Label: BENDAMUSTINE- bendamustine hcl injection, powder, lyophilized, for solution
BENDAMUSTINE- bendamustine hcl injection, powder, lyophilized, for solution

  • NDC Code(s): 71288-102-10, 71288-103-20
  • Packager: Meitheal Pharmaceuticals Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: Abbreviated New Drug Application

Drug Label Information

Updated June 5, 2023

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use BENDAMUSTINE HYDROCHLORIDE FOR INJECTION safely and effectively. See full prescribing information for BENDAMUSTINE HYDROCHLORIDE FOR INJECTION.
    BENDAMUSTINE HYDROCHLORIDE for injection, for intravenous use
    Initial U.S. Approval: 2008

    INDICATIONS AND USAGE

    Bendamustine Hydrochloride for 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

    Bendamustine hydrochloride is available in two formulations, a solution (Bendamustine Injection) and a lyophilized powder (Bendamustine for Injection). (2.1)

    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)

    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)

    DOSAGE FORMS AND STRENGTHS

    Bendamustine Hydrochloride for Injection: 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution. (3)

    CONTRAINDICATIONS

    Bendamustine hydrochloride is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine. Reactions have included anaphylaxis and anaphylactoid reactions. (4, 5.4)

    WARNINGS AND PRECAUTIONS

    • Myelosuppression: Delay or reduce dose and restart treatment based on ANC and platelet count recovery. (5.1)
    • Infections: Monitor for fever and other signs of infection or reactivation of infections and treat promptly. (5.2)
    • Progressive multifocal leukoencephalopathy (PML): Monitor for new or worsening neurological, cognitive or behavioral signs or symptoms suggestive of PML. (5.3)
    • Anaphylaxis and Infusion Reactions: Severe and anaphylactic reactions have occurred; monitor clinically and discontinue drug for severe reactions. Pre-medicate in subsequent cycles for milder reactions. (5.4)
    • Tumor Lysis Syndrome: May lead to acute renal failure and death; anticipate and use supportive measures in patients at high risk. (5.5)
    • Skin Reactions: Discontinue for severe skin reactions. Cases of SJS, DRESS and TEN, some fatal, have been reported. (5.6)
    • Hepatotoxicity: Monitor liver chemistry tests prior to and during treatment. (5.7)
    • Other Malignancies: Pre-malignant and malignant diseases have been reported. (5.8)
    • Extravasation Injury: Take precautions to avoid extravasation, including monitoring intravenous infusion site during and after administration. (5.9)
    • 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. (5.10, 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, pyrexia, nausea, vomiting. (6.1, 6.2)
    • 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. (6.1, 6.2)

    To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 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 bendamustine hydrochloride. (7)

    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 x ULN and AST or ALT 2.5-10 x ULN, or total bilirubin >3 x ULN. (8.7)

    Revised: 2/2023

  • Table of Contents

    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 Bendamustine 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 Progressive Multifocal Leukoencephalopathy (PML)

    5.4 Anaphylaxis and Infusion Reactions

    5.5 Tumor Lysis Syndrome

    5.6 Skin Reactions

    5.7 Hepatotoxicity

    5.8 Other Malignancies

    5.9 Extravasation Injury

    5.10 Embryo-Fetal Toxicity

    6 ADVERSE REACTIONS

    6.1 Clinical Trials Experience

    6.2 Postmarketing Experience

    7 DRUG INTERACTIONS

    7.1 Effect of Other Drugs on Bendamustine Hydrochloride

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    8.2 Lactation

    8.3 Females and Males of Reproductive Potential

    8.4 Pediatric Use

    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

    *
    Sections or subsections omitted from the full prescribing information are not listed.
  • 1 INDICATIONS AND USAGE

    1.1 Chronic Lymphocytic Leukemia (CLL)

    Bendamustine Hydrochloride for 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)

    Bendamustine Hydrochloride for 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 Selection of Bendamustine Formulation to Administer

    Bendamustine hydrochloride is available in two formulations, a solution (Bendamustine Injection) and a lyophilized powder (Bendamustine for Injection).

    Bendamustine Hydrochloride Injection and the reconstituted Bendamustine Hydrochloride 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.

    If a CSTD or adapter that contains polycarbonate or ABS is used as supplemental protection prior to dilution1, only use bendamustine hydrochloride for injection, the lyophilized powder formulation [see How Supplied/Storage and Handling (16)].

    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

    Delay bendamustine hydrochloride administration in the event of Grade 4 hematologic toxicity or clinically significant ≥ 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) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], reinitiate bendamustine hydrochloride 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.

    2.3 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

    Delay bendamustine hydrochloride 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 ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], reinitiate bendamustine hydrochloride 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.

    2.4 Preparation for Intravenous Administration

    Bendamustine hydrochloride is a hazardous drug. Follow applicable special handling and disposal procedures.1

    Bendamustine Hydrochloride for Injection (25 mg per vial or 100 mg per 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 bendamustine hydrochloride for injection, the lyophilized formulation.

