INDICATIONS & USAGE SECTION

Highlight: 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)

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.

DOSAGE & ADMINISTRATION SECTION

Highlight: 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)

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 for3 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.

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WARNINGS AND PRECAUTIONS SECTION

Highlight: * 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)

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)].

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DRUG INTERACTIONS SECTION

Highlight: Consider alternative therapies that are not CYP1A2 inducers or inhibitors during treatment with bendamustine hydrochloride. (7)

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.

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NONCLINICAL TOXICOLOGY SECTION

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.

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PATIENT COUNSELING INFORMATION

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

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HOW SUPPLIED SECTION

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:

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.

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