Label: TREANDA- bendamustine hydrochloride injection, solution, concentrate
TREANDA- bendamustine hydrochloride injection, powder, lyophilized, for solution

  • NDC Code(s): 63459-390-08, 63459-391-20, 63459-395-02, 63459-396-02
  • Packager: Cephalon, Inc.
  • Category: HUMAN PRESCRIPTION DRUG LABEL
  • DEA Schedule: None
  • Marketing Status: New Drug Application

Drug Label Information

Updated November 21, 2019

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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use TREANDA safely and effectively. See full prescribing information for TREANDA.

    TREANDA® (bendamustine hydrochloride) injection, for intravenous use
    TREANDA® (bendamustine hydrochloride) for injection, for intravenous use
    Initial U.S. Approval: 2008

    INDICATIONS AND USAGE

    TREANDA is an alkylating drug indicated for treatment of patients with:

    • Chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. (1.1)
    • Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. (1.2)

    DOSAGE AND ADMINISTRATION

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

    Do not use TREANDA injection with devices that contain polycarbonate or acrylonitrile-butadiene-styrene (ABS), including most Closed System Transfer Devices (CSTDs). (2.1, 2.4)

    For CLL:

    • 100 mg/m2 infused intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles (2.2)

     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

    Injection: 45 mg/0.5 mL or 180 mg/2 mL (90 mg/mL) in a single-dose vial. (3)
    For Injection: 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution. (3)

    CONTRAINDICATIONS

    TREANDA is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine. Reactions have included anaphylaxis and anaphylactoid reactions. (4, 5.3)

    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)
    • 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. (5.3)
    • Tumor Lysis Syndrome: May lead to acute renal failure and death; anticipate and use supportive measures in patients at high risk. (5.4)
    • Skin Reactions: Discontinue for severe skin reactions. Cases of SJS, DRESS and TEN, some fatal, have been reported. (5.5)
    • Hepatotoxicity: Monitor liver chemistry tests prior to and during treatment. (5.6)
    • Other Malignancies: Pre-malignant and malignant diseases have been reported. (5.7)
    • Extravasation Injury: Take precautions to avoid extravasation, including monitoring intravenous infusion site during and after administration. (5.8)
    • Embryo-Fetal Toxicity: 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,  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 TREANDA. (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)

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 11/2019

  • 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 TREANDA Formulation to Administer

    2.2  Dosing Instructions for CLL

    2.3  Dosing Instructions for NHL

    2.4  Preparation for Intravenous Administration

    2.5  Admixture Stability

    3 DOSAGE FORMS AND STRENGTHS

    4 CONTRAINDICATIONS

    5 WARNINGS AND PRECAUTIONS

    5.1  Myelosuppression

    5.2  Infections

    5.3  Anaphylaxis and Infusion Reactions

    5.4  Tumor Lysis Syndrome

    5.5  Skin Reactions

    5.6 Hepatotoxicity

    5.7  Other Malignancies

    5.8  Extravasation Injury

    5.9  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 TREANDA

    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

    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.
  • 1 INDICATIONS AND USAGE

    1.1  Chronic Lymphocytic Leukemia (CLL)

    TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

    1.2  Non-Hodgkin Lymphoma (NHL)

    TREANDA is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Selection of TREANDA Formulation to Administer

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

    Do not use TREANDA Injection if you intend to use closed system transfer devices (CSTDs), adapters and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS) prior to dilution in the infusion bag [see Dosage and Administration (2.4)].

    If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion bag, only use a polypropylene syringe with a metal needle and polypropylene hub to withdraw and transfer TREANDA Injection into the infusion bag. Polypropylene syringes are translucent in appearance.

    TREANDA Injection and the reconstituted TREANDA for Injection have different concentrations of bendamustine hydrochloride. The concentration of bendamustine hydrochloride in the solution is 90 mg/mL and the concentration of bendamustine hydrochloride in the reconstituted solution of lyophilized powder is 5 mg/mL. Do not mix or combine the two formulations.

    TREANDA Injection must be withdrawn and transferred for dilution in a biosafety cabinet (BSC) or containment isolator using a polypropylene syringe with a metal needle and a polypropylene hub.

    If a CSTD or adapter that contains polycarbonate or ABS is used as supplemental protection prior to dilution1, only use TREANDA for Injection, the lyophilized powder formulation [see How Supplied/Storage and Handling (16.1)].

