BENDAMUSTINE

Bendamustine hydrochloride is an alkylating agent. The chemical name of bendamustine hydrochloride monohydrate is 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1 methyl-, monohydrochloride monohydrate. Its empirical molecular formula is C 16 H 21 Cl 2 N 3 O 2 · HCl · H 2 O, and the molecular weight is 412.7. Bendamustine hydrochloride monohydrate contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula: Bendamustine Hydrochloride for Injection, USP (25 mg per vial or 100 mg per vial lyophilized powder) Bendamustine Hydrochloride for Injection, USP for intravenous use is supplied as a sterile nonpyrogenic white to off-white lyophilized powder in a single-dose vial. Each 25-mg vial contains 25 mg of bendamustine hydrochloride, USP and 42.5 mg of mannitol, USP. Each 100-mg vial contains 100 mg of bendamustine hydrochloride, USP and 170 mg of mannitol, USP. The pH of the reconstituted solution is 2.5 to 3.5. structural formula

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 ) 1.1 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.

Bendamustine hydrochloride is available in two formulations, a solution (Bendamustine Injection) and a lyophilized powder (Bendamustine for Injection). ( 2.1 ) 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 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 dilution 1 , 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/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 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 10 9 /L, platelets ≥ 75 x 10 9 /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/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 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 10 9 /L, platelets ≥ 75 x 10 9 /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/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 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 preparation 1 , only use bendamustine hydrochloride for injection, the lyophilized formulation. Each vial of bendamustine hydrochloride for injection is intended for single-dose only. Aseptically reconstitute each bendamustine hydrochloride for injection vial as follows: 25 mg bendamustine hydrochloride for injection vial: Add 5 mL of only Sterile Water for Injection, USP. 100 mg bendamustine hydrochloride for injection vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine hydrochloride concentration of 5 mg per mL. The lyophilized powder should completely dissolve in 5 minutes. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. If particulate matter is observed, the reconstituted product should not be used. Aseptically withdraw the volume needed for the required dose (based on 5 mg per mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine hydrochloride in the infusion bag should be within 0.2 to 0.6 mg per mL. After transferring, thoroughly mix the contents of the infusion bag. Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear and colorless to slightly yellow solution. Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. 2.5 Admixture Stability Bendamustine hydrochloride for injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Bendamustine Hydrochloride for Injection (25 mg per vial or 100 mg per vial lyophilized powder) Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours stored under refrigerated conditions at 2° to 8°C (36° to 46°F) or for 3 hours when stored at room temperature (15° to 30°C or 59° to 86°F) and room light. Administration of reconstituted and diluted bendamustine hydrochloride for injection must be completed within this period.

Bendamustine hydrochloride is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine [see Warnings and Precautions ( 5.4 )]. Bendamustine hydrochloride is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine. Reactions have included anaphylaxis and anaphylactoid reactions. ( 4 , 5.4 )

