`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: Can cause fetal harm. Advise females of reproductive
`potential of the potential risk to a fetus and to use an effective method of
`contraception. (5.9, 8.1, 8.3)
`
`------------------------------ADVERSE REACTIONS-------------------------------
` Adverse reactions (frequency >5%) during infusion and within 24 hours post-
`infusion are nausea and fatigue. (6.1)
` Most common adverse reactions (≥15%) for CLL are anemia,
`thrombocytopenia, neutropenia, lymphopenia, leukopenia,
`hyperbilirubinemia, pyrexia, nausea, vomiting. (6.2, 6.3)
` Most common adverse reactions (≥15%) for NHL are lymphopenia,
`leukopenia, anemia neutropenia, thrombocytopenia, nausea, fatigue, vomiting,
`diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased,
`dyspnea, rash, and stomatitis.(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-------------------------------
`Consider alternative therapies that are not CYP1A2 inducers or inhibitors during
`treatment with BENDEKA. (7.1)
`
`--------------------------USE IN SPECIFIC POPULATIONS---------------------
` Lactation: Advise not to breastfeed. (8.2)
`
`Infertility: May impair fertility. (8.3)
` Renal Impairment: Do not use in patients with creatinine clearance <30
`mL/min. (8.6)
` Hepatic Impairment: Do not use in patients with total bilirubin 1.5-3 × ULN
`and AST or ALT 2.5-10 × ULN, or total bilirubin > 3 × ULN. (8.7)
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`Revised: 10/2019
`
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`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
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`
`
`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 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)
`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)
`
`
`--------------------------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, and restart treatment based on
`ANC and platelet count recovery. (2.1, 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)
`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 Postmarketing Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.3 Females and Males of Reproductive Potential
`8.4 Pediatric Use
`
`Reference ID: 4503589
`
`1
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`
`Reference ID: 4503589
`
`1.1 Chronic Lymphocytic Leukemia (CLL)
`BENDEKA® 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 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:
`Delay BENDEKA administration 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],
`reinitiate BENDEKA (bendamustine hydrochloride) injection at the discretion of the treating physician. In addition, consider dose
`reduction. [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.
`Consider dose re-escalation in subsequent cycles at the discretion of the treating physician.
`
`2
`
`
`
`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:
`Delay BENDEKA administration in the event of a 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],
`reinitiate BENDEKA at the discretion of the treating physician. In addition, consider dose reduction. [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 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. Do not use the product if particulate matter is
`observed after achieving room temperature.
`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.
`
`3
`
`Reference ID: 4503589
`
`
`
`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
`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
`4.8
`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
`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
`3.6
`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
`
`4
`
`60 mg/m2
`2.4
`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
`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
`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
`
`Reference ID: 4503589
`
`
`
`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 contains no antimicrobial preservative. Prepare the admixture 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.
`
`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, store the partially used vial 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 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
`
`Reference ID: 4503589
`
`
`
`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 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 treatment to contact a
`physician immediately if they have symptoms or signs of infection.
`
`Patients treated with BENDEKA 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
`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 for patients with Grade 4 infusion
`reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering individual benefits, risks, and
`supportive care.
`
`6
`
`Reference ID: 4503589
`
`
`
`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.
`
`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
`BENDEKA therapy.
`
`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 bendamustine hydrochloride 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.
`
`7
`
`Reference ID: 4503589
`
`
`
`5.9 Embryo-Fetal Toxicity
`Based on findings from animal reproduction studies and the drug’s mechanism of action, BENDEKA can cause fetal harm when
`administered to a pregnant woman. Single intraperitoneal doses of bendamustine (that approximated the maximum recommended
`human dose based on body surface area) to pregnant mice and rats during organogenesis caused adverse developmental outcomes,
`including an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. Advise pregnant women
`of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment
`with BENDEKA and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use
`effective contraception during treatment with BENDEKA and for at least 3 months after the final dose. [see Use in Specific
`Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]
`
`6 ADVERSE REACTIONS
`The following clinically significant 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 Clinical Trials Experience
`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 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,
`
`8
`
`Reference ID: 4503589
`
`
`
`crossover study in 81 ‘end-of-life’ cancer patients treated with BENDEKA. In 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 reaction 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.
`
`9
`
`Reference ID: 4503589
`
`
`
`Body System
` Adverse Reaction
`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
`
`Reference ID: 4503589
`
`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.
