HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use
`BENDEKA safely and effectively. See full prescribing information for
`BENDEKA.
`
`
`BENDEKA® (bendamustine hydrochloride injection), for intravenous use
`
`Initial U.S. Approval: 2008
`
`
`
`-------------------------INDICATIONS AND USAGE----------------------------­
`BENDEKA (bendamustine hydrochloride) injection 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----------------------­
`
`For CLL:
`
`
` 100 mg/m2 infused intravenously over 10 minutes on Days 1 and 2 of a 28­
`day cycle, up to 6 cycles. (2.1)
`
`
` 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)
`
` 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)
`
`
` Dose re-escalation may be considered. (2.1)
`For NHL:
`
`
` 120 mg/m2 infused intravenously over 10 minutes on Days 1 and 2 of a 21­
`day cycle, up to 8 cycles. (2.2)
`
`  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)
`
` 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:
`
` Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥
`
`Grade 2 non-hematologic toxicity. (2.1, 2.2)
`
` Store BENDEKA at recommended refrigerated storage conditions (2-8° C or
`
`36-46° F). When refrigerated, the contents may partially freeze. Allow the
`vial to reach room temperature (15-30° C or 59-86° F) prior to use. (2.3)
`
`
`
` BENDEKA must be diluted prior to infusion. (2.3)
`
`
`--------------------------DOSAGE FORMS AND STRENGTHS------------------­
`Injection: 100 mg/4 mL (25 mg/mL) in a multiple-dose vial. (3)
`
`
`
`
`
`
`
`
`
`
`
`------------------------------CONTRAINDICATIONS-------------------------------­
`BENDEKA is contraindicated in patients with a history of a hypersensitivity
`
`
`reaction to bendamustine, polyethylene glycol 400, propylene glycol, or
`
`
`
`
`
`
`monothioglycerol. Reactions to bendamustine hydrochloride have included
`anaphylaxis and anaphylactoid reactions (4, 5.3)
`
`--------------------------WARNINGS AND PRECAUTIONS----------------------­
`
` 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)
`Infections: Monitor for fever and other signs of infection or reactivation of
`
`infections and treat promptly. (5.2)
`
` Anaphylaxis and Infusion Reactions: Severe anaphylactic reactions have
`
`occurred. Monitor clinically and discontinue drug for severe reactions. Pre­
`medicate in subsequent cycles for milder reactions. (5.3)
`
` Tumor Lysis Syndrome: May lead to acute renal failure and death; anticipate
`and use supportive measures in patients at high risk. (5.4)
`
` Skin Reactions: Discontinue for severe skin reactions. Cases of SJS, DRESS
`
`and TEN, some fatal, have been reported. (5.5).
`
`
` Hepatotoxicity: Monitor liver chemistry tests prior to and during treatment.
`(5.6)
`
` Other Malignancies: Pre-malignant and malignant diseases have been reported.
`
`(5.7)
`
` Extravasation Injury: Take precautions to avoid extravasation, including
`monitoring intravenous infusion site during and after administration. (5.8)
`
` Embryo-fetal toxicity: Fetal harm can occur when administered to a pregnant
`
`woman. Women should be advised to avoid becoming pregnant when
`
`receiving bendamustine hydrochloride. (5.9, 8.1)
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`
` Adverse reactions (frequency >5%) during infusion and within 24 hours post-
`infusion are nausea and fatigue. (6.1)
`
` Most common non-hematologic adverse reactions for CLL (frequency ≥15%)
`
`
`
`are pyrexia, nausea, and vomiting. (6.2)
`
`
` 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. (6.3)
`
` Most common hematologic abnormalities (frequency ≥15%) are lymphopenia,
`
`
`anemia, leukopenia, thrombocytopenia, and neutropenia. (6.2, 6.3)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Teva
`
`Pharmaceuticals at 1-888-483-8279 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 <30 mL/min. (8.6)
`
`
`
` Hepatic Impairment: Do not use in moderate or severe hepatic impairment.
`
`
`(8.7)
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`
`
`Revised: 07/2018
`
`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 Preparation for Intravenous Administration
` 
`2.4 Admixture Stability
` 
`2.5 Stability of Partially Used Vials (Needle Punched Vials)
` 
`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 Hepatotoxicity
` 
`5.7 Other Malignancies
` 
`5.8 Extravasation Injury
` 
`5.9 Embryo-fetal Toxicity
` 
`6 ADVERSE REACTIONS
` 
`6.1 Adverse Events in Clinical Trials
`
` 
`6.2 Clinical Trials Experience in CLL
` 
`6.3 Clinical Trials Experience in NHL
` 
`6.4 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
` 
`12.2 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
`
`Reference ID: 4299048
`
`1
`
`

