have completed our review of this supplemental new drug application, as amended. This
`supplement is approved.
`
`Based on provided stability data, a 12-month expiration dating period is granted for the
`drug product when stored at 2° to 8°C (36° to 46°F) in the original package in cartons.
`
`At the next printing correct the following sentence found in Section 2.3 Preparation for
`Intravenous Administration:
`
`
`Current: “Aseptically withdraw the volume needed for the required dose from the 90
`mg/mL solution TREANDA Injection vial.”
`
`Recommended: Aseptically withdraw the volume needed for the required dose from the
`90 mg/mL solution.
`
`Reference ID: 3373510
`
`

`

`NDA 22249/S-015
`Page 2
`
`
`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
`
`Submit final printed carton and immediate container labels that are identical to the carton and
`immediate-container labels submitted on June 28, 2013, as soon as they are available, but no
`more than 30 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 22249/S-015.”
`Approval of this submission by FDA is not required before the labeling is used.
`
`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
`
`
`We remind you that you must comply with the requirements for an approved NDA set forth
`under 21 CFR 314.80 and 314.81.
`
`
`Reference ID: 3373510
`
`

`

`NDA 22249/S-015
`Page 3
`
`
`If you have any questions, call Jewell Martin, Regulatory Project Manager, at (301) 796-2072.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Hasmukh Patel, Ph.D.
`Branch Chief, Branch III
`Division of New Drug Quality Assessment I
`Office of New Drug Quality Assessment
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`
`
`
`
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`
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`
`
`
`
`
`ENCLOSURE(S):
`Content of Labeling
`Carton and Container Labeling
`
`Reference ID: 3373510
`
`
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`HASMUKH B PATEL
`09/13/2013
`
`Reference ID: 3373510
`
`

`

` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TION NUMBER:
`
`
`APPLICATION NUMBER:
`NDA 22249/S-015
`NDA 22249/S-015
`
`
`OTHER ACTION LETTER(S)
`OTHER ACTION LETTER! S!
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`9%.”.
`
`5'D
`K“-1
`
`CDEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 022249/S-015-
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`COMPLETE RESPONSE
`
`Cephalon, Inc. (a wholly owned subsidiary of Teva Pharmaceuticals, Ltd.)
`Attention: Michael J. McGraw, PharmD, MS
`Director, Regulatory Affairs
`41 Moores Road
`PO. Box 4011
`
`Frazer, PA 19355
`
`Dear Dr. McGraw:
`
`lemental New
`
`Please refer to your S
`lications sNDA S—015 dated March 8, 2013,
`received March 8, 2013,
`submitted under section
`505(b) of the Federal Food, Drug, and Cometic Act (FDCA) for TREANDA (bendamustine
`hydrochloride) lyophilized solid for injection, 25 mg/vial; 100mg/vial.
`
`We acknowledge receipt of your amendments dated March 22, April 26, May 6, May 10 (2),
`May 21, May 30, June 3, June 7, June 12, June 21, June 27 (3), and June 28, 2013.
`
`This “Prior Approval” Chemistry, Manufacturing, and Controls supplemental new drug
`application (S-015) proposes a new liquid formulation of TREANDA that is intended to replace
`the existing lyophilized powder formulation of TREANDA.
`
`We have completed the review of your applications, as amended, and have determined that we
`cannot approve these applications in their present form. We have described our reasons for this
`action below and, where possible, our recommendations to address these issues.
`
`PRODUCT UALITY
`
`1-
`
`
`
`Reference ID: 3335614
`
`

`

`NDA 022249/s-015
`Page 2
`
`(b) (4)
`
`(b) (4)
`
`as
`
`recommended in our June 17th, 2013 information request letter.
`
`LABELING
`
`2. We reserve comment on the proposed labeling until the application is otherwise adequate.
`If you revise labeling, your response must include updated content of labeling
`[21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as described at
`hm ://www. fda . gov/ForIndusfl/DataStandards/StructuredProductLabelingzdefault.htm.
`
`3. As stated
`
`(DH-1) is
`
`unacceptable. In responding to the deficiencies associated with S-015, please include
`your request for
`. (hm) review and submit the request for
`(I’m)
`review to S-015.
`
`OTHER
`
`Within one year afier the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
`request an extension of time in which to resubmit the supplemental application. A resubmission
`must fully address all the deficiencies listed. A partial response to this letter will not be
`processed as a resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to
`discuss what steps you need to take before the application may be approved. If you wish to have
`such a meeting, submit your meeting request as described in the FDA Guidance for Industry,
`“Formal Meetings Between the FDA and Sponsors or Applicants,” May 2009 at
`hm ://www. fda . gov/downloads/Drugs/GuidanceComplianceRegulatogInformation/Guidances/U
`CM 1 5 3222 .pdf.
`
`This product may be considered to be misbranded under the Federal Food, Drug, and Cosmetic
`Act if it is marketed with this change before approval of this supplemental application.
`
`Reference ID: 3335614
`
`