    • Each vial of bendamustine hydrochloride for injection is intended for single-dose only.
    • Aseptically reconstitute each bendamustine hydrochloride for injection vial as follows:
      • 25 mg bendamustine hydrochloride for injection vial: Add 5 mL of only Sterile Water for Injection, USP.
      • 100 mg bendamustine hydrochloride 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 hydrochloride concentration of 5 mg per 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 per 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 hydrochloride in the infusion bag should be within 0.2 to 0.6 mg per 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.

    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

    Bendamustine hydrochloride for injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.

    Bendamustine Hydrochloride for Injection (25 mg per vial or 100 mg per 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 stored under refrigerated conditions at 2° to 8°C (36° to 46°F) or for 3 hours when stored at room temperature (15° to 30°C or 59° to 86°F) and room light. Administration of reconstituted and diluted bendamustine hydrochloride for injection must be completed within this period.

  • 3 DOSAGE FORMS AND STRENGTHS

    • Bendamustine Hydrochloride for Injection, USP: 25 mg or 100 mg white to off-white lyophilized powder in a single-dose vial for reconstitution.
  • 4 CONTRAINDICATIONS

    Bendamustine hydrochloride is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine [see Warnings and Precautions (5.4)].

  • 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 Adverse Reactions (6.1)]. 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).

    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 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, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports [see Adverse Reactions (6.1, 6.2)]. Patients with myelosuppression following treatment with bendamustine hydrochloride are more susceptible to infections. Advise patients with myelosuppression following bendamustine hydrochloride treatment to contact a physician 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 monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to administration.

    5.3 Progressive Multifocal Leukoencephalopathy (PML)

    Progressive multifocal leukoencephalopathy (PML), including fatal cases, have occurred following treatment with bendamustine, primarily in combination with rituximab or obinutuzumab [see Adverse Reactions (6.2)]. Consider PML in the differential diagnosis in patients with new or worsening neurological, cognitive or behavioral signs or symptoms. If PML is suspected, withhold bendamustine hydrochloride treatment and perform appropriate diagnostic evaluations. Consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

    5.4 Anaphylaxis and Infusion Reactions

    Infusion reactions to bendamustine hydrochloride have occurred commonly in clinical trials [see Adverse Reactions (6.1)]. 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 bendamustine hydrochloride for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.

    5.5 Tumor Lysis Syndrome

    Tumor lysis syndrome associated with bendamustine hydrochloride treatment has occurred in patients in clinical trials and in postmarketing reports [see Adverse Reactions (6.1)]. 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 (5.6)].

    5.6 Skin Reactions

    Fatal and serious skin reactions have been reported with bendamustine hydrochloride 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 [see Adverse Reactions (6.1, 6.2)]. Events occurred when bendamustine hydrochloride 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 bendamustine hydrochloride.

    5.7 Hepatotoxicity

    Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride [see Adverse Reactions (6.1)]. 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.

    5.8 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, bronchial carcinoma, and non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma [see Adverse Reactions (6.2)].

    Monitor patients for the development of secondary malignancies. Perform dermatologic evaluations during and after treatment with bendamustine hydrochloride.

    5.9 Extravasation Injury

    Bendamustine hydrochloride extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain [see Adverse Reactions (6.2)]. Assure good venous access prior to starting bendamustine hydrochloride infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of bendamustine hydrochloride.

    5.10 Embryo-Fetal Toxicity

    Based on findings from animal reproduction studies and the drug's mechanism of action, bendamustine hydrochloride 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 bendamustine hydrochloride and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with bendamustine hydrochloride and for 3 months after the last 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 label.

    • Myelosuppression [see Warnings and Precautions (5.1)]
    • Infections [see Warnings and Precautions (5.2)]
    • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)]
    • Anaphylaxis and Infusion Reactions [see Warnings and Precautions (5.4)]
    • Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]
    • Skin Reactions [see Warnings and Precautions (5.6)]
    • Hepatotoxicity [see Warnings and Precautions (5.7)]
    • Other Malignancies [see Warnings and Precautions (5.8)]
    • Extravasation Injury [see Warnings and Precautions (5.9)]

    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 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.

