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.
`(6.1)
`
` Most common hematologic abnormalities for both indications (frequency
`
`
`≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and
`neutropenia. (6.1)
`
`
`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: 09/2015
`
`
`
`
`
`
`
`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)
`09/2015
`
`
`Selection of TREANDA Formulation to Administer (2.1)
`09/2015
`Preparation for Intravenous Administration (2.4)
`09/2015
`
`
`03/2015
`Admixture Stability (2.5)
`
`
`-------------------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)
`
`
`
`
`
`
`
`
`Reference ID: 3814582
`
`

`

`
`
`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
`
`
`6.2 Postmarketing Experience
`
`7 DRUG INTERACTIONS
`
`
`*Sections or subsections omitted from the full prescribing information are not listed
`
`
`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
`
`
`
`
`
`Reference ID: 3814582
`
`

`

`
`
`
`
`
`
` 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 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 if you intend to use closed system transfer devices (CSTDs), adapters and syringes
`containing polycarbonate or acrylonitrile-butadiene-styrene (ABS) prior to dilution in the infusion bag [see Dosage
`and Administration (2.4)].
`
`If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion bag, only use a
`polypropylene syringe with a metal needle and polypropylene hub to withdraw and transfer TREANDA Injection
`into the infusion bag. 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 CSTD or adapter that contains polycarbonate or ABS is used as supplemental protection prior to dilution1, only use
`TREANDA for Injection, the lyophilized powder formulation [see How Supplied/Storage and Handling (16.1)].
`
`
`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.
`
`
`
`
`Reference ID: 3814582
`
`

`

`
`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 is a cytotoxic drug. Follow applicable special handling and disposal procedures.1
`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.
` When preparing and transferring the concentrated TREANDA Injection solution into the infusion bag, do not
`
`use devices that contain polycarbonate or ABS. However, after dilution of TREANDA Injection into the
`infusion bag, devices that contain polycarbonate or ABS, including infusion sets, may be used.
` TREANDA Injection contains N,N-dimethylacetamide (DMA), which is incompatible with devices that contain
`polycarbonate or ABS. Devices, including CSTDs, adapters, 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. Devices that are compatible for use in dilution of TREANDA Injection are
`available.
`
`
`
`
` 
`
`
`
`If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion
`bag,only use a polypropylene syringe with a metal needle and a polypropylene hub to withdraw and transfer
`
`TREANDA Injection into the infusion bag.
`
`
` 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.
`
`
`
` After dilution of TREANDA Injection into the infusion bag, devices that contain polycarbonate or ABS,
`
`
`including infusion sets, may be used.
`
`
`
`
`
`Reference ID: 3814582
`
`

`

`
`
` 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 adapter that contains polycarbonate or ABS 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
`
`
`
`
`Reference ID: 3814582
`
`

`

`
`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 Administration (2. 2) and (2. 3)]
`
`
`5.2 Infections
`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.
`
`
`
`5.3 Anaphylaxis and Infusion Reactions
`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.
`
`
`5.4 Tumor Lysis Syndrome
`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)].
`
`5.5 Skin Reactions
`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.
`
`
`
`
`
`Reference ID: 3814582
`
`

`

`
`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.
`
`
`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 Extravasation Injury
`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.
`
`
`5.8 Embryo-fetal Toxicity
` 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 following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in
`
`greater detail in other sections of the label.
`
` Myelosuppression [see Warnings and Precautions (5.1)]
`
`
`
`
`Infections [see Warnings and Precautions (5.2)]
`
`
`
`
` 
`
` Anaphylaxis and Infusion Reactions [see Warnings and Precautions (5.3)]
`
`
`
`
` Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]
`
`
`
`
`  Skin Reactions [see Warnings and Precautions (5.5)]
`
`
`
`
`
`
`  Other Malignancies [see Warnings and Precautions (5.6)]
`
`
`
`
`  Extravasation injury [see Warnings and Precautions (5.7)]
`
`
`
`
`
`
`
`
`
`
`
`6.1 Clinical Trials Experience
`
`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.
`
`Chronic Lymphocytic Leukemia
`
`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 years of age, 63% male, 100% white, and were treatment naïve. 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. 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 CLL trial and in none treated with
`
`chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral
`
`
`medications and resolved.
`
`
`
`
`
`
`
`Reference ID: 3814582
`
`