`
`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)
`
`52 (34)
`
`1 (<1)
`1 (<1)
`2 (1)
`
`
`6 (4)
`2 (1)
`0
`0
`
`2 (1)
`
`0
`3 (2)
`0
`
`0
`
`
`3 (2)
`
`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)
`
`10
`
`25 (17)
`
`1 (<1)
`0
`0
`
`
`2 (1)
`0
`0
`0
`
`0
`
`0
`1 (<1)
`0
`
`0
`
`
`0
`
`
`
`
`
`Reference ID: 4503589
`
`Respiratory, thoracic and
`mediastinal disorders
` Cough
`Skin and subcutaneous
`tissue disorders
` Rash
` Pruritus
`
`Laboratory
`Abnormality
`
`
`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
`Bendamustine Hydrochloride
` N=150
`
`Hemoglobin
`Decreased
`Platelets
`Decreased
`Leukocytes
`Decreased
`Lymphocytes
`Decreased
`Neutrophils
`Decreased
`
`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.
`
`11
`
`Number (%) of patients
`Bendamustine Hydrochloride
`(N=153)
`
`
`
`
`
`
`
`6 (4)
`
`
`1 (<1)
`
`
`7 (5)
`
`
`Chlorambucil
`(N=143)
`
`
`
`1 (<1)
`
`
`12 (8)
`8 (5)
`
`4 (3)
`0
`
`7 (5)
`2 (1)
`
`3 (2)
`0
`
`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)
`
`
`
`12
`
`13 (7)
`
`Reference ID: 4503589
`
`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)
`Body System
`Number (%) of patients*
`Adverse Reaction
`All Grades
`Total number of patients with at
`176 (100)
`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
`
`132 (75)
`71 (40)
`65 (37)
`51 (29)
`27 (15)
`22 (13)
`20 (11)
`18 (10)
`15 (9)
`8 (5)
`
`Grade 3/4
`94 (53)
`
`0
`
`7 (4)
`5 (3)
`6 (3)
`1 (<1)
`1 (<1)
`2 (1)
`0
`0
`1 (<1)
`0
`
`
`
`Body System
`Adverse Reaction
` 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
` Pneumonia
` Febrile neutropenia
` Oral candidiasis
` Nasopharyngitis
`Investigations
` Weight decreased
`Metabolism and nutrition disorders
` Anorexia
` Dehydration
`
`Number (%) of patients*
`All Grades
`8 (5)
`
`Grade 3/4
`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)
`0
`
`3 (2)
`
`3 (2)
`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)
`15 (9)
`14 (8)
`11 (6)
`11 (6)
`11 (6)
`
`31 (18)
`
`40 (23)
`24 (14)
`
`13
`
`Reference ID: 4503589
`
`
`
`Grade 3/4
`1 (<1)
`9 (5)
`
`5 (3)
`0
`2 (1)
`0
`
`0
`0
`0
`
`0
`1 (<1)
`0
`
`1 (<1)
`3 (2)
`1 (<1)
`0
`0
`
`1 (<1)
`0
`0
`
`Number (%) of patients*
`All Grades
`22 (13)
`15 (9)
`
`25 (14)
`11 (6)
`8 (5)
`8 (5)
`
`36 (21)
`25 (14)
`13 (7)
`
`23 (13)
`14 (8)
`10 (6)
`
`38 (22)
`28 (16)
`14 (8)
`8 (5)
`8 (5)
`
`28 (16)
`11 (6)
`9 (5)
`
`14
`
`Body System
`Adverse Reaction
` Decreased appetite
` Hypokalemia
`Musculoskeletal and connective tissue disorders
` Back pain
` Arthralgia
` Pain in extremity
` Bone pain
`Nervous system disorders
` Headache
` Dizziness
` Dysgeusia
`Psychiatric disorder
` Insomnia
` Anxiety
` Depression
`Respiratory, thoracic and mediastinal disorders
` Cough
` Dyspnea
` Pharyngolaryngeal pain
` Wheezing
` Nasal congestion
`Skin and subcutaneous tissue disorders
` Rash
` Pruritus
` Dry skin
`
`Reference ID: 4503589
`
`
`
`Number (%) of patients*
`All Grades
`9 (5)
`8 (5)
`
`10 (6)
`
`Grade 3/4
`0
`0
`
`2 (1)
`
`Reference ID: 4503589
`
`Body System
`Adverse Reaction
` Night sweats
` Hyperhidrosis
`Vascular disorders
` Hypotension
`*Patients may have reported more than 1 adverse reaction.
`NOTE: Patients counted only once in each preferred term category and once in each system organ class category.
`Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are
`described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1%
`of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine
`(2%), hyponatremia (2%), and hypocalcemia (2%).
`Table 4: Incidence of Hematology