`

` 
`16 HOW SUPPLIED/STORAGE AND HANDLING
` 
`16.1 Safe Handling and Disposal
` 
`16.2 How Supplied
` 
`16.3 Storage
` 
`17 PATIENT COUNSELING INFORMATION
`
`FULL PRESCRIBING INFORMATION
`
`
`
`
`
` 1 INDICATIONS AND USAGE
`
`
`
`*Sections or subsections omitted from the full prescribing information are not
`
`listed.
`
`
`1.1 Chronic Lymphocytic Leukemia (CLL)
`BENDEKA® (bendamustine hydrochloride) injection 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)
`
`BENDEKA (bendamustine hydrochloride) injection 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 Dosing Instructions for CLL
`Recommended Dosage:
`
`The recommended dose is 100 mg/m2 administered intravenously over 10 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:
`BENDEKA (bendamustine hydrochloride) injection administration should be delayed in the
`event of Grade 4 hematologic toxicity or clinically significant greater than or equal to Grade 2
`non-hematologic toxicity. Once non-hematologic toxicity has recovered to less than or equal to
`Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) greater than
`or equal to 1 x 109/L, platelets greater than or equal to 75 x 109/L], BENDEKA (bendamustine
`
` hydrochloride) injection 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 10 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:
`
`BENDEKA (bendamustine hydrochloride) injection administration should be delayed in the
`event of a Grade 4 hematologic toxicity or clinically significant greater than or equal to Grade 2
`2
`
`Reference ID: 4299048
`
`

`

`non-hematologic toxicity. Once non-hematologic toxicity has recovered to less than or equal to
`Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) greater than
`or equal to 1 x 109/L, platelets greater than or equal to 75 x 109/L], BENDEKA (bendamustine
`hydrochloride) injection 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 Preparation for Intravenous Administration
`BENDEKA (bendamustine hydrochloride) injection is a cytotoxic drug. Follow applicable
`special handling and disposal procedures.1
`BENDEKA is in a multiple-dose vial. At room temperature, BENDEKA is a clear, and colorless
`to yellow ready-to-dilute solution. Store BENDEKA at recommended refrigerated storage
`conditions (2-8°C or 36-46°F). When refrigerated, the contents may partially freeze. Allow the
`vial to reach room temperature (15-30°C or 59-86°F) prior to use. If particulate matter is
`observed after achieving room temperature, the product should not be used.
`
`Intravenous Infusion
` Aseptically withdraw the volume needed for the required dose from the 25 mg/mL solution
`
`as per Table A below and immediately transfer the solution to a 50 mL infusion bag of one of
`the following diluents:
`
` 0.9% Sodium Chloride Injection, USP; or
`
` 2.5% Dextrose/0.45% Sodium Chloride Injection, USP; or
`
` 5% Dextrose Injection, USP.
`The resulting final concentration of bendamustine hydrochloride in the infusion bag should be
`within 1.85 mg/mL – 5.6 mg/mL. After transferring, thoroughly mix the contents of the infusion
`bag. The admixture should be a clear, and colorless to yellow solution.
`No other diluents have been shown to be compatible. The 5% Dextrose Injection, USP, offers a
`sodium-free method of administration for patients with certain medical conditions requiring
`restricted sodium intake.
`
`Table A: Volume (mL) of BENDEKA required for dilution into 50 mL of 0.9% saline, or
`0.45% saline/2.5% dextrose or 5% dextrose for a given dose (mg/m2) and Body Surface
`
`Area (m2)
`
`Body Surface Area (m2)
`
`
`
`
`Volume of BENDEKA to withdraw (mL)
`
`1
`
`120 mg/m2
`4.8
`
`100 mg/m2
`4
`
`
` 90 mg/m2
`3.6
`
`
` 60 mg/m2
`2.4
`
`
` 50 mg/m2
`2
`
`
`
` 25 mg/m2
`1
`
`Reference ID: 4299048
`
`3
`
`