`

`
`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.
`
`
`Table 1: Non- Hematologic Adverse Reactions Occurring in Randomized CLL
`
`Clinical Study in at Least 5% of Patients
`
`
`Number (%) of patients
`
`
`
`Chlorambucil
`TREANDA
`
`
`(N=143)
`(N=153)
`
`
`Grade
`Grade 3/4
`All
`
`
`3/4
`Grades
`
`
`
`
`25 (17)
`
`All
`
`Grades
`
`
`
`121 (79)
`
`
`
`52 (34)
`
`
`
`96 (67)
`
`
`
`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
`
`
`
`
`
`
`
`Reference ID: 3814582
`
`
`
`
`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)
`
`
`
`
`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
`
`
`
`
`21 (15)
`
`9 (6)
`
`5 (3)
`
`
`
`
`
`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)
`
`
`
`
`1 (<1)
`0
`0
`
`
`
`
`
`2 (1)
`0
`0
`0
`
`
`
`0
`
`
`
`0
`
`1 (<1)
`0
`
`
`0
`
`
`
`0
`
`
`
`
`
`1 (<1)
`
`
`
`
`3 (2)
`0
`
`

`

`Chlorambucil
`N=141
`
`
`All Grades
`n (%)
`
`
`Grade 3/4
`n (%)
`
`
`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
`N=150
`Grade
`
`3/4
`n (%)
`20 (13)
`
`
`Hemoglobin
`Decreased
`Platelets
`Decreased
`Leukocytes
`Decreased
`Lymphocytes
`Decreased
`Neutrophils
`Decreased
`
` In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or
`
`
`
`
`
`
` 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients,
` respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected,
`
`
` monitoring of these parameters should be continued to ensure that further deterioration does not occur.
`
`
`
`
`
`Non-Hodgkin Lymphoma
`The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-
`arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White,
`7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2
`
`intravenously on Days 1 and 2 for up to eight 21-day cycles.
`
`
`The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most
`common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%)
`and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile
`neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.
`
`
`
`Laboratory
`Abnormality
`
`All
`
`Grades
`n (%)
`134 (89)
`
`
`12 (9)
`
`
`14 (10)
`
`
`4 (3)
`
`
`6 (4)
`
`
`30 (21)
`
`
`115 (82)
`
`
`116 (77)
`
`
`16 (11)
`
`
`110 (78)
`
`
`92 (61)
`
`
`42 (28)
`
`
`102 (68)
`
`
`70 (47)
`
`
`113 (75)
`
`
`65 (43)
`
`
`26 (18)
`
`
`27 (19)
`
`
`86 (61)
`
`
`
`
`
`Reference ID: 3814582
`
`

`

`
`
`
`Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA
`by System Organ Class and Preferred Term (N=176)
`System organ class Number (%) of patients*
` Preferred term
`All
`Grades
`
`
`Grade 3/4
`
`
`
`176 (100)
`
`
`13 (7)
`
`
`
`
`
`
`
`
`
`
`
`
`94 (53)
`
`
`0
`
`7 (4)
`
`5 (3)
`
`6 (3)
`
`1 (<1)
`1 (<1)
`2 (1)
`
`0
`0
`
`1 (<1)
`0
`
`0
`
`
`19 (11)
`
`
`3 (2)
`
`
`0
`
`1 (<1)
`
`4 (2)
`
`
`1 (<1)
`
`0
`
`0
`
`0
`
`
`5 (3)
`
`0
`
`4 (2)
`
`
`0
`9 (5)
`
`11 (6)
`
`2 (1)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Total number of
`patients with at least
`1 adverse reaction
`Cardiac disorders
`
` Tachycardia
`Gastrointestinal
`disorders
`
` Nausea
` Vomiting
` Diarrhea
` Constipation
`
` Stomatitis
` Abdominal pain
`
` Dyspepsia
`Gastroesophageal
`reflux disease
`
`
` Dry mouth
` Abdominal pain
`upper
`
`
` Abdominal
`distension
`General disorders
`and administration
`site conditions
`Fatigue
`
` Pyrexia
`
` Chills
`
` Edema peripheral
`Asthenia
` Chest pain
`
` Infusion site pain
`Pain
`
`Catheter site pain
`Infections and
`infestations
`Herpes zoster
` Upper respiratory
`tract infection
` Urinary tract
`infection
`Sinusitis
`15 (9)
`
`
` Pneumonia
`14 (8)
`
` Febrile neutropenia 11 (6)
`
`11 (6)
` Oral candidiasis
`
`
`132 (75)
`
`71 (40)
`
`65 (37)
`
`51 (29)
`
`27 (15)
`
`22 (13)
`
`20 (11)
`18 (10)
`
`
`15 (9)
`
`8 (5)
`
`
`8 (5)
`
`
`
`
`101 (57)
`
`59 (34)
`
`24 (14)
`
`23 (13)
`
`19 (11)
`
`11 (6)
`
`11 (6)
`
`10 (6)
`
`8 (5)
`
`
`
`18 (10)
`
`18 (10)
`
`
`17 (10)
`
`
`
`
`
`Reference ID: 3814582
`
`
`
`

`

`11 (6)
`
`
`31 (18)
`
`
`
`
`25 (14)
`
`11 (6)
`
`8 (5)
`
`8 (5)
`
`
`
`36 (21)
`
`25 (14)
`
`13 (7)
`
`
`23 (13)
`
`14 (