    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)
    Body System/Adverse ReactionAll
    Grades    		Grade 3/4All
    Grades    		Grade 3/4
    Total number of patients with at least 1 adverse reaction121 (79)52 (34)96 (67)25 (17)
    Gastrointestinal disorders
    Nausea
    Vomiting
    Diarrhea    		31 (20)
    24 (16)
    14 (9)    		1 (<1)
    1 (<1)
    2 (1)    		21 (15)
    9 (6)
    5 (3)    		1 (<1)
    0
    0
    General disorders and administration site conditions
    Pyrexia
    Fatigue
    Asthenia
    Chills    		36 (24)
    14 (9)
    13 (8)
    9 (6)    		6 (4)
    2 (1)
    0
    0    		8 (6)
    8 (6)
    6 (4)
    1 (<1)    		2 (1)
    0
    0
    0
    Immune system disorders
    Hypersensitivity    		7 (5)2 (1)3 (2)0
    Infections and infestations
    Nasopharyngitis
    Infection
    Herpes simplex    		10 (7)
    9 (6)
    5 (3)    		0
    3 (2)
    0    		12 (8)
    1 (<1)
    7 (5)    		0
    1 (<1)
    0
    Investigations
    Weight decreased11 (7)05 (3)0
    Metabolism and nutrition disorders
    Hyperuricemia11 (7)3 (2)2 (1)0
    Respiratory, thoracic and mediastinal disorders
    Cough6 (4)1 (<1)7 (5)1 (<1)
    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
    Bendamustine Hydrochloride
    N=150    		Chlorambucil
    N=141
    Laboratory AbnormalityAll Grades
    n (%)    		Grade 3/4
    n (%)    		All Grades
    n (%)    		Grade 3/4
    n (%)
    Hemoglobin Decreased134 (89)20 (13)115 (82)12 (9)
    Platelets
    Decreased    		116 (77)16 (11)110 (78)14 (10)
    Leukocytes Decreased92 (61)42 (28)26 (18)4 (3)
    Lymphocytes Decreased102 (68)70 (47)27 (19)6 (4)
    Neutrophils Decreased113 (75)65 (43)86 (61)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 further deterioration does not occur.

    Non-Hodgkin Lymphoma

    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 (N=176)

    *Patients may have reported more than 1 adverse reaction.

    NOTE: Patients counted only once in each adverse reaction category and once in each body system category.
    Body System/Adverse ReactionNumber (%) of patients*
    All GradesGrade 3/4
    Total number of patients with at least 1 adverse reaction

    176 (100)

    94 (53)
    Cardiac disorders
    Tachycardia    		13 (7)0
    Gastrointestinal disorders
    Nausea
    Vomiting
    Diarrhea
    Constipation
    Stomatitis
    Abdominal pain
    Dyspepsia    		132 (75)
    71 (40)
    65 (37)
    51 (29)
    27 (15)
    22 (13)
    20 (11)    		7 (4)
    5 (3)
    6 (3)
    1 (<1)
    1 (<1)
    2 (1)
    0
    Gastroesophageal reflux disease18 (10)0
    Dry mouth
    Abdominal pain upper
    Abdominal distension    		15 (9)
    8 (5)
    8 (5)    		1 (<1)
    0
    0
    General disorders and administration site conditions
    Fatigue
    Pyrexia
    Chills
    Edema peripheral
    Asthenia
    Chest pain
    Infusion site pain
    Pain
    Catheter site pain    		101 (57)
    59 (34)
    24 (14)
    23 (13)
    19 (11)
    11 (6)
    11 (6)
    10 (6)
    8 (5)    		19 (11)
    3 (2)
    0
    1 (<1)
    4 (2)
    1 (<1)
    0
    0
    0
    Infections and infestations
    Herpes zoster18 (10)5 (3)
    Upper respiratory tract infection18 (10)0
    Urinary tract infection17 (10)4 (2)
    Sinusitis15 (9)0
    Pneumonia14 (8)9 (5)
    Febrile neutropenia11 (6)11 (6)
    Oral candidiasis11 (6)2 (1)
    Nasopharyngitis11 (6)0
    Investigations
    Weight decreased    		31 (18)3 (2)
    Metabolism and nutrition disorders
    Anorexia
    Dehydration
    Decreased appetite
    Hypokalemia    		40 (23)
    24 (14)
    22 (13)
    15 (9)    		3 (2)
    8 (5)
    1 (<1)
    9 (5)
    Musculoskeletal and connective tissue disorders
    Back pain
    Arthralgia
    Pain in extremity
    Bone pain    		25 (14)
    11 (6)
    8 (5)
    8 (5)    		5 (3)
    0
    2 (1)
    0
    Nervous system disorders
    Headache
    Dizziness
    Dysgeusia    		36 (21)
    25 (14)
    13 (7)    		0
    0
    0
    Psychiatric disorders
    Insomnia
    Anxiety
    Depression    		23 (13)
    14 (8)
    10 (6)    		0
    1 (<1)
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
    Dyspnea
    Pharyngolaryngeal pain
    Wheezing
    Nasal congestion    		38 (22)
    28 (16)
    14 (8)
    8 (5)
    8 (5)    		1 (<1)
    3 (2)
    1 (<1)
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
    Pruritus
    Dry skin
    Night sweats
    Hyperhidrosis    		28 (16)
    11 (6)
    9 (5)
    9 (5)
    8 (5)    		1 (<1)
    0
    0
    0
    0
    Vascular disorders
    Hypotension
    10 (6)
    2 (1)

    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 Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride in the NHL Studies
    HematologyPercent of patients
    variableAll GradesGrade 3/4
    Lymphocytes Decreased9994
    Leukocytes Decreased9456
    Hemoglobin
    Decreased    		8811
    Neutrophils
    Decreased    		8660
    Platelets
    Decreased    		8625

    In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving bendamustine hydrochloride. The most common serious adverse reactions occurring in ≥5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome.

    Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions. Adverse reactions occurring less frequently but possibly related to bendamustine hydrochloride treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.

    6.2 Postmarketing Experience

    The following adverse reactions have been identified during post-approval use of bendamustine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    Blood and lymphatic systems disorders: Pancytopenia

    Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation

    General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling)

    Immune system disorders: Anaphylaxis

    Infections and infestations: Pneumocystis jiroveci pneumonia, progressive multifocal leukoencephalopathy (PML)

    Renal and urinary disorders: Nephrogenic diabetes insipidus (NDI)

    Respiratory, thoracic and mediastinal disorders: Pneumonitis

    Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), non-melanoma skin cancer (NMSC), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)

  • 7 DRUG INTERACTIONS

    7.1 Effect of Other Drugs on Bendamustine Hydrochloride

    CYP1A2 Inhibitors

    The coadministration of bendamustine hydrochloride with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with bendamustine hydrochloride [see Clinical Pharmacology (12.3)]. Consider alternative therapies that are not CYP1A2 inhibitors during treatment with bendamustine hydrochloride.

    CYP1A2 Inducers

    The coadministration of bendamustine hydrochloride with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of bendamustine hydrochloride [see Clinical Pharmacology (12.3)]. Consider alternative therapies that are not CYP1A2 inducers during treatment with bendamustine hydrochloride.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6 to 1.8 times the maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth (see Data). There are no available data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus.

    The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

    Data

    Animal data

    Bendamustine hydrochloride was intraperitoneally administered once to mice from 210 mg/m2 (approximately 1.8 times the MRHD) during organogenesis and caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities), and decreased fetal body weights. This dose did not appear to be maternally toxic and lower doses were not evaluated. Repeat intraperitoneal administration of bendamustine hydrochloride to mice on gestation days 7 to 11 resulted in an increase in resorptions from 75 mg/m2 (approximately 0.6 times the MRHD) and an increase in abnormalities from 112.5 mg/m2 (approximately 0.9 times the MRHD), similar to those seen after a single intraperitoneal administration.

    Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m2 (approximately the MRHD) on gestation days 4, 7, 9, 11, or 13 and caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in external (effect on tail, head, and herniation of external organs [exomphalos]) and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats.

    8.2 Lactation

    Risk Summary

    There are no data on the presence of bendamustine hydrochloride or its metabolites in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise patients that breastfeeding is not recommended during treatment with bendamustine hydrochloride, and for 1 week after the last dose.

    8.3 Females and Males of Reproductive Potential

    Bendamustine hydrochloride can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

    Pregnancy Testing

    Pregnancy testing is recommended for females of reproductive potential prior to initiation of treatment with bendamustine hydrochloride.

    Contraception

    Females

    Bendamustine hydrochloride can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with bendamustine hydrochloride and for 6 months after the last dose.

    Males

    Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with bendamustine hydrochloride and for 3 months after the last dose [see Nonclinical Toxicology (13.1)].

    Infertility

    Males

    Based on findings from clinical studies, bendamustine hydrochloride may impair male fertility. Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs. In some instances spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Patients should be warned of the potential risk to their reproductive capacities.

    Based on findings from animal studies, bendamustine hydrochloride may impair male fertility due to an increase in morphologically abnormal spermatozoa. The long-term effects of bendamustine hydrochloride on male fertility, including the reversibility of adverse effects, have not been studied [see Nonclinical Toxicology (13.1)].

    8.4 Pediatric Use

    Safety and effectiveness in pediatric patients have not been established.

    Safety, pharmacokinetics and efficacy were assessed in a single open-label trial (NCT01088984) in patients aged 1 to 19 years with relapsed or refractory acute leukemia, including 27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute myeloid leukemia (AML). Bendamustine hydrochloride was administered as an intravenous infusion over 60 minutes on Days 1 and 2 of each 21-day cycle. There was no treatment response (CR+ CRp) in any patient in the Phase 2 portion of the trial at a dose of 120 mg/m2. However, 2 patients with ALL achieved CR at a dose of 90 mg/m2 in the Phase 1 portion of the study. The safety profile in these patients was consistent with that seen in adults, and no new safety signals were identified.

    The pharmacokinetics of bendamustine in 43 patients, aged 1 to 19 years (median age of 10 years) were within range of values previously observed in adults given the same dose based on body surface area.