`

`Body Surface Area (m2)
`
`
`
`
`Volume of BENDEKA to withdraw (mL)
`
`1.1
`
`1.2
`
`1.3
`1.4
`1.5
`
`1.6
`
`1.7
`
`1.8
`
`1.9
`2
`2.1
`
`2.2
`
`2.3
`
`2.4
`2.5
`2.6
`2.7
`2.8
`2.9
`
`3
`
`120 mg/m2
`5.3
`
`5.8
`
`6.2
`6.7
`7.2
`
`7.7
`
`8.2
`
`8.6
`
`9.1
`9.6
`
`10.1
`
`10.6
`
`11
`
`11.5
`
`12
`
`12.5
`
`13
`
`13.4
`
` 13.9
`14.4
`
`100 mg/m2
`4.4
`4.8
`5.2
`5.6
`6
`6.4
`6.8
`7.2
`7.6
`8
`
`8.4
`8.8
`9.2
`9.6
`
`10
`
`10.4
`
`10.8
`
`11.2
`
` 11.6
`12
`
`
` 90 mg/m2
`4
`4.3
`4.7
`5
`5.4
`5.8
`6.1
`6.5
`6.8
`7.2
`
`7.6
`7.9
`8.3
`8.6
`9
`
`9.4
`
`9.7
`
`10.1
`
` 10.4
`
`10.8
`
`
` 60 mg/m2
`2.6
`
`2.9
`
`3.1
`3.4
`3.6
`
`3.8
`
`4.1
`
`4.3
`
`4.6
`4.8
`
`5
`
`5.3
`
`5.5
`
`5.8
`6
`
`6.2
`
`6.5
`
`6.7
`
` 7
`
`7.2
`
`
` 50 mg/m2
`2.2
`
`2.4
`
`2.6
`2.8
`3
`
`3.2
`
`3.4
`
`3.6
`
`3.8
`4
`
`4.2
`
`4.4
`
`4.6
`
`4.8
`5
`
`5.2
`
`5.4
`
`5.6
`
` 5.8
`
`6
`
`
`
` 25 mg/m2
`1.1
`
`1.2
`
`1.3
`1.4
`1.5
`
`1.6
`
`1.7
`
`1.8
`
`1.9
`2
`
`2.1
`
`2.2
`
`2.3
`
`2.4
`2.5
`
`2.6
`
`2.7
`
`2.8
`
` 2.9
`
`3
`
`
`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.
`
` 2.4 Admixture Stability
`
`BENDEKA (bendamustine hydrochloride) injection contains no antimicrobial preservative. The
`admixture should be prepared as close as possible to the time of patient administration.
`If diluted with 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
`46°F) or for 6 hours when stored at room temperature (15-30°C or 59-86°F) and room light.
`Administration of diluted BENDEKA (bendamustine hydrochloride) injection must be
`completed within this period of time.
`In the event that 5% Dextrose Injection, USP is utilized, the final admixture is stable for 24 hours
`when stored refrigerated (2-8°C or 36-46°F) or for only 3 hours when stored at room temperature
`
`(15-30°C or 59-86°F) and room light. Administration of diluted BENDEKA must be completed
`within this period of time.
`
`Retain the partially used vial in original package to protect from light and store refrigerated (2­
`8°C or 36-46°F) if additional dose withdrawal from the same vial is intended.
`
`Reference ID: 4299048
`
`4
`
`

`

`2.5 Stability of Partially Used Vials (Needle Punched Vials)
`BENDEKA is supplied in a multiple-dose vial. Although it does not contain any antimicrobial
`preservative, BENDEKA is bacteriostatic. The partially used vials are stable for up to 28 days
`
` when stored in its original carton under refrigeration (2-8°C or 36-46°F). Each vial is not
`recommended for more than a total of six (6) dose withdrawals.
`After first use, the partially used vial should be stored in the refrigerator in the original carton at
`2°-8°C or 36-46°F and then discarded after 28 days.
`
`3 DOSAGE FORMS AND STRENGTHS
`
`Injection: 100 mg/4 mL (25 mg/mL) as a clear and colorless to yellow ready-to-dilute solution in
`a multiple-dose vial.
`
`
`4 CONTRAINDICATIONS
`
`BENDEKA (bendamustine hydrochloride) injection is contraindicated in patients with a known
`hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene
`glycol 400, propylene glycol, or monothioglycerol. [see Warnings and Precautions (5.3)]
`
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Myelosuppression
`
`Bendamustine hydrochloride 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).
`BENDEKA (bendamustine hydrochloride) injection causes myelosuppression. Monitor complete
`blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In
`the clinical trials, blood counts were monitored every week initially. Hematologic nadirs
`occurred 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 (2.1)
`
`
`5.2 Infections
`Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult
`and pediatric patients in clinical trials and in postmarketing reports for bendamustine
`hydrochloride. Patients with myelosuppression following treatment with bendamustine
`hydrochloride are more susceptible to infections. Advise patients with myelosuppression
`following BENDEKA (bendamustine hydrochloride) injection treatment to contact a physician
`immediately if they have symptoms or signs of infection.
`
`Patients treated with bendamustine hydrochloride are at risk for reactivation of infections
`including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and
`herpes zoster. Patients should undergo appropriate measures (including clinical and laboratory
`
`Reference ID: 4299048
`
`5
`
`

