VIVIMUSTA_- bendamustine hydrochloride_injection

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. Based on the pharmacokinetics/pharmacodynamics analyses of data from adult patients with NHL, nausea increased with increasing bendamustine maximum concentrations (C max Cardiac Electrophysiology 2 2 Absorption Following a single IV dose of bendamustine hydrochloride C max Distribution ss Elimination 2 ½ ½ Metabolism Excretion Specific Populations Race/Ethnicity Drug Interaction Studies In Vitro Studies Effect of Bendamustine Hydrochloride on CYP Substrates: Effect of Transporters on Bendamustine Hydrochloride:.

VIVIMUSTA is an alkylating drug indicated for treatment of patients with: 1. 2 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. 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.

For CLL 2 2. 1 For NHL 2 2. 2 Recommended Dosage 2 Dose Delays, Dose Modifications and Re-initiation of Therapy for CLL 9 9 see Warnings and Precautions ( 5. 1 2 2 2 Recommended Dosage 2 Dose Delays, Dose Modifications and Re-initiation of Therapy for NHL 9 9 [see Warnings and Precautions ( 5. 1 2 2 2 2 VIVIMUSTA is a hazardous drug. Follow applicable special handling and disposal procedures. 1 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 The resulting final concentration of bendamustine hydrochloride in the infusion bag should be within 0. 1 mg/mL to 1. 36 mg/mL 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 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. 5 12 10 9 6 5 2. 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. 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 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.

The following clinically significant adverse reactions are described elsewhere in the labelling: [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4 [see Warnings and Precautions ( 5. 5 [see Warnings and Precautions ( 5. 6 [see Warnings and Precautions ( 5. 7 [see Warnings and Precautions ( 5. 8 [see Warnings and Precautions ( 5. 9 Adverse reactions (> 5%) during infusion and within 24 hours post-infusion are nausea, and fatigue. 1 To report SUSPECTED ADVERSE REACTIONS, contact Azurity Pharmaceuticals, Inc. at 1-800-461-7449 or FDA at 1-800-FDA-1088 or www. gov/medwatch 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. 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 [see Warnings and Precautions ( 5 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 4: Non-Hematologic Adverse Reactions that Occurred in at Least 5% of Patients who Received Bendamustine Hydrochloride in the NHL Studies Bendamustine Hydrochloride Adverse Reaction All Grades Grade 3 or 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 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: 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 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: Cardiovascular disorders: General disorders and administration site conditions: Immune system disorders: Infections and infestations: Renal and urinary disorders: Respiratory, thoracic and mediastinal disorders: Skin and subcutaneous tissue disorders:.

VIVIMUSTA is contraindicated in patients with a known hypersensitivity (e. , 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.

Lactation 8. 2 Infertility 8. 3 Renal Impairment 8. 6 Hepatic Impairment 8. 7 Risk Summary (see Data). Data Animal Data 2 2 2 2 Risk Summary VIVIMUSTA can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8. 1 Pregnancy Testing. Contraception Females Males Nonclinical Toxicology ( 13. 1 Infertility see Nonclinical Toxicology ( 13. 1 Safety and effectiveness in pediatric patients have not been established. 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 bendamustine hydrochloride 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 bendamustine (19 months vs. No overall differences in efficacy in patients with non-Hodgkin Lymphoma were observed between geriatric patients and younger patients. Do not use VIVIMUSTA in patients with creatinine clearance (CLcr) less than 30 mL/min [see Clinical Pharmacology ( 12. 3 Do not use VIVIMUSTA in patients with AST or ALT 2. 5 to 10 times upper limit of normal (ULN) and total bilirubin 1. 5 to 3 times ULN or total bilirubin greater than 3 times ULN [see Clinical Pharmacology ( 12.

Consider alternative therapies that are not CYP1A2 inducers or inhibitors during treatment with VIVIMUSTA. 1 CYP1A2 Inhibitors [see Clinical Pharmacology ( 12. 3 CYP1A2 Inducers [see Clinical Pharmacology ( 12.

OVERDOSAGE
The intravenous lethal dose 50 (LD 50 2 2
NONCLINICAL TOXICOLOGY
Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m 2 2 2 2 2
CLINICAL STUDIES
The efficacy of bendamustine hydrochloride was evaluated in an open-label, randomized, controlled multicenter trial comparing bendamustine hydrochloride 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. Patients were randomly assigned to receive either bendamustine hydrochloride 100 mg/m 2 9 9 see Table 6: Efficacy Data for CLL Bendamustine Hydrochloride (N=153) Chlorambucil (N=148) p-value Response Rate n (%) Overall response rate 90 (59) 38 (26) <0. 0001 (95% CI) (51, 66. 7) Complete response (CR)* 13 (8) 1 (<1) Nodular partial response (nPR)** 4 (3) 0 Partial response (PR) dagger 73 (48) 37 (25) Progression-Free Survival Median, months (95% CI) 18 (11. 6) Hazard ratio (95% CI) 0. 0001 CI = confidence interval * CR was defined as peripheral lymphocyte count <= 4 x 109/L, neutrophils >= 1. 5 x 109/L, platelets >100 x 109/L, ** nPR was defined as described for CR with the exception that the bone marrow biopsy shows persistent nodules. Progression-Free Survival figure-1 The efficacy of bendamustine hydrochloride 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 bendamustine hydrochloride 120 mg/m 2 Table 7: Efficacy Data for NHL* Bendamustine Hydrochloride (N=100) Response Rate (%) Overall response rate (CR+CRu+PR) 74 (95% CI) (64. 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. 8) CI = confidence interval.
REFERENCES
1. OSHA Hazardous Drugs. OSHA

Azurity Pharmaceuticals, Inc.

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