    8.5 Geriatric Use

    No overall differences in safety were observed between patients ≥65 years of age and younger patients. Efficacy was lower in patients 65 and over with CLL receiving bendamustine hydrochloride based upon an overall response rate of 47% for patients 65 and over and 70% for younger patients. Progression free survival was also longer in younger patients with CLL receiving bendamustine hydrochloride (19 months vs. 12 months). No overall differences in efficacy in patients with non-Hodgkin Lymphoma were observed between geriatric patients and younger patients.

    8.6 Renal Impairment

    Do not use bendamustine hydrochloride in patients with creatinine clearance (CLcr) < 30 mL/min [see Clinical Pharmacology (12.3)].

    8.7 Hepatic Impairment

    Do not use bendamustine hydrochloride in patients with AST or ALT 2.5-10 x upper limit of normal (ULN) and total bilirubin 1.5-3 x ULN, or total bilirubin > 3 x ULN [see Clinical Pharmacology (12.3)].

  • 10 OVERDOSAGE

    The intravenous LD50 of bendamustine hydrochloride is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress.

    Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients) and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients.

    No specific antidote for bendamustine hydrochloride overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.

  • 11 DESCRIPTION

    Bendamustine hydrochloride is an alkylating agent. The chemical name of bendamustine hydrochloride monohydrate is 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1 methyl-, monohydrochloride monohydrate. Its empirical molecular formula is C16H21Cl2N3O2 · HCl · H2O, and the molecular weight is 412.7. Bendamustine hydrochloride monohydrate contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula:

    structural formula

    Bendamustine Hydrochloride for Injection, USP (25 mg per vial or 100 mg per vial lyophilized powder)

    Bendamustine Hydrochloride for Injection, USP for intravenous use is supplied as a sterile nonpyrogenic white to off-white lyophilized powder in a single-dose vial. Each 25-mg vial contains 25 mg of bendamustine hydrochloride, USP and 42.5 mg of mannitol, USP. Each 100-mg vial contains 100 mg of bendamustine hydrochloride, USP and 170 mg of mannitol, USP. The pH of the reconstituted solution is 2.5 to 3.5.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways. Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action of bendamustine remains unknown.

    12.2 Pharmacodynamics

    Based on the pharmacokinetics/pharmacodynamics analyses of data from adult NHL patients, nausea increased with increasing bendamustine Cmax.

    Cardiac Electrophysiology

    The effect of bendamustine on the QTc interval was evaluated in 53 patients with indolent NHL and mantle cell lymphoma on Day 1 of Cycle 1 after administration of rituximab at 375 mg/m2 intravenous infusion followed by a 30-minute intravenous infusion of bendamustine at 90 mg/m2/day. No mean changes greater than 20 milliseconds were detected up to one hour post-infusion. The potential for delayed effects on the QT interval after one hour was not evaluated.

    12.3 Pharmacokinetics

    Absorption

    Following a single IV dose of bendamustine hydrochloride Cmax typically occurred at the end of infusion. The dose proportionality of bendamustine has not been studied.

    Distribution

    The protein binding of bendamustine ranged from 94 to 96% and was concentration independent from 1 to 50 mcg/mL. The blood to plasma concentration ratios in human blood ranged from 0.84 to 0.86 over a concentration range of 10 to 100 mcg/mL.

    The mean steady-state volume of distribution (Vss) of bendamustine was approximately 20 to 25 L.

    Elimination

    After a single intravenous dose of 120 mg/m2 of bendamustine over 1 hour, the intermediate half-life (t½) of the parent compound is approximately 40 minutes. The mean terminal elimination t½ of two active metabolites, γ-hydroxybendamustine (M3) and N desmethylbendamustine (M4) are approximately 3 hours and 30 minutes, respectively. Bendamustine clearance in humans is approximately 700 mL/min.

    Metabolism

    Bendamustine is extensively metabolized via hydrolytic, oxidative, and conjugative pathways. Bendamustine is primarily metabolized via hydrolysis to monohydroxy (HP1) and dihydroxy-bendamustine (HP2) metabolites with low cytotoxic activity in vitro. Two active minor metabolites, M3 and M4, are primarily formed via CYP1A2 in vitro. M3 and M4 concentrations in plasma are 1/10th and 1/100th that of the parent compound, respectively.

    Excretion

    Following IV infusion of radiolabeled bendamustine hydrochloride in cancer patients, approximately 76% of the dose was recovered. Approximately 50% of the dose was recovered in the urine (3.3% unchanged) and approximately 25% of the dose was recovered in the feces. Less than 1% of the dose was recovered in the urine as M3 and M4, and less than 5% of the dose was recovered in the urine as HP2.

    Specific Populations

    No clinically meaningful effects on the pharmacokinetics of bendamustine were observed based on age (31 to 84 years), sex, mild to moderate renal impairment (CLcr ≥ 30 mL/min), or hepatic impairment with total bilirubin 1.5 < ULN and AST or ALT < 2.5 × ULN. The effects of severe renal impairment (CLcr < 30 mL/min), or hepatic impairment with total bilirubin 1.5-3 × ULN and AST or ALT 2.5-10 × ULN or total bilirubin > 3 × ULN on the pharmacokinetics of bendamustine is unknown.

