CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
` NDA 22-249/S-1
`
`
`
`
`
` Treanda
`
`bendamustine hydrochloride, for Injection, 100 mg
`
`Cephalon, Inc.
`
`May 1, 2009
`
`provides for the addition of a new 25 mg vial
`
`
`
`
`Trade Name:
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`
`
`Approval Date:
`
`
`Indication:
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`NDA 22-249/S-1
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Clinical Review
`Chemistry Review
`Environmental Assessment
`Pharmacology/Toxicology Review
`Statistical Review
`Product Microbiology Review
`Clinical Pharmacology Review
`Other Reviews
`Risk Assessment and Risk Mitigation Review
`Proprietary Name Review
`Administrative/Correspondence Document
`
`
`X
`
`X
`
`
`
`
`
`
`X
`
`
`
`X
`
`X
`
`
`
`
`

`

`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`RESEARCH
`
`APPLICA TI0N NUMBER:
`
`NDA 22-249/S-1
`
`
`
`APPLICATION NUMBER:
`NDA 22-249/S-1
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`

`

`
`
`
`
`
`
` DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`
`Public Health Service
`
`Food and Drug Administration
`
`Rockville, MD 20857
`
`
`
`NDA 22-249/S-001
`
`
`Cephalon, Inc.
`Attention: Carol S. Marchione
`Senior Director and Group Leader
`41 Moores Road
`Frazer, PA 19355
`
`
`Dear Ms. Marchione:
`
`Please refer to your supplemental new drug application dated August 27, 2008, received
`August 28, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`for Treanda® (bendamustine hydrochloride) for Injection, 100 mg.
`
`We acknowledge receipt of your submissions dated August 27, 2008 and November 19, 2008.
`
`This supplemental new drug application provides for the addition of a 25 mg vial for the use of
`Treanda® (bendamustine hydrochloride) for Injection for the treatment of patients with Chronic
`Lymphocytic Leukemia and for the treatment of patients with indolent B-cell non-Hodgkin’s
`
`lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab­
`containing regimen.
`
`We completed our review of this application, as amended. This application is approved, effective on
`the date of this letter, for use as recommended in the agreed-upon labeling text.
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format as described at
`
` http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed labeling (text for the
`package insert). Upon receipt, we will transmit that version to the National Library of Medicine for
`public dissemination. For administrative purposes, please designate this submission, “SPL for
`approved NDA 22-249/S-001.”
`
`We remind you of your outstanding postmarketing study commitments listed in the March 20, 2008,
`approval letter. These commitments are listed below.
`
`
`1.
`
`Cephalon commits to providing an updated study report of Protocol 02CLLIII titled “Phase III,
`Open-Label, Randomized, Multicenter Efficacy and Safety Study of Bendamustine
`Hydrochloride Versus Chlorambucil in Treatment-Naive Patients with (Binet Stage B/C) BCLL
`Requiring Therapy” at data cut off date in May 2008. Response rate, progression-free survival,
`overall survival and safety updates will be provided in this study report.
`
`
`
`
`
`

