Vivimusta

Bendamustine Hydrochloride · Injection · Intravenous

Uses

1 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 and 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.

Dosage forms and strengths

Injection: 100 mg/4 mL (25 mg/mL) as a clear and colorless to yellow solution in multiple-dose vial. Injection: 100 mg/4 mL (25 mg/mL) in a multiple-dose vial ( 3 ).

Contraindications

4 CONTRAINDICATIONS 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 )

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-Related 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 VIVIMUSTA causes 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. Delay the next cycle of therapy if ANC less than 1 x 10 9 /L or platelet count less than 75 x 10 9 /L [see Dosage and Administration ( 2.1 , 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 VIVIMUSTA treatment to contact healthcare provider immediately if they have symptoms or signs of infection. Patients treated with VIVIMUSTA are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Implement 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 VIVIMUSTA 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-Related Reactions Infusion-related reactions to bendamustine hydrochloride have occurred commonly in clinical trials. 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-related reactions after their first cycle of therapy. Do not rechallenge patients who experienced Grade 3 or worse allergic-type reactions. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion-related reactions. Discontinue VIVIMUSTA for patients with Grade 4 infusion-related reactions. Consider discontinuation for Grade 3 infusion-related 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 postmarketing reports. The onset tends to be within the first treatment cycle of bendamustine hydrochloride and, without intervention, may lead to acute renal failure and death. Administer vigorous hydration and monitor blood chemistry, particularly potassium and uric acid levels at baseline and closely during treatment with VIVIMUSTA. 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 )].

Side effects

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.

Drug interactions

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.

Use in specific populations

• Lactation : Advise not to breastfeed. ( 8.2 )
• Infertility : May impair fertility. ( 8.3 )
• Renal Impairment : Do not use in patients with creatinine clearance < 30 mL/min. ( 8.6 )
• Hepatic Impairment : Do not use in patients with total bilirubin 1.5-3 x ULN and AST or ALT 2.5-1.0 x ULN, or total bilirubin > 3 x ULN. ( 8.7 ) 8.1 Pregnancy Risk Summary In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6 to 1.8 times the maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth (see Data). There are no available data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Bendamustine hydrochloride was intraperitoneally administered once to mice from 210 mg/m 2 (approximately 1.8 times the MRHD) during organogenesis and caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) and decreased fetal body weights. This dose did not appear to be maternally toxic and lower doses were not evaluated. Repeat intraperitoneal administration of bendamustine hydrochloride in mice on gestation days 7 to 11 resulted in an increase in resorptions from 75 mg/m 2 (approximately 0.6 times the MRHD) and an increase in abnormalities from 112.5 mg/m 2 (approximately 0.9 times the MRHD), similar to those seen after a single intraperitoneal administration. Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m 2 (approximately the MRHD) on gestation days 4, 7, 9, 11, or 13 and caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in external (effect on tail, head, and herniation of external organs [exomphalos]) and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats. 8.2 Lactation Risk Summary There are no data on the presence of bendamustine hydrochloride or its metabolites in either human or animal milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with VIVIMUSTA and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential VIVIMUSTA can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )]. Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiation of treatment with VIVIMUSTA . Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with VIVIMUSTA and for 6 months after the last dose. Males Based on genotoxicity findings, advise males with female partners of reproductive potential to use effective contraception during treatment with VIVIMUSTA and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )]. Infertility Based on findings from clinical studies, VIVIMUSTA may impair male fertility. Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs. In some instances spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Advise patients of the potential risk to their reproductive capacities. Based on findings from animal studies, VIVIMUSTA may impair male fertility due to an increase in morphologically abnormal spermatozoa. The long-term effects of VIVIMUSTA on male fertility, including the reversibility of adverse effects, have not been studied [ see Nonclinical Toxicology ( 13.1 )]. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Safety, pharmacokinetics and efficacy were assessed in a single open-label trial (NCT01088984) in patients aged 1-19 years with relapsed or refractory acute leukemia, including 27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute myeloid leukemia (AML). Bendamustine hydrochloride was administered as an intravenous infusion over 60 minutes on Days 1 and 2 of each 21-day cycle. There was no treatment response (CR+ CRp) in any patient. The safety profile in these patients was consistent with that seen in adults and no new safety signals were identified. The pharmacokinetics of bendamustine in 43 patients, aged 1 to 19 years (median age of 10 years) were within range of values previously observed in adults given the same dose based on body surface area. 8.5 Geriatric Use 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. 12 months). No overall differences in efficacy in patients with non-Hodgkin Lymphoma were observed between geriatric patients and younger patients.