    Race/Ethnicity

    Exposures in Japanese subjects (n=6) were 40% higher than that in non-Japanese subjects receiving the same dose. The clinical importance of this difference on the safety and efficacy of bendamustine hydrochloride in Japanese subjects has not been established.

    Drug Interaction Studies

    In Vitro Studies

    Effect of Bendamustine on CYP Substrates

    Bendamustine did not inhibit CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5. Bendamustine did not induce metabolism of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5.

    Effect of Transporters on Bendamustine Hydrochloride

    Bendamustine is a substrate of P-glycoprotein and breast cancer resistance protein (BCRP).

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m2/day (the lowest dose tested, approximately 0.3 times the maximum recommended human dose [MRHD])) and 75 mg/m2/day (approximately 0.6 times the MRHD) for 4 days, peritoneal sarcomas in female AB/Jena mice were produced. Oral administration at 187.5 mg/m2/day (the only dose tested, approximately 1.6 times the MRHD) for 4 days induced mammary carcinomas and pulmonary adenomas.

    Bendamustine is a mutagen and clastogen. In a bacterial reverse mutation assay (Ames assay), bendamustine was shown to increase revertant frequency in the absence and presence of metabolic activation. Bendamustine was clastogenic in human lymphocytes in vitro, and in rat bone marrow cells in vivo (increase in micronucleated polychromatic erythrocytes) from 37.5 mg/m2 (the lowest dose tested, approximately 0.3 times the MRHD).

    Bendamustine induced morphologic abnormalities in spermatozoa in mice. Following tail vein injection of bendamustine at 120 mg/m2 or a saline control on days 1 and 2 for a total of 3 weeks, the number of spermatozoa with morphologic abnormalities was 16% higher in the bendamustine-treated group as compared to the saline control group.

  • 14 CLINICAL STUDIES

    14.1 Chronic Lymphocytic Leukemia (CLL)

    The safety and efficacy of bendamustine hydrochloride were evaluated in an open-label, randomized, controlled multicenter trial comparing bendamustine hydrochloride to chlorambucil. The trial was conducted in 301 previously-untreated patients with Binet Stage B or C (Rai Stages I - IV) CLL requiring treatment. Need-to-treat criteria included hematopoietic insufficiency, B-symptoms, rapidly progressive disease or risk of complications from bulky lymphadenopathy. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia, Richter's syndrome, or transformation to prolymphocytic leukemia were excluded from the study.

    The patient populations in the bendamustine hydrochloride and chlorambucil treatment groups were balanced with regard to the following baseline characteristics: age (median 63 vs. 66 years), gender (63% vs. 61% male), Binet stage (71% vs. 69% Binet B), lymphadenopathy (79% vs. 82%), enlarged spleen (76% vs. 80%), enlarged liver (48% vs. 46%), hypercellular bone marrow (79% vs. 73%), “B” symptoms (51% vs. 53%), lymphocyte count (mean 65.7x109/L vs. 65.1x109/L), and serum lactate dehydrogenase concentration (mean 370.2 vs. 388.4 U/L). Ninety percent of patients in both treatment groups had immuno-phenotypic confirmation of CLL (CD5, CD23 and either CD19 or CD20 or both).

    Patients were randomly assigned to receive either bendamustine hydrochloride at 100 mg/m2, administered intravenously over a period of 30 minutes on Days 1 and 2 or chlorambucil at 0.8 mg/kg (Broca's normal weight) administered orally on Days 1 and 15 of each 28-day cycle. Efficacy endpoints of objective response rate and progression-free survival were calculated using a pre-specified algorithm based on NCI working group criteria for CLL.

    The results of this open-label randomized study demonstrated a higher rate of overall response and a longer progression-free survival for bendamustine hydrochloride compared to chlorambucil (see Table 5). Survival data are not mature.

    Table 5: Efficacy Data for CLL

    CI = confidence interval

    * CR was defined as peripheral lymphocyte count ≤ 4.0 x 109/L, neutrophils ≥ 1.5 x 109/L, platelets >100 x 109/L, hemoglobin > 110 g/L, without transfusions, absence of palpable hepatosplenomegaly, lymph nodes ≤ 1.5 cm, < 30% lymphocytes without nodularity in at least a normocellular bone marrow and absence of “B” symptoms. The clinical and laboratory criteria were required to be maintained for a period of at least 56 days.

    ** nPR was defined as described for CR with the exception that the bone marrow biopsy shows persistent nodules.

    † PR was defined as ≥ 50% decrease in peripheral lymphocyte count from the pretreatment baseline value, and either ≥50% reduction in lymphadenopathy, or ≥50% reduction in the size of spleen or liver, as well as one of the following hematologic improvements: neutrophils ≥ 1.5 x 109/L or 50% improvement over baseline, platelets >100 x 109/L or 50% improvement over baseline, hemoglobin >110 g/L or 50% improvement over baseline without transfusions, for a period of at least 56 days.