`

`NDA 22-249/S-001
`Page 2
`
`
`Protocol Submission: N/A
`
`Study Start: N/A
`
`Final Report Submission: February 28, 2009
`
`
`
`2.
`
`
`
`3.
`
`
`
`4.
`
`
`
`5.
`
`
`
`6.
`
`
`
`Cephalon commits to submitting the results and data from the ADME Study 1039 titled "An
`Open-Label Study to Investigate the Pharmacokinetics (Distribution, Metabolism, and
`Excretion) of Bendamustine Hydrochloride Following Intravenous Infusion of
`[14C]Bendamustine Hydrochloride in Patients With Relapsed or Refractory Malignancy
`(Hematologic or Nonhematologic)". Results from this study may indicate a need for dedicated
`renal and/or hepatic organ impairment studies.
`
`Protocol Submission: May 31, 2008
`
`Study Start: December 31, 2008
`
`Final Report Submission: March 31, 2010
`
`
`Cephalon commits to conducting a study to assess the potential for bendamustine to prolong the
`QT interval in patients. The QT plan will be submitted prior to initiation for IRT review and
`concurrence.
`
`Protocol Submission: July 31, 2008
`
`Study Start: December 31, 2008
`
`Final Report Submission: June 30, 2010
`
`
`Since bendamustine is a CYP1A2 substrate in vitro, Cephalon agrees to perform an in vivo drug
`interaction study of the ability of fluvoxamine (CYP1A2 inhibitor) to alter the
`pharmacokinetics of a single dose of bendamustine. The necessity to conduct this study will be
`predicated upon the results from Study 1039.
`
`Protocol Submission: March 31, 2010
`
`Study Start: September 30, 2010
`
`Final Report Submission: July 31, 2012
`
`
`Since bendamustine is a CYP1A2 substrate in vitro, Cephalon agrees to perform an in vivo drug
`interaction study of the ability of smoking (CYP1A2 inducer) to alter the pharmacokinetics of a
`single dose of bendamustine. The necessity to conduct this study will be predicated upon the
`results from Study 1039.
`
`Protocol Submission: March 31, 2010
`
`Study Start: September 30, 2010
`
`Final Report Submission: December 31, 2012
`
`
`Cephalon commits to conducting in vitro screens to determine if bendamustine is a
`p-glycoprotein substrate or inhibitor.
`
`Protocol Submission: March 31, 2008
`
`Study Start: September 30, 2007
`
`Final Report Submission: June 30, 2008
`
`
`
`
`

`

`NDA 22-249/S-001
`Page 3
`
`
`
`Cephalon commits to assess the physico-chemical compatibility of Treanda with the following
`diluents as admixtures to reconstituted TREANDA: D5W, lactated Ringers and half normal
`saline (0.45% sodium chloride).
`
`7.
`
`
`
`Protocol submission: April 1, 2008
`Study start: May 15, 2008
`Final Report: September 1, 2008
`
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all study final reports to this NDA. In addition, under
`21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you should include a status summary of each
`commitment in your annual report to this NDA. The status summary should include expected
`summary completion and final report submission dates, any changes in plans since the last annual
`report, and, for clinical studies, number of patients entered into each study. All submissions, including
`supplements, relating to these postmarketing study commitments must be prominently labeled
`“Postmarketing Study Commitment Protocol”, “Postmarketing Study Commitment Final
`Report”, or “Postmarketing Study Commitment Correspondence.”
`
`In addition, submit three copies of the introductory promotional materials that you propose to use for
`this product. Submit all proposed materials in draft or mock-up form, not final print. Send one copy to
`this division/ the Division of Drug Oncology Products and two copies of both the promotional
`materials and the package insert directly to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`If you issue a letter communicating important information about this drug product (i.e., a “Dear Health
`Care Professional” letter), we request that you submit a copy of the letter to this NDA and a copy to
`the following address:
`
`
`
`
`
`
`
`
`
`
`
`MEDWATCH
`
`
`Food and Drug Administration
`Suite 12B05
`
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`
`
`
`
`
`
`
`
`
`

`

`NDA 22-249/S-001
`Page 4
`
`
`If you have any questions, call Milinda Vialpando, Regulatory Project Manager, at
`(301) 796-1444.
`
`
`
`
`Enclosure: Labeling
`
`
`
`Sincerely,
`
` {See appended electronic signature page}
`
`Robert L. Justice, M.D., M.S.
`Director
`
`Division of Drug Oncology Products
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`/s/
`
`---------------------
`Amna Ibrahim
`
`5/1/2009 01:01:36 PM
`
`For Dr Robert Justice
`
`
`

`

`
` CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`NDA 22-249/S-1
`
`LABELING
`
`NDA 22-249/S-1
`
`APPLICA TI0N NUMBER:
`
`LABELING
`
`