    2.2  Dosing Instructions for CLL

    Recommended Dosage:       

    The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.

    Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL:

    Delay TREANDA 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 TREANDA 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 TREANDA 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 TREANDA 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

    TREANDA is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

    TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution)

    TREANDA Injection must be diluted in a biosafety cabinet (BSC) or containment isolator.

    • When preparing and transferring the concentrated TREANDA Injection solution into the infusion bag, do not use devices that contain polycarbonate or ABS. However, after dilution of TREANDA Injection into the infusion bag, devices that contain polycarbonate or ABS, including infusion sets, may be used.

      TREANDA Injection contains N,N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS. Devices, including CSTDs, adapters, and syringes that contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA which is present in the product. This incompatibility leads to device failure (e.g., leaking, breaking, or operational failure of CSTD components), possible product contamination, and potential serious adverse health consequences to the practitioner, including skin reactions; or to the patient, including but not limited to, the risk of small blood vessel blockage if they receive product contaminated with dissolved ABS or polycarbonate. Devices that are compatible for use in dilution of TREANDA Injection are available.

    • If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion bag, only use a polypropylene syringe with a metal needle and a polypropylene hub to withdraw and transfer TREANDA Injection into the infusion bag.

    • Each vial of TREANDA Injection is intended for single dose only.

    • Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution using a polypropylene syringe with a metal needle and a polypropylene hub.

    • Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.7 mg/mL.

    • After dilution of TREANDA Injection into the infusion bag, devices that contain polycarbonate or ABS, including infusion sets, may be used.

    • Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear colorless to yellow solution.

    Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible.

    TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder)

    If a closed system transfer device or adapter that contains polycarbonate or ABS is to be used as supplemental protection during preparation1, only use TREANDA for Injection, the lyophilized formulation.

    • Each vial of TREANDA for Injection is intended for single-dose only.

    • Aseptically reconstitute each TREANDA for Injection vial as follows:
      • 25 mg TREANDA for Injection vial: Add 5 mL of only Sterile Water for Injection, USP.
      • 100 mg TREANDA for Injection vial: Add 20 mL of only Sterile Water for Injection, USP.

    • Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. If particulate matter is observed, the reconstituted product should not be used.

    • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.6 mg/mL. After transferring, thoroughly mix the contents of the infusion bag.

    • Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear and colorless to slightly yellow solution.

    Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible.

    Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.

    2.5  Admixture Stability

    TREANDA Injection and TREANDA for Injection contain no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.

    TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution)

    Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours stored under refrigerated conditions at 2°-8°C (36°-46°F) or for

    2 hours when stored at room temperature (15°-30°C or 59°-86°F) and room light. Administration of diluted TREANDA Injection must be completed within this period.

    TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder)

    Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours stored under refrigerated conditions at 2°-8°C (36°-46°F) or for

    3 hours when stored at room temperature (15°-30°C or 59°-86°F) and room light. Administration of reconstituted and diluted TREANDA for Injection must be completed within this period.

  • 3 DOSAGE FORMS AND STRENGTHS

    • TREANDA Injection: 45 mg/0.5 mL or 180 mg/2 mL as a clear and colorless to yellow ready-to dilute solution in a single-dose vial. 
    • TREANDA for Injection: 25 mg or 100 mg white to off-white lyophilized powder in a single-dose vial for reconstitution.
  • 4 CONTRAINDICATIONS

    TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [see Warnings and Precautions (4, 5.3)]

  • 5 WARNINGS AND PRECAUTIONS

    5.1  Myelosuppression

    TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 4). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).

    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. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.

    Patients treated with TREANDA 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 TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.

    5.4  Tumor Lysis Syndrome

    Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].

    5.5  Skin Reactions

    Fatal and serious skin reactions have been reported with TREANDA 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 TREANDA 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 TREANDA.

    5.6 Hepatotoxicity

    Fatal and serious cases of liver injury have been reported with TREANDA. 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.

    5.7  Other Malignancies

    There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with bendamustine hydrochloride therapy has not been determined.

    5.8  Extravasation Injury

    TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA.

    5.9  Embryo-Fetal Toxicity

    Based on findings from animal reproduction studies and the drug’s mechanism of action, TREANDA 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 TREANDA 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 TREANDA 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 TREANDA in clinical trials and are discussed in greater detail in other sections of the label.