`

`NDA 022249/S-015
`Page 3
`
`
`
`If you have any questions, call Theresa Carioti, Regulatory Project Manager, at (301) 796-2848.
`
`
`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
`
`
`
`Reference ID: 3335614
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`07/02/2013
`
`Reference ID: 3335614
`
`

`

` CENTER FOR DRUG EVALUATION AND RESEARCH
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 22249/S-015
`NDA 22249/S-015
`
`
`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
`infusion
`Initial U.S. Approval: 2008
`
`----------------------------RECENT MAJOR CHANGES -------------------------
`Dosage and Administration,
`Preparation for Intravenous Administration (2.3)
`Dosage and Administration, Admixture Stability (2.4)
`
`XX/2013
`XX/2013
`
`----------------------------INDICATIONS AND USAGE---------------------------
`TREANDA is an alkylating drug indicated for treatment of patients with:
`(cid:120) Chronic lymphocytic leukemia (CLL). Efficacy relative to first line
`therapies other than chlorambucil has not been established. (1.1)
`(cid:120) 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------------------------
`For CLL:
`(cid:120) 100 mg/m2 infused intravenously over 30 minutes on Days 1 and 2 of a 28-
`day cycle, up to 6 cycles (2.1)
`(cid:120) 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. (2.1)
`(cid:120) 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. (2.1)
`(cid:120) Dose re-escalation may be considered. (2.1)
`For NHL:
`(cid:120) 120 mg/m2 infused intravenously over 60 minutes on Days 1 and 2 of a 21-
`day cycle, up to 8 cycles (2.2)
`(cid:120) 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. (2.2)
`(cid:120) 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. (2.2)
`General Dosing Considerations:
`(cid:120) Delay treatment for Grade 4 hematologic toxicity or clinically significant
`(cid:149) (cid:42)(cid:85)(cid:68)(cid:71)(cid:72) (cid:21) (cid:81)(cid:82)(cid:81)-hematologic toxicity. (2.1, 2.2)
`(cid:120) TREANDA must be diluted prior to infusion. (2.3)
`------------------------DOSAGE FORMS AND STRENGTHS-------------------
`Injection: 45 mg/0.5 mL or 180 mg/2 mL in a single-use vial. (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----------------------
`(cid:120) Myelosuppression: Delay or reduce dose. Restart treatment based on ANC
`and platelet count recovery. (2.1) Complications of myelosuppression may
`lead to death. (5.1)
`(cid:120) Infections: Monitor for fever and other signs of infection and treat
`promptly. (5.2)
`(cid:120) 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)
`(cid:120) Tumor Lysis Syndrome: Acute renal failure and death; anticipate and use
`supportive measures. (5.4)
`(cid:120) 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)
`(cid:120) Other Malignancies: Pre-malignant and malignant diseases have been
`reported. (5.6)
`(cid:120) Extravasation: Assure good venous access and monitor infusion site during
`and after administration. (5.7)
`(cid:120) 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-----------------------------
`(cid:120) Most common non-hematologic adverse reactions for CLL (frequency
`(cid:116)15%) are pyrexia, nausea, and vomiting. (6.1)
`(cid:120) Most common non-hematologic adverse reactions for NHL (frequency
`(cid:116)15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation,
`anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis.
`(6.2)
`(cid:120) Most common hematologic abnormalities for both indications (frequency
`(cid:149)(cid:20)(cid:24)(cid:8)(cid:12) 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--------------------
`(cid:120) Renal impairment: Do not use if CrCL is <40 mL/min. Use with caution
`in lesser degrees of renal impairment. (8.6)
`(cid:120) 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 0X/2013
`
`_______________________________________________________________________________________________________________________________________
`
`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 Dosing Instructions for CLL
`2.2 Dosing Instructions for NHL
`2.3 Reconstitution/Preparation for Intravenous Administration
`2.4 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
`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
`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
`
`Reference ID: 3373510
`
`