`

`------------------------DOSAGE FORMS AND STRENGTHS-------------------
`TREANDA for Injection single-use vial containing either 25 mg or 100 mg of
`
`bendamustine HCl as lyophilized powder (3)
`---------------------------------CONTRAINDICATIONS----------------------------
`
`Known hypersensitivity to bendamustine or mannitol (4)
`-------------------------WARNINGS AND PRECAUTIONS---------------------­
`
`y Myelosuppression: May warrant treatment delay or dose reduction.
`
`
`Monitor closely and restart treatment based on ANC and platelet count
`
`
`recovery. Complications of myelosuppression may lead to death. (5.1)
`
`
`y Infections: Monitor for fever and other signs of infection and treat
`promptly. (5.2)
`
`
`y Infusion Reactions and Anaphylaxis: Severe anaphylactic reactions have
`occurred. Monitor clinically and discontinue drug for severe reactions. Ask
`patients about reactions after the first cycle. Consider pre-treatment for
`
`cycles subsequent to milder reactions. (5.3)
`
`y Tumor Lysis Syndrome: May lead to acute renal failure and death. Take
`
`precautions in patients at high risk. (5.4)
`
`y Skin Reactions: Discontinue for severe skin reactions. (5.5)
`
`y Other Malignancies: Pre-malignant and malignant diseases have been
`reported. (5.6)
`
`y Use in Pregnancy: Fetal harm can occur when administered to a pregnant
`
`woman. Women should be advised to avoid becoming pregnant when
`
`receiving TREANDA. (5.7, 8.1)
`--------------------------------ADVERSE REACTIONS-----------------------------
`Most common non-hematologic adverse reactions for CLL (frequency u15%)
`
`
`
`are pyrexia, nausea, and vomiting. (6.1)
`
`
`Most common non-hematologic adverse reactions for NHL (frequency u15%)
`
`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 Cephalon,
`
`Inc., 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-------------------­
`
`y Renal impairment: Do not use if CrCL is <40 mL/min. Use with caution
`
`in lesser degrees of renal impairment. (8.6)
`
`
`y 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: 4/2009
`
`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) for Injection, for intravenous
`infusion
`Initial U.S. Approval: 2008
`----------------------------RECENT MAJOR CHANGES -------------------------
`Indications and Usage, Non-Hodgkin’s Lymphoma (NHL) (1.2)
`10/2008
`
`Dosage and Administration, Dosing Instructions for NHL (2.2)
`10/2008
`Dosage and Administration, Reconstitution/Preparation for
` 11/2008
`Intravenous Administration (2.4)
`
`
`
`10/2008
`Dosage and Administration, Admixture Stability (2.5)
`
` 10/2008
`Warnings and Precautions, Myelosuppression (5.1)
`
`
`10/2008
`Warnings and Precautions, Skin Reactions (5.5)
`
` 10/2008
`Warnings and Precautions, Other Malignancies (5.6)
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`TREANDA for Injection is an alkylating drug indicated for treatment of
`patients with:
`
`y Chronic lymphocytic leukemia (CLL). Efficacy relative to first line
`therapies other than chlorambucil has not been established. (1.1)
`
`
`
`y Indolent B-cell non-Hodgkin’s 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:
`y 100 mg/m2 infused intravenously over 30 minutes on Days 1 and 2 of a 28­
`
`day cycle, up to 6 cycles (2.1)
`
`y 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)
`
`
`y 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)
`
`
`y Dose re-escalation may be considered. (2.1)
`
`For NHL:
`
`y 120 mg/m2 infused intravenously over 60 minutes on Days 1 and 2 of a 21­
`
`day cycle, up to 8 cycles (2.2)
`
`y 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)
`
`
`
`y 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:
`
`y Delay treatment for Grade 4 hematologic toxicity or clinically significant
`≥ Grade 2 non-hematologic toxicity (2.1, 2.2)
`
`
`
`y TREANDA for Injection must be reconstituted and further diluted prior to
`infusion. (2.4)
`
`
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`INDICATIONS AND USAGE
`1
`1.1 Chronic Lymphocytic Leukemia (CLL)
`
`
`1.2 Non-Hodgkin’s Lymphoma (NHL)
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Dosing Instructions for CLL
`
`2.2 Dosing Instructions for NHL
`
`2.3 General Considerations for Tumor Lysis Syndrome
`
`2.4 Reconstitution/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 Infusion Reactions and Anaphylaxis
`
`5.4 Tumor Lysis Syndrome
`
`
`5.5 Skin Reactions
`
`5.6 Other Malignancies
`
`
`5.7 Use in Pregnancy
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience in CLL
`
`6.2 Clinical Trials Experience in NHL
`
`6.3 Post-Marketing 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
`
`12 3 Pharmacokinetics
`
`12.4 Pharmacokinetics/Pharmacodynamics
`
`1
`
`
`
`