The following clinically significant adverse reactions have been associated with bendamustine hydrochloride in clinical trials and are discussed in greater detail in other sections of the label. Myelosuppression [see Warnings and Precautions ( 5.1 )] Infections [see Warnings and Precautions ( 5.2 )] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions ( 5.3 )] Anaphylaxis and Infusion Reactions [see Warnings and Precautions ( 5.4 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.5 )] Skin Reactions [see Warnings and Precautions ( 5.6 )] Hepatotoxicity [see Warnings and Precautions ( 5.7 )] Other Malignancies [see Warnings and Precautions ( 5. 8)] Extravasation Injury [see Warnings and Precautions ( 5.9 )] Adverse reactions (frequency >5%) during infusion and within 24 hours post-infusion are nausea and fatigue. ( 6.1 ) Most common adverse reactions (≥15%) for CLL are anemia, thrombocytopenia, neutropenia, lymphopenia, leukopenia, pyrexia, nausea, vomiting. ( 6.1 , 6.2 ) Most common adverse reactions (≥15%) for NHL are lymphopenia, leukopenia, anemia, neutropenia, thrombocytopenia, nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chronic Lymphocytic Leukemia The data described below reflect exposure to bendamustine hydrochloride in 153 patients. Bendamustine hydrochloride was studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m 2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the bendamustine hydrochloride group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. Worsening hypertension was reported in 4 patients treated with bendamustine hydrochloride in the randomized CLL clinical study and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving bendamustine hydrochloride were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients Bendamustine Hydrochloride (N=153) Chlorambucil (N=143) Body System/Adverse 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 Vomiting Diarrhea 31 (20) 24 (16) 14 (9) 1 (<1) 1 (<1) 2 (1) 21 (15) 9 (6) 5 (3) 1 (<1) 0 0 General disorders and administration site conditions Pyrexia Fatigue Asthenia Chills 36 (24) 14 (9) 13 (8) 9 (6) 6 (4) 2 (1) 0 0 8 (6) 8 (6) 6 (4) 1 (<1) 2 (1) 0 0 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis Infection Herpes simplex 10 (7) 9 (6) 5 (3) 0 3 (2) 0 12 (8) 1 (<1) 7 (5) 0 1 (<1) 0 Investigations Weight 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 Pruritus 12 (8) 8 (5) 4 (3) 0 7 (5) 2 (1) 3 (2) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2 . These findings confirm the myelosuppressive effects seen in patients treated with bendamustine hydrochloride. Red blood cell transfusions were administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride or Chlorambucil in the Randomized CLL Clinical Study Bendamustine Hydrochloride N=150 Chlorambucil N=141 Laboratory 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 bendamustine hydrochloride may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur. Non-Hodgkin Lymphoma The data described below reflect exposure to bendamustine hydrochloride in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was 31-84 years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received bendamustine hydrochloride at a dose of 120 mg/m 2 intravenously on Days 1 and 2 for up to eight 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3 . The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with Bendamustine Hydrochloride (N=176) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each adverse reaction category and once in each body system category. Body System/Adverse Reaction Number (%) of patients* 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 Vomiting Diarrhea Constipation Stomatitis Abdominal pain Dyspepsia 132 (75) 71 (40) 65 (37) 51 (29) 27 (15) 22 (13) 20 (11) 7 (4) 5 (3) 6 (3) 1 (<1) 1 (<1) 2 (1) 0 Gastroesophageal reflux disease 18 (10) 0 Dry mouth Abdominal pain upper Abdominal distension 15 (9) 8 (5) 8 (5) 1 (<1) 0 0 General disorders and administration site conditions Fatigue Pyrexia Chills Edema peripheral Asthenia Chest pain Infusion site pain Pain Catheter site pain 101 (57) 59 (34) 24 (14) 23 (13) 19 (11) 11 (6) 11 (6) 10 (6) 8 (5) 19 (11) 3 (2) 0 1 (<1) 4 (2) 1 (<1) 0 0 0 Infections and infestations Herpes 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 Dehydration Decreased appetite Hypokalemia 40 (23) 24 (14) 22 (13) 15 (9) 3 (2) 8 (5) 1 (<1) 9 (5) Musculoskeletal and connective tissue disorders Back pain Arthralgia Pain in extremity Bone pain 25 (14) 11 (6) 8 (5) 8 (5) 5 (3) 0 2 (1) 0 Nervous system disorders Headache Dizziness Dysgeusia 36 (21) 25 (14) 13 (7) 0 0 0 Psychiatric disorders Insomnia Anxiety Depression 23 (13) 14 (8) 10 (6) 0 1 (<1) 0 Respiratory, thoracic and mediastinal disorders Cough Dyspnea Pharyngolaryngeal pain Wheezing Nasal congestion 38 (22) 28 (16) 14 (8) 8 (5) 8 (5) 1 (<1) 3 (2) 1 (<1) 0 0 Skin and subcutaneous tissue disorders Rash Pruritus Dry skin Night sweats Hyperhidrosis 28 (16) 11 (6) 9 (5) 9 (5) 8 (5) 1 (<1) 0 0 0 0 Vascular disorders Hypotension 10 (6) 2 (1) Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4 . Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at Grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride in the NHL Studies Hematology Percent of patients 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 bendamustine hydrochloride. The most common serious adverse reactions occurring in ≥5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions. Adverse reactions occurring less frequently but possibly related to bendamustine hydrochloride treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of bendamustine hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic systems disorders: Pancytopenia Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling) Immune system disorders: Anaphylaxis Infections and infestations: Pneumocystis jiroveci pneumonia, progressive multifocal leukoencephalopathy (PML) Renal and urinary disorders: Nephrogenic diabetes insipidus (NDI) Respiratory, thoracic and mediastinal disorders: Pneumonitis Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), non-melanoma skin cancer (NMSC), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN)

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

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.