    • Myelosuppression [see Warnings and Precautions (5.1)]
    • Infections [see Warnings and Precautions (5.2)]
    • Anaphylaxis and Infusion Reactions [see Warnings and Precautions (5.3)]
    • Tumor Lysis Syndrome [see Warnings and Precautions (5.4)]
    • Skin Reactions [see Warnings and Precautions (5.5)]
    • 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

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

    Chronic Lymphocytic Leukemia

    The data described below reflect exposure to TREANDA in 153 patients. TREANDA 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 TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).  

    Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. 

    Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and 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 TREANDA were hypersensitivity (2%) and pyrexia (1%).

    Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

    Table 1: Non- Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients 

    Number (%) of patients

     

    TREANDA
    (N=153)

    Chlorambucil
    (N=143)

    Body System/ Adverse 
    Reaction

    All Grades

    Grade 3/4

    All Grades

    Grade 3/4

    Total number of patients with at least 1 adverse reaction

    121 (79)

    52 (34)

    96 (67)

    25 (17)

    Gastrointestinal disorders

       Nausea

    31 (20)

    1 (<1)

    21 (15)

    1 (<1)

      Vomiting

    24 (16)

    1 (<1)

    9 (6)

    0

      Diarrhea

    14 (9)

    2 (1)

    5 (3)

    0

    General disorders and administration site conditions

      Pyrexia

    36 (24)

    6 (4)

    8 (6)

    2 (1)

      Fatigue

    14 (9)

    2 (1)

    8 (6)

    0

      Asthenia

    13 (8)

    0

    6 (4)

    0

      Chills

    9 (6)

    0

    1 (<1)

    0

    Immune system disorders

      Hypersensitivity

    7 (5)

    2 (1)

    3 (2)

    0

    Infections and infestations

      Nasopharyngitis

    10 (7)

    0

    12 (8)

    0

      Infection

    9 (6)

    3 (2)

    1 (<1)

    1 (<1)

      Herpes simplex

    5 (3)

    0

    7 (5)

    0

    Investigations

      Weight decreased

    11 (7)

    0

    5 (3)

    0

    Metabolism and nutrition disorders

      Hyperuricemia

    11 (7)

    3 (2)

    2 (1)

    0

    Respiratory, thoracic and mediastinal disorders

      Cough

    6 (4)

    1 (<1)

    7 (5)

    1 (<1)

    Skin and subcutaneous tissue disorders

      Rash

    12 (8)

    4 (3)

    7 (5)

    3 (2)

      Pruritus

    8 (5)

    0

    2 (1)

    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 TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

    Table 2:  Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study

     

    TREANDA
    N=150

    Chlorambucil
    N=141

    Laboratory Abnormality

    All Grades
    n (%)

    Grade 3/4
    n (%)

    All Grades
    n (%)

    Grade 3/4
    n (%)

    Hemoglobin
    Decreased

    134 (89)

    20 (13)

    115 (82)

    12 (9)

    Platelets
    Decreased

    116 (77)

    16 (11)

    110 (78)

    14 (10)

    Leukocytes
    Decreased

    92 (61)

    42 (28)

    26 (18)

    4 (3)

    Lymphocytes
    Decreased

    102 (68)

    70 (47)

    27 (19)

    6 (4)

    Neutrophils
    Decreased

    113 (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 TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur.

    Non-Hodgkin Lymphoma

    The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies.  The population was 31-84 years of age, 60% male, and 40% female.  The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles.

    The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%).  The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

    Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with TREANDA (N=176)

    Body System/ Adverse

    Number (%) of patients*

     Reaction

    All Grades

    Grade 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

    132 (75)

    7 (4)

        Vomiting

    71 (40)

    5 (3)

        Diarrhea

    65 (37)

    6 (3)

        Constipation

    51 (29)

    1 (<1)

        Stomatitis

    27 (15)

    1 (<1)

        Abdominal pain

    22 (13)

    2 (1)

        Dyspepsia

    20 (11)

    0

        Gastroesophageal reflux disease

    18 (10)

    0

        Dry mouth

    15 (9)

    1 (<1)

        Abdominal pain upper

    8 (5)

    0

        Abdominal distension

    8 (5)

    0

    General disorders and administration
    site conditions

        Fatigue

    101 (57)

    19 (11)

        Pyrexia

    59 (34)