    †† PFS was defined as time from randomization to progression or death from any cause.
    Bendamustine Hydrochloride
    (N=153)    		Chlorambucil (N=148)p-value
    Response Rate n (%)
    Overall response rate90 (59)38 (26)<0.0001
    (95% CI)(51.0, 66.6)(18.6, 32.7)
    Complete response (CR)*13 (8)1 (<1)
    Nodular partial response (nPR)**4 (3)0
    Partial response (PR)†73 (48)37 (25)
    Progression-Free Survival††
    Median, months (95% CI)18 (11.7, 23.5)6 (5.6, 8.6)
    Hazard ratio (95% CI)0.27 (0.17, 0.43)<0.0001

    Kaplan-Meier estimates of progression-free survival comparing bendamustine hydrochloride with chlorambucil are shown in Figure 1.

    Figure 1

    14.2 Non-Hodgkin Lymphoma (NHL)

    The efficacy of bendamustine hydrochloride was evaluated in a single arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Patients were included if they relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. All patients received bendamustine hydrochloride intravenously at a dose of 120 mg/m2, on Days 1 and 2 of a 21-day treatment cycle. Patients were treated for up to 8 cycles.

    The median age was 60 years, 65% were male, and 95% had a baseline WHO performance status of 0 or 1. Major tumor subtypes were follicular lymphoma (62%), diffuse small lymphocytic lymphoma (21%), and marginal zone lymphoma (16%). Ninety-nine percent of patients had received previous chemotherapy, 91% of patients had received previous alkylator therapy, and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab.

    Efficacy was based on the assessments by a blinded independent review committee (IRC) and included overall response rate (complete response + complete response unconfirmed + partial response) and duration of response (DR) as summarized in Table 6.

    Table 6: Efficacy Data for NHL*

    CI = confidence interval

    * IRC assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that a persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be ≥20 mm.
    Bendamustine Hydrochloride
    (N=100)
    Response Rate (%)
    Overall response rate (CR+CRu+PR)74
    (95% CI)(64.3, 82.3)
    Complete response (CR)13
    Complete response unconfirmed (CRu)4
    Partial response (PR)57
    Duration of Response (DR)
    Median, months (95% CI)9.2 months
    (7.1, 10.8)

  • 15 REFERENCES

    1. OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html
  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    Safe Handling and Disposal

    Bendamustine hydrochloride is a hazardous drug. Follow applicable special handling and disposal procedures1. Care should be exercised in the handling and preparation of solutions prepared from Bendamustine Hydrochloride for Injection, USP. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of bendamustine hydrochloride contacts the skin, wash the skin immediately and thoroughly with soap and water. If bendamustine hydrochloride contacts the mucous membranes, flush thoroughly with water.

    How Supplied

    Bendamustine Hydrochloride for Injection, USP is supplied as follows:

    NDCBendamustine Hydrochloride for Injection, USPPackage Factor
    71288-102-1025 mg white to off-white lyophilized powder in a 10 mL amber single-dose vial1 vial per carton
    71288-103-20100 mg white to off-white lyophilized powder in a 20 mL amber single-dose vial1 vial per carton

    Sterile, Nonpyrogenic, Preservative-free.
    The container closure is not made with natural rubber latex.

    Storage

    Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.]

    Retain in original package until time of use to protect from light.

    Discard unused portion.

  • 17 PATIENT COUNSELING INFORMATION

    Allergic (Hypersensitivity) Reactions

    Inform patients of the possibility of mild or serious allergic reactions and to immediately report rash, facial swelling, or difficulty breathing during or soon after infusion [see Warnings and Precautions (5.4)].

    Myelosuppression

    Inform patients of the likelihood that bendamustine hydrochloride will cause a decrease in white blood cells, platelets, and red blood cells, and the need for frequent monitoring of blood counts. Advise patients to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection [see Warnings and Precautions (5.1)].

    Progressive Multifocal Leukoencephalopathy (PML)

    Inform patients to immediately contact their healthcare provider if they experience confusion, memory loss, trouble thinking, difficulty talking or walking, vision loss or other neurological or cognitive symptoms [see Warnings and Precautions (5.3)].

    Hepatotoxicity

    Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising [see Warnings and Precautions (5.7)].

    Fatigue

    Advise patients that bendamustine hydrochloride may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect [see Adverse Reactions (6.1)].

    Nausea and Vomiting

    Advise patients that bendamustine hydrochloride may cause nausea and/or vomiting. Patients should report nausea and vomiting so that symptomatic treatment may be provided [see Adverse Reactions (6.1)].