`

`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
`
`*Sections or subsections omitted from the full prescribing information are not
`listed
`
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`Chronic Lymphocytic Leukemia (CLL)
`1.1
`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.
`
`Non-Hodgkin Lymphoma (NHL)
`1.2
`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.
`
`DOSAGE AND ADMINISTRATION
`2
`Dosing Instructions for CLL
`2.1
`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 Gra(cid:71)(cid:72) (cid:23) (cid:75)(cid:72)(cid:80)(cid:68)(cid:87)(cid:82)(cid:79)(cid:82)(cid:74)(cid:76)(cid:70) (cid:87)(cid:82)(cid:91)(cid:76)(cid:70)(cid:76)(cid:87)(cid:92) (cid:82)(cid:85) (cid:70)(cid:79)(cid:76)(cid:81)(cid:76)(cid:70)(cid:68)(cid:79)(cid:79)(cid:92) (cid:86)(cid:76)(cid:74)(cid:81)(cid:76)(cid:73)(cid:76)(cid:70)(cid:68)(cid:81)(cid:87) (cid:149) (cid:42)(cid:85)(cid:68)(cid:71)(cid:72) (cid:21) (cid:81)(cid:82)(cid:81)-hematologic
`toxicity. Once non-(cid:75)(cid:72)(cid:80)(cid:68)(cid:87)(cid:82)(cid:79)(cid:82)(cid:74)(cid:76)(cid:70) (cid:87)(cid:82)(cid:91)(cid:76)(cid:70)(cid:76)(cid:87)(cid:92) (cid:75)(cid:68)(cid:86) (cid:85)(cid:72)(cid:70)(cid:82)(cid:89)(cid:72)(cid:85)(cid:72)(cid:71) (cid:87)(cid:82) (cid:148) (cid:42)(cid:85)(cid:68)(cid:71)(cid:72) (cid:20) (cid:68)(cid:81)(cid:71)(cid:18)(cid:82)(cid:85) (cid:87)(cid:75)(cid:72) (cid:69)(cid:79)(cid:82)(cid:82)(cid:71) (cid:70)(cid:82)(cid:88)(cid:81)(cid:87)(cid:86) (cid:75)(cid:68)(cid:89)(cid:72) (cid:76)(cid:80)(cid:83)(cid:85)(cid:82)(cid:89)(cid:72)(cid:71) (cid:62)(cid:36)(cid:69)(cid:86)(cid:82)(cid:79)(cid:88)(cid:87)(cid:72) (cid:49)(cid:72)(cid:88)(cid:87)(cid:85)(cid:82)(cid:83)(cid:75)(cid:76)(cid:79) (cid:38)(cid:82)(cid:88)(cid:81)(cid:87) (cid:11)(cid:36)(cid:49)(cid:38)(cid:12) (cid:149) 1 x
`109/L(cid:15) (cid:83)(cid:79)(cid:68)(cid:87)(cid:72)(cid:79)(cid:72)(cid:87)(cid:86) (cid:149) 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.
`
`Dosing Instructions for NHL
`2.2
`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 (cid:86)(cid:76)(cid:74)(cid:81)(cid:76)(cid:73)(cid:76)(cid:70)(cid:68)(cid:81)(cid:87) (cid:149) (cid:42)(cid:85)(cid:68)(cid:71)(cid:72) (cid:21) (cid:81)(cid:82)(cid:81)-hematologic
`toxicity. Once non-(cid:75)(cid:72)(cid:80)(cid:68)(cid:87)(cid:82)(cid:79)(cid:82)(cid:74)(cid:76)(cid:70) (cid:87)(cid:82)(cid:91)(cid:76)(cid:70)(cid:76)(cid:87)(cid:92) (cid:75)(cid:68)(cid:86) (cid:85)(cid:72)(cid:70)(cid:82)(cid:89)(cid:72)(cid:85)(cid:72)(cid:71) (cid:87)(cid:82) (cid:148) (cid:42)(cid:85)(cid:68)(cid:71)(cid:72) (cid:20) (cid:68)(cid:81)(cid:71)(cid:18)(cid:82)(cid:85) (cid:87)(cid:75)(cid:72) (cid:69)(cid:79)(cid:82)(cid:82)(cid:71) (cid:70)(cid:82)(cid:88)(cid:81)(cid:87)(cid:86) (cid:75)(cid:68)(cid:89)(cid:72) (cid:76)(cid:80)(cid:83)(cid:85)(cid:82)(cid:89)(cid:72)(cid:71) (cid:62)(cid:36)(cid:69)(cid:86)(cid:82)(cid:79)(cid:88)(cid:87)(cid:72) (cid:49)(cid:72)(cid:88)(cid:87)(cid:85)(cid:82)(cid:83)(cid:75)(cid:76)(cid:79) (cid:38)(cid:82)(cid:88)(cid:81)(cid:87) (cid:11)(cid:36)(cid:49)(cid:38)(cid:12) (cid:149) 1 x
`109/L(cid:15) (cid:83)(cid:79)(cid:68)(cid:87)(cid:72)(cid:79)(cid:72)(cid:87)(cid:86) (cid:149) 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.
`
`Preparation for Intravenous Administration
`2.3
`Each vial of TREANDA Injection is intended for single use only. Aseptically withdraw the volume needed for the required dose from the 90 mg/mL
`solution TREANDA Injection vial.
`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. 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.
`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.
`
`Admixture Stability
`2.4
`TREANDA Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient
`administration.
`
`Reference ID: 3373510
`
`