    3 (2)

        Chills

    24 (14)

    0

        Edema peripheral

    23 (13)

    1 (<1)

        Asthenia

    19 (11)

    4 (2)

        Chest pain

    11 (6)

    1 (<1)

        Infusion site pain

    11 (6)

    0

        Pain

    10 (6)

    0

        Catheter site pain

    8 (5)

    0

    Infections and infestations

        Herpes zoster

    18 (10)

    5 (3)

        Upper respiratory tract infection

    18 (10)

    0

        Urinary tract infection

    17 (10)

    4 (2)

        Sinusitis

    15 (9)

    0

        Pneumonia

    14 (8)

    9 (5)

        Febrile neutropenia

    11 (6)

    11 (6)

        Oral candidiasis

    11 (6)

    2 (1)

        Nasopharyngitis

    11 (6)

    0

    Investigations

        Weight decreased

    31 (18)

    3 (2)

    Metabolism and nutrition disorders

        Anorexia

    40 (23)

    3 (2)

        Dehydration

    24 (14)

    8 (5)

        Decreased appetite

    22 (13)

    1 (<1)

        Hypokalemia

    15 (9)

    9 (5)

    Musculoskeletal and connective tissue
    disorders

        Back pain

    25 (14)

    5 (3)

        Arthralgia

    11 (6)

    0

        Pain in extremity

    8 (5)

    2 (1)

        Bone pain

    8 (5)

    0

    Nervous system disorders

        Headache

    36 (21)

    0

        Dizziness

    25 (14)

    0

        Dysgeusia

    13 (7)

    0

    Psychiatric disorders

        Insomnia

    23 (13)

    0

        Anxiety

    14 (8)

    1 (<1)

        Depression

    10 (6)

    0

    Respiratory, thoracic and mediastinal
    disorders

        Cough

    38 (22)

    1 (<1)

        Dyspnea

    28 (16)

    3 (2)

        Pharyngolaryngeal pain

    14 (8)

    1 (<1)

        Wheezing

    8 (5)

    0

        Nasal congestion

    8 (5)

    0

    Skin and subcutaneous tissue disorders

        Rash

    28 (16)

    1 (<1)

        Pruritus

    11 (6)

    0

        Dry skin

    9 (5)

    0

        Night sweats

    9 (5)

    0

        Hyperhidrosis

    8 (5)

    0

    Vascular disorders

        Hypotension

    10 (6)

    2 (1)

    *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.

    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 TREANDA in the NHL Studies

    Percent of patients

    Hematology variable

    All Grades

    Grade 3/4

    Lymphocytes 
    Decreased

    99

    94

    Leukocytes
    Decreased

    94

    56

    Hemoglobin 
    Decreased

    88

    11

    Neutrophils
    Decreased

    86

    60

    Platelets
    Decreased

    86

    25

    In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA.  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 [see Warnings and Precautions (5)]. Adverse reactions occurring less frequently but possibly related to TREANDA 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 TREANDA.  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

    Respiratory, thoracic and mediastinal disorders: Pneumonitis

    Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, Toxic epidermal necrolysis, DRESS (Drug reaction with eosinophilia and systemic symptoms). [see Warnings and Precautions (5.5)]

  • 7 DRUG INTERACTIONS

    7.1 Effect of Other Drugs on TREANDA

    CYP1A2 Inhibitors

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

    CYP1A2 Inducers

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

  • 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 2-4% and 15-20%, 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 7-11 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 TREANDA, and for at least 1 week after the last dose.

    8.3 Females and Males of Reproductive Potential

    TREANDA can cause fetal harm when administered to a pregnant woman [see Warnings and Precautions (5.9) and Use in Specific Populations (8.1)].

    Pregnancy Testing

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

    Contraception

    Females

    TREANDA 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 TREANDA and for at least 6 months after the final dose.

    Males

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

    Infertility

    Males

    Based on findings from clinical studies, TREANDA 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, TREANDA may impair male fertility due to an increase in morphologically abnormal spermatozoa. The long-term effects of TREANDA 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 1-19 years with relapsed or refractory acute leukemia, including 27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute myeloid leukemia (AML). TREANDA 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 TREANDA 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 TREANDA (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 TREANDA in patients with creatinine clearance (CLcr) < 30 mL/min.  [see Clinical Pharmacology (12.3)]

    8.7  Hepatic Impairment

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

  • 10 OVERDOSAGE

    The intravenous LD50 of bendamustine HCl 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 TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.

