VIVIMUSTA

Bendamustine hydrochloride is an alkylating agent. The chemical name of bendamustine hydrochloride monohydrate is 5-[Bis(2-chloroethyl)-amino]-1-methyl-1H-benzimidazole-2- butanoic acid hydrochloride 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 412.74. Bendamustine hydrochloride monohydrate contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula: VIVIMUSTA (bendamustine hydrochloride injection) is intended for intravenous use after dilution with either 0.9% Sodium Chloride Injection, USP or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP. It is supplied as a sterile, clear, and colorless to yellow solution in a clear glass multiple-dose vial. Each milliliter contains 25 mg of bendamustine hydrochloride equivalent to 22.7 mg of bendamustine, 5 mg of monothioglycerol, 39.45 mg (5% v/v) of absolute alcohol, and q.s. to 1 mL polyethylene glycol 400. Sodium hydroxide is used to adjust pH of polyethylene glycol 400. VIVIMUSTA Structure

INDICATIONS & USAGE VIVIMUSTA 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) VIVIMUSTA 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) VIVIMUSTA 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 & ADMINISTRATION For CLL : • 100 mg/m 2 infused intravenously over 20 minutes on Days 1 and 2 of a 28­ day cycle, up to 6 cycles ( 2.1 ) For NHL : • 120 mg/m 2 infused intravenously over 20 minutes on Days 1 and 2 of a 21­ day cycle, up to 8 cycles ( 2.2 ) 2.1 Dosing Instructions for CLL Recommended Dosage The recommended dosage is 100 mg/m 2 administered intravenously over 20 minutes on Days 1 and 2 of a 28-day cycle for up to 6 cycles. Dose Delays, Dose Modifications and Re-initiation of Therapy for CLL Delay VIVIMUSTA for Grade 4 hematologic toxicity or clinically significant Grade 2 or greater 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) greater than or equal to 1 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L], reinitiate VIVIMUSTA at the discretion of the healthcare provider. 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 healthcare provider. 2.2 Dosing Instructions for NHL Recommended Dosage The recommended dosage is 120 mg/m 2 administered intravenously over 20 minutes on Days 1 and 2 of a 21-day cycle for up to 8 cycles. Dose Delays, Dose Modifications and Re-initiation of Therapy for NHL Delay VIVIMUSTA for Grade 4 hematologic toxicity or clinically significant Grade 2 or greater 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) greater than or equal to 1 x 10 9 /L and platelets greater than or equal to 75 x 10 9 /L], reinitiate VIVIMUSTA at the discretion of the healthcare provider. 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. 2.3 Preparation and Administration VIVIMUSTA is a hazardous drug. Follow applicable special handling and disposal procedures. 1 VIVIMUSTA is a clear and colorless to yellow solution in a multiple-dose vial. Store VIVIMUSTA refrigerated at 2°C to 8°C (36°F to 46°F). When refrigerated, the contents may partially freeze. Allow the vial to reach room temperature (15°C to 30°C or 59°F to 86°F) prior to use. Observe the contents of the vial for any visible solid or particulate matter. Do not use the product if solid or particulate matter is observed after reaching room temperature. Intravenous Infusion Aseptically withdraw the volume needed for the required dose from the 25 mg/mL solution as per Table 1 below and immediately transfer to a 250 mL infusion bag of one of the following diluents: 0.9% Sodium Chloride Injection, USP; or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP. The resulting final concentration of bendamustine hydrochloride in the infusion bag should be within 0.1 mg/mL to 1.36 mg/mL . After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. No other diluents have been shown to be compatible [see Dosage and Administration ( 2.4 )]. Table 1: Volume of VIVIMUSTA required for Dilution into 250 mL of 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP for a Given Dose and Body Surface Area Body Surface Area (m 2 ) Volume of VIVIMUSTA to Withdraw (mL) from Vial 120 mg/m 2 100 mg/m 2 90 mg/m 2 60 mg/m 2 50 mg/m 2 25 mg/m 2 1 4.8 4 3.6 2.4 2 1 1.1 5.3 4.4 4 2.6 2.2 1.1 1.2 5.8 4.8 4.3 2.9 2.4 1.2 1.3 6.2 5.2 4.7 3.1 2.6 1.3 1.4 6.7 5.6 5 3.4 2.8 1.4 1.5 7.2 6 5.4 3.6 3 1.5 1.6 7.7 6.4 5.8 3.8 3.2 1.6 1.7 8.2 6.8 6.1 4.1 3.4 1.7 1.8 8.6 7.2 6.5 4.3 3.6 1.8 1.9 9.1 7.6 6.8 4.6 3.8 1.9 2 9.6 8 7.2 4.8 4 2 2.1 10.1 8.4 7.6 5 4.2 2.1 2.2 10.6 8.8 7.9 5.3 4.4 2.2 2.3 11 9.2 8.3 5.5 4.6 2.3 2.4 11.5 9.6 8.6 5.8 4.8 2.4 2.5 12 10 9 6 5 2.5 2.6 12.5 10.4 9.4 6.2 5.2 2.6 2.7 13 10.8 9.7 6.5 5.4 2.7 2.8 13.4 11.2 10.1 6.7 5.6 2.8 2.9 13.9 11.6 10.4 7 5.8 2.9 3 14.4 12 10.8 7.2 6 3 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Discard any unused solution according to institutional procedures for hazardous drugs. 2.4 Admixture Stability VIVIMUSTA contains no antimicrobial preservative. Prepare the admixture as close as possible to the time of patient administration. Once diluted with 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2°C to 8°C or 36°F to 46°F) or for 3 hours when stored at room temperature (15°C to 30°C or 59°F to 86°F) and room light. Complete administration of diluted VIVIMUSTA within this period of time. VIVIMUSTA (bendamustine hydrochloride injection) is supplied in a multiple-dose vial. Retain the partially used vial in original package to protect from light and store refrigerated (2°C to 8°C or 36°F to 46°F) if additional dose withdrawal from the same vial is intended. 2.5 Stability of Partially Used Vials (Needle Punched Vials) VIVIMUSTA is supplied as a multiple-dose vial. Although it does not contain any antimicrobial preservative, VIVIMUSTA is bacteriostatic. The partially used vials are stable for up to 28 days when stored in its original carton under refrigeration (2°C to 8°C or 36°F to 46°F). Each vial is not recommended for more than a total of six (6) dose withdrawals. After first use, store the partially used vial in the original carton at 2°C to 8°C (36°F to 46°F) and then discard after 28 days.