`

`monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to
`administration.
`
`5.3 Anaphylaxis and Infusion Reactions
`Infusion reactions to bendamustine hydrochloride 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
`experienced Grade 3 or worse allergic-type reactions were not typically 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
`BENDEKA (bendamustine hydrochloride) injection for patients with Grade 4 infusion reactions.
`Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering
`individual benefits, risks, and supportive care.
`
`5.4 Tumor Lysis Syndrome
`Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in
`clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle
`of bendamustine hydrochloride 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 bendamustine hydrochloride therapy. However, there may be an increased risk of severe skin
`toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly. [see
`
`Warnings and Precautions (5.5)]
`
`
`5.5 Skin Reactions
`Fatal and serious skin reactions have been reported with bendamustine hydrochloride injection
`treatment in clinical trials and postmarketing safety reports, including toxic skin reactions
`[Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with
`eosinophilia and systemic symptoms (DRESS)], bullous exanthema, and rash. Events occurred
`when bendamustine hydrochloride injection was given as a single agent and in combination with
`other anticancer agents or allopurinol.
`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 BENDEKA (bendamustine hydrochloride) injection.
`
`5.6 Hepatotoxicity
`Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride
`injection. Combination therapy, progressive disease or reactivation of hepatitis B were
`confounding factors in some patients [see Warnings and Precautions (5.2)]. Most cases were
`reported within the first three months of starting therapy. Monitor liver chemistry tests prior to
`and during bendamustine therapy.
`
`Reference ID: 4299048
`
`6
`
`

`

`5.7 Other Malignancies
`There are reports of pre-malignant and malignant diseases that have developed in patients who
`have been treated with bendamustine hydrochloride, including myelodysplastic syndrome,
`myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association
`with BENDEKA (bendamustine hydrochloride) injection therapy has not been determined.
`
`5.8 Extravasation Injury
`
`Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in
`
`hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to
`starting drug infusion and monitor the intravenous infusion site for redness, swelling, pain,
`infection, and necrosis during and after administration of BENDEKA (bendamustine
`hydrochloride) injection.
`
`5.9 Embryo-fetal Toxicity
`
`Bendamustine hydrochloride 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 bendamustine hydrochloride
`in clinical trials and are discussed in greater detail in other sections of the prescribing
`information.
`
` 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)]
`
`
`
` Hepatotoxicity [see Warnings and Precautions (5.6)]
`
`
`
` Other Malignancies [see Warnings and Precautions (5.7)]
`
`
`
`
` Extravasation Injury [see Warnings and Precautions (5.8)]
`
`
`
`
`6.1 Adverse Events in Clinical Trials
`The data described below reflect exposure to bendamustine hydrochloride in 329 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.
`The safety of BENDEKA (bendamustine hydrochloride) injection administered IV as a 50 mL
`
`admixture over a 10-minute infusion is supported by clinical trials using bendamustine
`hydrochloride administered IV as a 500 mL admixture over 30-60 minutes infusion time, as well
`as an open-label, crossover study in 81 ‘end-of-life’ cancer patients treated with BENDEKA. In
`
`Reference ID: 4299048
`
`7
`
`