  • 11 DESCRIPTION

    TREANDA (bendamustine hydrochloride) is an alkylating agent. The chemical name of bendamustine hydrochloride is 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1 methyl-, monohydrochloride. Its empirical molecular formula is C16H21Cl2N3O2  HCl, and the molecular weight is 394.7. Bendamustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula: 

    Structural Formula

    TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution)

    TREANDA (bendamustine HCl) Injection for intravenous use is supplied as a sterile clear colorless to yellow solution in a single-dose vialEach 0.5 mL vial contains 45 mg of bendamustine hydrochloride, 162 mg of Propylene Glycol, USP and 293 mg of N,N-Dimethylacetamide, EP. Each 2 mL vial contains 180 mg of bendamustine hydrochloride, 648 mg of Propylene Glycol, USP and 1172 mg of N,N-Dimethylacetamide, EP. An overfill of 0.2 mL is included in each vial.

    TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder)

    TREANDA (bendamustine HCl) for Injection for intravenous use  is supplied as a sterile non-pyrogenic white to off-white lyophilized powder in a single-dose vial. Each 25-mg vial contains 25 mg of bendamustine hydrochloride and 42.5 mg of mannitol, USP. Each 100-mg vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol, USP.  The pH of the reconstituted solution is 2.5 - 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 94-96% and was concentration independent from 1-50 µg/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 µg/mL.

    The mean steady-state volume of distribution (Vss) of bendamustine was approximately 20-25 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 TREANDA were evaluated in an open-label, randomized, controlled multicenter trial comparing TREANDA 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 TREANDA 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 TREANDA 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 TREANDA compared to chlorambucil (see Table 5). Survival data are not mature.

    Table 5: Efficacy Data for CLL

    TREANDA

    (N=153)

    Chlorambucil

    (N=148)

    p-value

    Response Rate n (%)

      Overall response rate

    90 (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

    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 > 110g/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 >110g/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.

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

    Figure 1. Progression-Free Survival

    14.2 Non-Hodgkin Lymphoma (NHL)

    The efficacy of TREANDA 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 TREANDA 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*

    TREANDA
    (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) 

    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.

  • 15 REFERENCES

    1. OSHA Hazardous Drugs. OSHA. [Accessed on July 21, 2015, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]
  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    16.1  Safe Handling and Disposal

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

    16.2  How Supplied

    TREANDA (bendamustine hydrochloride) Injection is supplied as a 90 mg/mL clear colorless to yellow solution in individual cartons as follows:

    • NDC 63459-395-02: 45 mg/0.5 mL of solution in an amber single-dose vial
    • NDC 63459-396-02: 180 mg/2 mL of solution in an amber single-dose vial

    TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows:

    • NDC 63459-390-08: 25 mg white to off-white lyophilized powder in a 8 mL amber single-dose vial
    • NDC 63459-391-20: 100 mg white to off-white lyophilized powder in a 20 mL amber single-dose vial

    16.3  Storage

    TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution)

    Store TREANDA Injection in refrigerator 2° to8°C (36° to46°F).  Retain in original package until time of use to protect from light.

    TREANDA for Injection (25 mg/vial or 100 mg/vial lyophilized powder)

    TREANDA for Injection may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

  • 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 (5.3)].

    Myelosuppression

    Inform patients of the likelihood that TREANDA 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)].

    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 (5.6)].

    Fatigue

    Advise patients that TREANDA 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 TREANDA 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 TREANDA 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 TREANDA. Advise patients to immediately report severe or worsening rash or itching [see Warnings and Precautions (5.5)].

    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 (5.9), 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 TREANDA and for at least 6 months after the final 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 TREANDA and for at least 3 months after the final dose [see Use in Specific Populations (8.3), and Nonclinical Toxicology (13.1)].

    Lactation

    Advise females not to breastfeed during treatment with TREANDA and for at least 1 week after the final dose [see Use in Specific Populations (8.2)].

    Infertility

    Advise males of reproductive potential that TREANDA may impair fertility [see Use in Specific Populations (8.3)].

    Distributed By:
    Teva Pharmaceuticals USA, Inc.
    North Wales, PA 19454

    TREANDA is a trademark of Cephalon, Inc. or its affiliates. 