`

`13 NONCLINICAL TOXICOLOGY
`
`
`
`
` 13 1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Chronic Lymphocytic Leukemia (CLL)
`
`14.2 Non-Hodgkin’s 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
`
`
`1
`
`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’s Lymphoma (NHL)
`
`TREANDA for Injection is indicated for the treatment of patients with
`indolent B-cell non-Hodgkin’s lymphoma that has progressed during or within
`six months of treatment with rituximab or a rituximab-containing regimen.
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 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.
`
`
`
`2.2 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.
`
`
`2.3 General Considerations for Tumor Lysis Syndrome
`Consider using allopurinol as prevention for patients at high risk of
`tumor lysis syndrome for the first few weeks of treatment.
`
`
`
`2.4 Reconstitution/Preparation for Intravenous Administration
`
`
`2
`
`
`
`
`y
`
`
`
`
`y
`
`
`
`
`Aseptically reconstitute each TREANDA vial as follows:
`
`
`o
`
`
`o
`
`25 mg TREANDA vial: Add 5mL of only Sterile Water for
`
`
`Injection, USP.
`
`100 mg TREANDA 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. 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. The reconstituted solution must be transferred to the infusion
`
`bag within 30 minutes of reconstitution. After transferring, thoroughly
`mix the contents of the infusion bag. 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.
`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 contains no antimicrobial preservative. The admixture
`should be prepared as close as possible to the time of patient administration.
`
`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 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.
`
`
`Administration of TREANDA must be completed within this period.
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`TREANDA for Injection single-use vial containing either 25 mg or 100
`mg of bendamustine HCl as white to off-white lyophilized powder.
`
`
`4 CONTRAINDICATIONS
`TREANDA is contraindicated in patients with a known hypersensitivity
`
`(e.g., anaphylactic and anaphylactoid reactions) to bendamustine or mannitol.
`
`
`[See Warnings and Precautions (5.3)]
`
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Myelosuppression
`Patients treated with TREANDA are likely to experience
`
`myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4
`
`myelosuppression (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 closely. In the clinical trials,
`
`blood counts were monitored every week initially. Hematologic nadirs were
`observed predominantly in the third week of therapy. Hematologic nadirs may
`
`
`
`