`

`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 (59°-
`86°F) and room light. Administration of TREANDA must be completed within this period.
`
`DOSAGE FORMS AND STRENGTHS
`3
`TREANDA Injection is supplied in single-use vials containing either 45 mg/0.5 mL or 180 mg/2 mL of bendamustine HCl.
`
`CONTRAINDICATIONS
`4
`TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See
`Warnings and Precautions (5.3)]
`
`WARNINGS AND PRECAUTIONS
`5
`Myelosuppression
`5.1
`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 (cid:116) 1 x 109/L and the platelet count should (cid:69)(cid:72) (cid:149) 75 x 109/L.
`[See Dosage and Administration (2.1) and (2.2)]
`
`Infections
`5.2
`Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing
`reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with
`myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.
`
`Anaphylaxis and Infusion Reactions
`5.3
`Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances
`severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and
`discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who
`experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including
`antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue
`TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate
`considering individual benefits, risks, and supportive care.
`
`Tumor Lysis Syndrome
`5.4
`Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends
`to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include
`vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the
`beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered
`concomitantly [see Warnings and Precautions (5.5)].
`
`Skin Reactions
`5.5
`Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions
`and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents.
`In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported
`for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA
`was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be
`determined.
`Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If
`skin reactions are severe or progressive, withhold or discontinue TREANDA.
`
`Other Malignancies
`5.6
`There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including
`myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA
`therapy has not been determined.
`
`Extravasation Injury
`5.7
`TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good
`venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis
`during and after administration of TREANDA.
`
`Embryo-fetal Toxicity
`5.8
`TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats
`administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. [See Use
`in Specific Populations (8.1)]
`
`Reference ID: 3373510
`
`

`

`ADVERSE REACTIONS
`6
`The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections of
`the label.
`(cid:120) Myelosuppression [See Warnings and Precautions (5.1)]
`Infections [See Warnings and Precautions (5.2)]
`(cid:120)
`Anaphylaxis and Infusion Reactions [See Warnings and Precautions (5.3)]
`(cid:120)
`Tumor Lysis Syndrome [See Warnings and Precautions (5.4)]
`(cid:120)
`Skin Reactions [See Warnings and Precautions (5.5)]
`(cid:120)
`Other Malignancies [See Warnings and Precautions (5.6)]
`(cid:120)
`Extravasation injury [See Warnings and Precautions (5.7)]
`(cid:120)
`
`The data described below reflect exposure to TREANDA in 329 patients who participated in an actively-controlled trial (N=153) for the treatment of
`CLL and two single-arm trials (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying
`conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and
`may not reflect the rates observed in practice.
`
`Clinical Trials Experience in CLL
`6.1
`The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial. The population
`was 45-77 yea