bendamustine hydrochloride 25 MG/ML Injectable Solution [Bendeka]

INDICATIONS AND USAGE Bendamustine Hydrochloride Injection is an alkylating drug indicated for treatment of adult 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 ) 1.1 Chronic Lymphocytic Leukemia (CLL) Bendamustine q Hydrochloride Injection is indicated for the treatment of adult 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 Injection is indicated for the treatment of adult 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 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/m 2 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/m 2 infused intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles ( 2.3 ) 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 dilution 1 , only use TREANDA 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/m 2 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 10 9 /L, platelets ≥ 75 x 10 9 /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/m 2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m 2 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/m 2 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/m 2 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 10 9 /L, platelets ≥ 75 x 10 9 /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/m 2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m 2 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/m 2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m 2 on Days 1 and 2 of each cycle. 2.4 Preparation for Intravenous Administration TREANDA is a hazardous 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 preparation 1 , 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 mi

WARNINGS AND PRECAUTIONS Myelosuppression: Delay or reduce dose and restart treatment based on ANC and platelet count recovery. ( 5.1 ) Infections: Monitor for fever and other signs of infection or reactivation of infections and treat promptly. ( 5.2 ) Progressive multifocal leukoencephalopathy (PML): Monitor for new or worsening neurological, cognitive or behavioral signs or symptoms suggestive of PML. ( 5.3 ) Anaphylaxis and Infusion Reactions: Severe 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 and males with female partners of reproductive potential of the potential risk to a fetus and to use an effective method of contraception. ( 5.10 , 8.1 , 8.3 ) 5.1 Myelosuppression Bendamustine hydrochloride caused severe myelosuppression (Grade 3 to 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). Bendamustine hydrochloride injection causes myelosuppression. Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs 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 10 9 /L and the platelet count should be ≥ 75 x 10 9 /L. [see Dosage and Administration ( 2.2 )]. 5.2 Infections Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports for bendamustine hydrochloride [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 injection treatment to contact a physician immediately if they have symptoms or signs of infection. Patients treated with bendamustine hydrochloride injection 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 hydrochloride, 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 injection 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 injection for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering individual benefits, risks, and supportive care. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in clinical trials and in post-marketing 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 and 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 injection. 5.7 Hepatotoxicity Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride injection [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 hydrochloride injection 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 injection. 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 acce

CONTRAINDICATIONS Bendamustine hydrochloride injection is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, absolute ethanol, sodium hydroxide and monothioglycerol. [see Warnings and Precautions ( 5.4 )] Bendamustine hydrochloride injection is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, absolute ethanol, sodium hydroxide and monothioglycerol. Reactions to bendamustine hydrochloride have included anaphylaxis and anaphylactoid reactions. ( 4 , 5.4 )

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.