`

`
`
`
`
`
`
`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.
`
`y Myelosuppression [See Warnings and Precautions (5.1)]
`
`
`
`
`y
` Infections [See Warnings and Precautions (5.2)]
`
`
`
`
`y
` Infusion Reactions and Anaphylaxis [See Warnings and Precautions
`
`
` (5.3)]
`
`y
`
`
` Tumor Lysis Syndrome [See Warnings and Precautions (5.4)]
`
`y
` Skin Reactions [See Warnings and Precautions (5.5)]
`
`
`
`
`y Other Malignancies [See Warnings and Precautions (5.6)]
`
`
`
`
`
`6.1 Clinical Trials Experience in CLL
`The data described below reflect exposure to TREANDA in 153
`patients. TREANDA was studied in an active-controlled trial. The
`population was 45-77 years of age, 63% male, 100% white, and had treatment
`naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously
`
`over 30 minutes on days 1 and 2 every 28 days.
`Adverse reactions were reported according to NCI CTC v.2.0. In the
`
`randomized CLL clinical study, non-hematologic adverse reactions (any
`
`grade) in the TREANDA group that occurred with a frequency greater than
`
`15% were pyrexia (24%), nausea (20%), and vomiting (16%).
`
`Other adverse reactions seen frequently in one or more studies included
`
`asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough;
`
`constipation; headache; mucosal inflammation and stomatitis.
`Worsening hypertension was reported in 4 patients treated with
`TREANDA in the randomized CLL clinical study and none treated with
`chlorambucil. Three of these 4 adverse reactions were described as a
`
`
`hypertensive crisis and were managed with oral medications and resolved.
`
`The most frequent adverse reactions leading to study withdrawal for
`
`patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%).
`
`Table 1 contains the treatment emergent adverse reactions, regardless of
`attribution, that were reported in ≥ 5% of patients in either treatment group in
`
`the randomized CLL clinical study.
`
`
`
`require dose delays if recovery to the recommended values have 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 u 1 x 109/L and the platelet count should
`be ≥ 75 x 109/L. [See Dosage and Administration (2.1) and (2.2)]
`
`
`
`
`
`5.2 Infections
`Infection, including pneumonia and sepsis, has been reported in patients
`in clinical trials and in post-marketing reports. Infection has been associated
`with hospitalization, septic shock and death. Patients with myelosuppression
`
`
`following treatment with TREANDA are more susceptible to infections.
`Patients with myelosuppression following TREANDA treatment should be
`
`advised to contact a physician if they have symptoms or signs of infection.
`
`
`
`
`5.3 Infusion Reactions and Anaphylaxis
`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. Patients should be asked about
`
`symptoms suggestive of infusion reactions after their first cycle of therapy.
`
`Patients who experienced Grade 3 or worse allergic-type reactions were not
`
`typically rechallenged. Measures to prevent severe reactions, including
`
`antihistamines, antipyretics and corticosteroids should be considered in
`subsequent cycles in patients who have previously experienced Grade 1 or 2
`infusion reactions. Discontinuation should be considered in patients with
`Grade 3 or 4 infusion reactions.
`
`
`
`5.4 Tumor Lysis Syndrome
`
`Tumor lysis syndrome associated with TREANDA treatment has been
`reported in patients in clinical trials and in post-marketing 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 maintaining adequate volume status, close monitoring of blood
`chemistry, particularly potassium and uric acid levels, and the use of
`allopurinol during the first few weeks of TREANDA therapy in patients at
`
`high risk.
`
`
`
`5.5 Skin Reactions
`A number of skin reactions have been reported in clinical trials and post-
`marketing safety reports. These events have included rash, toxic skin
`reactions and bullous exanthema. Some events occurred when TREANDA
`was given in combination with other anticancer agents, so the precise
`relationship to TREANDA is uncertain. 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). The relationship to TREANDA cannot be determined. Where skin
`
`
`reactions occur, they may be progressive and increase in severity with further
`
`
`
`treatment. If skin reactions are severe or progressive, TREANDA should be
`withheld or discontinued.
`
`
`
`5.6 Other Malignancies
`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.
`
`
`
`
`5.7 Use in Pregnancy
`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)]
`
`
`
`6 ADVERSE REACTIONS
`The data described below reflect exposure to TREANDA in 349 patients
`who participated in an actively-controlled trial (N=153) for the treatment of
`
`CLL and two single-arm studies (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.
`
`
`3
`
`
`
`