    ©2008-2019 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries, Ltd. or its affiliates.

    United States Patent Nos. 8436190, 8445524, 8609863, 8669279, 8791270, 8883836, 8895756, 9533955.

    All rights reserved.

    TRE-016

  • Package/Label Display Panel

     

    Treanda - 25 mg Carton

     

     

    Treanda® (bendamustine HCl) for Injection 25 mg/Single Use Vial, Carton Text

    • NDC 63459-390-08 Rx only
    • Sterile Single-Use Vial

    Discard unused portion

    TREANDA®

    (bendamustine HCl)

    for Injection

    25 mg/vial

    For Intravenous Infusion Only

    Reconstitution and Dilution

    Required (see insert)

    Retain in carton until time of use

     

     

  • Package/Label Display Panel

    Treanda 100 mg - Carton

    Treanda® (bendamustine HCl) for Injection 100 mg/Single Use Vial, Carton Text

    • NDC63459-391-20Rx only
    • Sterile Single-Use Vial

    Discard unused portion

    TREANDA®

    (bendamustine HCl)

    for Injection

    100 mg/vial

    For Intravenous Infusion Only

    Reconstitution and Dilution

    Required (see insert)

    Retain in carton until time of use

  • Package/Label Display Panel

    Packaging

    Treanda® (bendamustine HCl) Injection 45 mg/0.5 mL Single-Dose Vial, Carton Text

    Do NOT use with devices that contain polycarbonate or acrylonitrile butadiene-styrene (ABS).

    NDC 63459-395-02 Rx only

    Sterile Refrigerate

    Treanda® (bendamustine HCl) Injection 45 mg/0.5 mL

    For Intravenous Infusion Only

    Further dilution is required (see insert).

    Single-Dose Vial

    Discard Unused Portion

    Retain in carton until time of use.

  • Package/Label Display Panel

    Packaging

    Treanda® (bendamustine HCl) Injection 180 mg/2 mL Single-Dose Vial, Carton Text

    Do NOT use with devices that contain polycarbonate or acrylonitrile butadiene-styrene (ABS).

    NDC 63459-396-02 Rx only

    Sterile Refrigerate

    Treanda® (bendamustine HCl) Injection 180 mg/2 mL (90 mg/mL)

    For Intravenous Infusion Only

    Further dilution is required (see insert).

    Single-Dose Vial

    Discard Unused Portion

    Retain in carton until time of use.

  • INGREDIENTS AND APPEARANCE
    TREANDA 
    bendamustine hydrochloride injection, solution, concentrate
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:63459-395
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    BENDAMUSTINE HYDROCHLORIDE (UNII: 981Y8SX18M) (BENDAMUSTINE - UNII:9266D9P3PQ) BENDAMUSTINE HYDROCHLORIDE45 mg  in 0.5 mL
    Inactive Ingredients
    Ingredient NameStrength
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    N,N-DIMETHYLACETAMIDE (UNII: JCV5VDB3HY)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:63459-395-021 in 1 CARTON11/05/201404/30/2017
    10.5 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02224911/05/201404/30/2017
    TREANDA 
    bendamustine hydrochloride injection, solution, concentrate
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:63459-396
    Route of AdministrationINTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    BENDAMUSTINE HYDROCHLORIDE (UNII: 981Y8SX18M) (BENDAMUSTINE - UNII:9266D9P3PQ) BENDAMUSTINE HYDROCHLORIDE180 mg  in 2 mL
    Inactive Ingredients
    Ingredient NameStrength
    PROPYLENE GLYCOL (UNII: 6DC9Q167V3)  
    N,N-DIMETHYLACETAMIDE (UNII: JCV5VDB3HY)  
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC:63459-396-021 in 1 CARTON11/05/201405/31/2017
    12 mL in 1 VIAL, SINGLE-DOSE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02224911/05/201405/31/2017
    TREANDA 
    bendamustine hydrochloride injection, powder, lyophilized, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:63459-390
    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:63459-390-081 in 1 CARTON01/05/2010
    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
    NDANDA02224901/05/2010
    TREANDA 
    bendamustine hydrochloride injection, powder, lyophilized, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:63459-391
    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:63459-391-201 in 1 CARTON03/31/2008
    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
    NDANDA02224903/31/2008
    Labeler - Cephalon, Inc. (183236314)