`

`total, safety data from clinical studies are available from over 400 cancer patients exposed to
`bendamustine hydrochloride at doses in the range used in the treatment of CLL and NHL.
`No clinically significant differences in the adverse event profile were noted among bendamustine
`hydrochloride administered as a 500 mL admixture over standard infusion time (30-60 minutes)
`and BENDEKA administered as a 50 mL admixture in a ‘short-time’ infusion over 10 minutes.
`The safety and tolerability of BENDEKA was evaluated in an 8-week clinical study of
`BENDEKA in 81 ‘end-of-life’ cancer patients, diagnosed with solid tumors and hematologic
`malignancies (excluding CLL). The population was 40-82 years of age, 58% females, 84%
`white, 12.3% Black, 1.2% Asian and 2.5% were classified as ‘other’. BENDEKA was
`administered IV at a 120 mg/m2 dose as a 50 mL admixture over 10 minutes. Patients in the
`study received BENDEKA (50 mL IV, over 10 minutes) or bendamustine hydrochloride (500
`mL IV, over 60 minutes) on Days 1 and 2 every 28 days for two consecutive 2-day cycles.
`Adverse reactions (any grade) that occurred with a frequency greater than 5% during BENDEKA
`infusion and within one hour post-infusion were nausea (8.2%) and fatigue (5.5%).
`Adverse reactions (any grade) that occurred with a frequency greater than 5% within 24 hours of
`BENDEKA were nausea (10.9%) and fatigue (8.2%).
`Adverse reactions leading to study withdrawal in 4 patients receiving BENDEKA were pyrexia
`(1.2%), nausea (1.2%), vomiting (1.2%), pneumonia (1.2%) and fatigue (1.2%).
`
`
`6.2 Clinical Trials Experience in CLL
`The data described below reflect exposure to bendamustine hydrochloride in 153
`patients. Bendamustine hydrochloride was studied in an active-controlled randomized 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 bendamustine hydrochloride 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 bendamustine hydrochloride in
`the randomized CLL clinical study 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.
`The most frequent adverse reactions leading to study withdrawal for patients receiving
`bendamustine hydrochloride 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.
`
`
`Reference ID: 4299048
`
`8
`
`

`

`Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical
`Study in at Least 5% of Patients
`
`
` Number (%) of patients
`Bendamustine Hydrochloride
`
`(N=153)
`
`
`
`Chlorambucil
`(N=143)
`
`
`
`All Grades
`
`Grade 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)
`
`
`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)
`
`
`96 (67)
`
`
`
`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)
`
`
`25 (17)
`
`
`1 (<1)
`
`0
`0
`
`
`
`2 (1)
`
`0
`0
`0
`
`0
`
`0
`
`1 (<1)
`0
`
`
`0
`
`
`0
`
`
`1 (<1)
`
`
`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
`
`
`
`12 (8)
`
`8 (5)
`
`
`4 (3)
`0
`
`
`7 (5)
`
`2 (1)
`
`
`3 (2)
`0
`
`
`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 bendamustine hydrochloride. Red blood cell transfusions were
`administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of
`
`patients receiving chlorambucil.
`Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received
`bendamustine hydrochloride or Chlorambucil in the Randomized CLL Clinical Study
`
`Reference ID: 4299048
`
`9
`
`

`

` Laboratory
`
` Abnormality
`
`
`Hemoglobin
`
`Decreased
`Platelets
`
`Decreased
`Leukocytes
`
`Decreased
`Lymphocytes
`
`Decreased
`Neutrophils
`
`Decreased
`
`Bendamustine Hydrochloride
` N=150
`
`All Grades
`
`n (%)
`
`134 (89)
`
`Grade 3/4
`
`n (%)
`
`20 (13)
`
`Chlorambucil
`
` N=141
`
`All Grades
`
`n (%)
`
`115 (82)
`
`Grade 3/4
`
`n (%)
`
`
`12 (9)
`
`116 (77)
`
`
`92 (61)
`
`
`102 (68)
`
`
`113 (75)
`
`
`16 (11)
`
`
`42 (28)
`
`
`70 (47)
`
`
`65 (43)
`
`
`110 (78)
`
`
`26 (18)
`
`
`27 (19)
`
`
`86 (61)
`
`
`
`14 (10)
`
`
`4 (3)
`
`
`6 (4)
`
`
`30 (21)
`
`
`In the randomized 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 bendamustine hydrochloride may also have changes in their
`creatinine levels. If abnormalities are detected, monitoring of these parameters should be
`continued to ensure that significant deterioration does not occur.
`
`6.3 Clinical Trials Experience in NHL
`The data described below reflect exposure to bendamustine hydrochloride 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 bendamustine hydrochloride 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.
`Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients
`Treated with bendamustine hydrochloride by System Organ Class and Preferred Term
`(N=176)
` System organ class
`Preferred Term
`
`Total number of patients with at
`
`least 1 adverse reaction
`
`Cardiac Disorders
`
` Tachycardia
`
`Gastrointestinal disorders
`
` Nausea
`
` Vomiting
`
`
`
`
`
`
`
` Number (%) of patients*
`All Grades
`
`176 (100)
`
`
`Grade 3/4
`
`94 (53)
`
`
`13 (7)
`
`
`132 (75)
`
`71 (40)
`
`
`0
`
`7 (4)
`
`5 (3)
`
`
`Reference ID: 4299048
`
`10
`
`

`

`
`
` System organ class
`Preferred Term
`
` 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
`