`

`
`
`
`
`
`
`
`
` Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL
` Clinical Study in at Least 5% of Patients
`
` Number (%) of patients
`
`
`TREANDA
`Chlorambucil
`
`(N=153)
`(N=143)
`
`All
`Grade
`
`
`Grades
`3/4
`
`
`
`All
`
`Grades
`
`Grade 3/4
`
`121 (79)
`
`
`
`31 (20)
`
`24 (16)
`
`14 (9)
`
`
`36 (24)
`
`14 (9)
`13 (8)
`9 (6)
`
`
`
`7 (5)
`
`
`10 (7)
`
`9 (6)
`
`5 (3)
`
`11 (7)
`
`
`
`11 (7)
`
`
`6 (4)
`
`
`
`12 (8)
`8 (5)
`
`
`52 (34)
`
`
`
`1 (<1)
`
`1 (<1)
`
`2 (1)
`
`
`
`6 (4)
`
`2 (1)
`
`0
`
`0
`
`
`2 (1)
`
`
`
`0
`3 (2)
`0
`
`
`0
`
`
`3 (2)
`
`
`
`1 (<1)
`
`
`
`4 (3)
`
`0
`
`96 (67)
`
`
`
`21 (15)
`
`9 (6)
`
`5 (3)
`
`
`25 (17)
`
`
`
`
`1 (<1)
`
`0
`0
`
`
`
`8 (6)
`
`8 (6)
`6 (4)
`1 (<1)
`
`
`
`3 (2)
`
`
`12 (8)
`
`1 (<1)
`7 (5)
`
`5 (3)
`
`
`
`2 (1)
`
`
`7 (5)
`
`
`
`7 (5)
`2 (1)
`
`
`2 (1)
`
`0
`
`0
`
`0
`
`
`0
`
`
`
`0
`1 (<1)
`
`0
`
`
`0
`
`
`0
`
`
`
`1 (<1)
`
`
`
`3 (2)
`
`0
`
`
`
`
`System organ class
`
`
`Preferred term
`
`
`Total number of patients
`
`
`with at least 1 adverse
`
`
`
`reaction
`
`Gastrointestinal
`
`
`disorders
`
`
`Nausea
`
`Vomiting
`
`Diarrhea
`
`General disorders and
`
`
`administration site
`
`
`conditions
`
`
`Pyrexia
`
`Fatigue
`
`Asthenia
`
`Chills
`
`Immune system
`
`
`disorders
`
`
`Hypersensitivity
`
`Infections and
`
`
`infestations
`
`
`Nasopharyngitis
`
`Infection
`
`Herpes simplex
`Investigations
`
`Weight decreased
`
`
`Metabolism and
`
`nutrition disorders
`
`
`Hyperuricemia
`
`Respiratory, thoracic
`
`
`and mediastinal
`
`
`disorders
`
`
`Cough
`Skin and subcutaneous
`
`tissue disorders
`
`Rash
`
`Pruritus
`
`
`The Grade 3 and 4 hematology laboratory test values by treatment group
`
`in the randomized CLL clinical study are described in Table 2. These findings
`confirm the myelosuppressive effects seen in patients treated with
`TREANDA. Red blood cell transfusions were administered to 20% of
`patients receiving TREANDA compared with 6% of patients receiving
`chlorambucil.
`
`
`
`
`
`
` Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who
`
`
`
`
`
`
`Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study
`
`
`
`TREANDA
`Chlorambucil
`
`
`
`N=150
`
`N=141
`
`
`
`
`Grade 3/4
`
`All Grades
`
`All Grades
`
`Grade 3/4
`
`
`n (%)
`
`n (%)
`
`n (%)
`
`n (%)
`
`
`
`
`20 (13)
`
`
`
`134 (89)
`
`
`
`115 (82)
`
`
`
`
`12 (9)
`
`
`
`116 (77)
`
`
`
`92 (61)
`
`
`
`
`102 (68)
`
`
`
`
`113 (75)
`
`
`
`
`16 (11)
`
`
`
`42 (28)
`
`
`
`70 (47)
`
`
`
`65 (43)
`
`
`
`110 (78)
`
`
`
`14 (10)
`
`
`
`26 (18)
`
`
`
`27 (19)
`
`
`
`86 (61)
`
`
`
`4 (3)
`
`
`
`6 (4)
`
`
`30 (21)
`
`
`
`Laboratory
`
`
`Abnormality
`
`
`
`Hemoglobin
`
`
`Decreased
`
`
`Platelets
`
`
`Decreased
`
`
`Leukocytes
`
`
`Decreased
`
`
`Lymphocytes
`
`
`Decreased
`
`
`Neutrophils
`
`
`Decreased
`
`
`In the randomized CLL clinical study, 34% of patients had bilirubin
`elevations, some without associated significant elevations in AST and