VIVIMUSTA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, dehydrated alcohol, or monothioglycerol [see Warnings and Precautions ( 5.4 )] History of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, dehydrated alcohol, or monothioglycerol. Reactions to bendamustine hydrochloride have included anaphylaxis and anaphylactoid reactions. ( 4 , 5.4 )

The following clinically significant adverse reactions are described elsewhere in the labelling: • 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-Related 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 (> 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, hyperbilirubinemia, pyrexia, nausea, vomiting. ( 6.1 ) • 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 ) To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 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 (CLL) 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% were male, 100% were White, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the bendamustine hydrochloride group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. Worsening hypertension was reported in 4 patients treated with bendamustine hydrochloride 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 2 summarizes the adverse reactions that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 2: Non-Hematologic Adverse Reactions that Occurred in at Least 5% of Patients Who Received Bendamustine Hydrochloride or Chlorambucil in the Randomized CLL Clinical Study Adverse Reaction Bendamustine Hydrochloride (N=153) Chlorambucil (N=143) All Grades n (%) Grade 3 or 4 n (%) All Grades n (%) Grade 3 or 4 n (%) 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 Hematology laboratory abnormalities are described in Table 3. Red blood cell transfusions were administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of patients receiving chlorambucil. Bilirubin elevation occurred in 34% of patients, 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. Table 3: Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride or Chlorambucil in the Randomized CLL Clinical Study Laboratory Abnormality Bendamustine Hydrochloride (N=150) Chlorambucil (N=141) All Grades n (%) Grade 3 or 4 n (%) All Grades n (%) Grade 3 or 4 n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Non-Hodgkin Lymphoma (NHL) 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% were male; 89% were White, 7% were Black, 3% were Hispanic, 1% were other, and <1% were 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. In both studies, serious adverse reactions, were reported in 37% of patients receiving bendamustine hydrochloride. The most frequent 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 adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion-related reactions [see Warnings and Precautions ( 5 )]. 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. 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. Non-hematologic adverse reactions are shown in Table 4. Table 4: Non-Hematologic Adverse Reactions that Occurred in at Least 5% of Patients who Received Bendamustine Hydrochloride in the NHL Studies Bendamustine Hydrochloride (N=176*) Adverse Reaction All Grades n(%) Grade 3 or 4 n(%) 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 disorder 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 preferred term category and once in each body system category. Hematologic toxicities, based on laboratory values and CTC grade, in patients with NHL treated in both single arm studies combined are described in Table 5. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in patients with NHL who were treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 5: Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride in the NHL Studies Hematology Variable Bendamustine Hydrochloride All Grades (%) Grade 3 or 4 (%) Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval 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: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and non-melanoma skin cancer (NMSC).

Consider alternative therapies that are not CYP1A2 inducers or inhibitors during treatment with VIVIMUSTA. ( 7.1 ) 7.1 Effect of Other Drugs on VIVIMUSTA CYP1A2 Inhibitors The coadministration of VIVIMUSTA with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with VIVIMUSTA [see Clinical Pharmacology ( 12.3 )]. Consider alternative therapies that are not CYP1A2 inhibitors during treatment with VIVIMUSTA. CYP1A2 Inducers The coadministration of VIVIMUSTA with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of VIVIMUSTA [see Clinical Pharmacology ( 12.3 )]. Consider alternative therapies that are not CYP1A2 inducers during treatment with VIVIMUSTA.