    Diarrhea

    Advise patients that bendamustine hydrochloride may cause diarrhea. Patients should report diarrhea to the physician so that symptomatic treatment may be provided [see Adverse Reactions (6.1)].

    Rash

    Advise patients that a rash or itching may occur during treatment with bendamustine hydrochloride. Advise patients to immediately report severe or worsening rash or itching [see Warnings and Precautions (5.6)].

    Non-Melanoma Skin Cancer (NMSC)

    Advise patients to undergo regular skin cancer screenings, and to report any suspicious skin changes to their healthcare provider [see Warnings and Precautions (5.8)].

    Embryo-Fetal Toxicity

    Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.10), Use in Specific Populations (8.1, 8.3), and Nonclinical Toxicology (13.1)]. Advise female patients of reproductive potential to use effective contraception during treatment with Bendamustine Hydrochloride for Injection, USP and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)]. Advise males with female partners of reproductive potential to use effective contraception during treatment with Bendamustine Hydrochloride for Injection, USP and for 3 months after the last dose [see Use in Specific Populations (8.3), and Nonclinical Toxicology (13.1)].

    Lactation

    Advise females not to breastfeed during treatment with Bendamustine Hydrochloride for Injection, USP and for 1 week after the last dose [see Use in Specific Populations (8.2)].

    Infertility

    Advise males of reproductive potential that Bendamustine Hydrochloride for Injection, USP may impair fertility [see Use in Specific Populations (8.3)].

    meitheal®
    Mfd. for Meitheal Pharmaceuticals
    Chicago, IL 60631 (USA)
    ©2023 Meitheal Pharmaceuticals Inc.

    Mfd. by Kindos Pharmaceuticals Co., Ltd.
    Chengdu, China 611731

    February 2023

    LB-595-V1

  • PRINCIPAL DISPLAY PANEL – Bendamustine HCl for Injection, USP 25 mg Vial Label

    NDC 71288-102-10

    Rx only

    Bendamustine HCl for Injection, USP

    25 mg per vial

    Cytotoxic Agent

    Single-Dose Vial

    For Intravenous Infusion Only

    Reconstitution and Dilution Required (see insert)

    PRINCIPAL DISPLAY PANEL – Bendamustine HCl for Injection, USP 25 mg Vial Label

  • PRINCIPAL DISPLAY PANEL – Bendamustine HCl for Injection, USP 25 mg Carton

    NDC 71288-102-10

    1 Single-Dose Vial

    Discard unused portion

    Bendamustine HCl for Injection, USP

    25 mg per vial

    Cytotoxic Agent

    For Intravenous Infusion Only

    Reconstitution and Dilution Required (see insert)

    Retain in carton until time of use

    Rx only

    PRINCIPAL DISPLAY PANEL – Bendamustine HCl for Injection, USP 25 mg Carton

  • PRINCIPAL DISPLAY PANEL – Bendamustine HCl for Injection, USP 100 mg Vial Label

    NDC 71288-103-20

    Rx only

    Bendamustine HCl for Injection, USP

    100 mg per vial

    Cytotoxic Agent

    Single-Dose Vial

    For Intravenous Infusion Only

    Reconstitution and Dilution Required (see insert)

    PRINCIPAL DISPLAY PANEL – Bendamustine HCl for Injection, USP 100 mg Vial Label

  • PRINCIPAL DISPLAY PANEL – Bendamustine HCl for Injection, USP 100 mg Carton

    NDC 71288-103-20

    1 Single-Dose Vial

    Discard unused portion

    Bendamustine HCl for Injection, USP

    100 mg per vial

    Cytotoxic Agent

    For Intravenous Infusion Only

    Reconstitution and Dilution Required (see insert)

    Retain in carton until time of use

    Rx only

    PRINCIPAL DISPLAY PANEL – Bendamustine HCl for Injection, USP 100 mg Carton

  • INGREDIENTS AND APPEARANCE
    BENDAMUSTINE 
    bendamustine hcl injection, powder, lyophilized, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:71288-102
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    bendamustine hydrochloride (UNII: 981Y8SX18M) (bendamustine - UNII:9266D9P3PQ) bendamustine hydrochloride25 mg  in 5 mL
    Inactive Ingredients
    Ingredient NameStrength
    mannitol (UNII: 3OWL53L36A)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:71288-102-101 in 1 CARTON06/05/2023
    15 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21100106/05/2023
    BENDAMUSTINE 
    bendamustine hcl injection, powder, lyophilized, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:71288-103
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    bendamustine hydrochloride (UNII: 981Y8SX18M) (bendamustine - UNII:9266D9P3PQ) bendamustine hydrochloride100 mg  in 20 mL
    Inactive Ingredients
    Ingredient NameStrength
    mannitol (UNII: 3OWL53L36A)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:71288-103-201 in 1 CARTON06/05/2023
    120 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA21100106/05/2023
    Labeler - Meitheal Pharmaceuticals Inc. (080548348)
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