Pregnancy

8.1 Pregnancy Risk Summary In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6 to 1.8 times the maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth (see Data). There are no available data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Bendamustine hydrochloride was intraperitoneally administered once to mice from 210 mg/m 2 (approximately 1.8 times the MRHD) during organogenesis and caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) and decreased fetal body weights. This dose did not appear to be maternally toxic and lower doses were not evaluated. Repeat intraperitoneal administration of bendamustine hydrochloride in mice on gestation days 7 to 11 resulted in an increase in resorptions from 75 mg/m 2 (approximately 0.6 times the MRHD) and an increase in abnormalities from 112.5 mg/m 2 (approximately 0.9 times the MRHD), similar to those seen after a single intraperitoneal administration. Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m 2 (approximately the MRHD) on gestation days 4, 7, 9, 11, or 13 and caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in external (effect on tail, head, and herniation of external organs [exomphalos]) and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats.

Pediatric use

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Safety, pharmacokinetics and efficacy were assessed in a single open-label trial (NCT01088984) in patients aged 1-19 years with relapsed or refractory acute leukemia, including 27 patients with acute lymphocytic leukemia (ALL) and 16 patients with acute myeloid leukemia (AML). Bendamustine hydrochloride was administered as an intravenous infusion over 60 minutes on Days 1 and 2 of each 21-day cycle. There was no treatment response (CR+ CRp) in any patient. The safety profile in these patients was consistent with that seen in adults and no new safety signals were identified. The pharmacokinetics of bendamustine in 43 patients, aged 1 to 19 years (median age of 10 years) were within range of values previously observed in adults given the same dose based on body surface area.

Geriatric use

8.5 Geriatric Use 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. 12 months). No overall differences in efficacy in patients with non-Hodgkin Lymphoma were observed between geriatric patients and younger patients.

Overdosage

The intravenous lethal dose 50 (LD 50 ) of bendamustine hydrochloride is 240 mg/m 2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m 2 . Three of four patients who received this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients) and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for bendamustine hydrochloride overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.

Description

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

Mechanism of action

12.1 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.

How supplied

How Supplied VIVIMUSTA (bendamustine hydrochloride injection) is a sterile clear, colorless to yellow solution for intravenous use supplied in individual cartons of multiple-dose vials providing 100 mg bendamustine hydrochloride per 4 mL. 100 mg/4 mL (25 mg/mL) NDC 24338-270-01 Safe Handling and Disposal VIVIMUSTA (bendamustine hydrochloride injection) is a hazardous drug. Follow applicable special handling and disposal procedures 1 . Care should be exercised in the handling and preparation of solutions prepared from VIVIMUSTA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If gloves come in contact with VIVIMUSTA prior to dilution, remove gloves and follow disposal procedures. If a solution of VIVIMUSTA (bendamustine hydrochloride injection) contacts the skin, wash the skin immediately and thoroughly with soap and water. If VIVIMUSTA (bendamustine hydrochloride injection) contacts the mucous membranes, flush thoroughly with water. Storage Store VIVIMUSTA (bendamustine hydrochloride injection) refrigerated at 2°C to 8°C (36°F to 46°F). Retain in original carton until time of use to protect from light.

Patient information

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 ) ]. Anaphylaxis and Infusion-Related Reactions Inform patients of the possibility of serious or mild allergic reactions and to immediately report rash, facial swelling, or difficulty breathing during or soon after infusion [see Warnings and Precautions ( 5.4 )]. Skin Reactions Advise patients that a rash or itching may occur during treatment with VIVIMUSTA. Advise patients to immediately report severe or worsening rash or itching [see Warnings and Precautions ( 5.6 )] . Hepatotoxicity Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their healthcare provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising [see Warnings and Precautions ( 5.7 )] . Fatigue Advise patients that VIVIMUSTA 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 VIVIMUSTA 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 VIVIMUSTA may cause diarrhea. Patients should report diarrhea to the healthcare provider so that symptomatic treatment may be provided [see Adverse Reactions ( 6.1 )]. 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 VIVIMUSTA 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 VIVIMUSTA 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 VIVIMUSTA and for 1 week after the last dose [see Use in Specific Populations ( 8.2 )]. Infertility Advise males of reproductive potential that VIVIMUSTA may impair fertility [see Use in Specific Populations ( 8.3 )]. Manufactured for: Azurity Pharmaceuticals, Inc. Woburn, MA 01801 USA Vivimusta ® is a trademark of Azurity Pharmaceuticals, Inc. Manufactured at: Latina Pharma S.p.A. 04013 Sermoneta (LT), Italy. Rev. MAR2025 VIV-PI-PE1-01

Label text from the FDA structured product label by Azurity Pharmaceuticals, Inc. (revised Apr 3, 2025). Long sections are shortened; the complete label is on DailyMed.

Active ingredients

Bendamustine Hydrochloride in 2 products

Vivimusta NDC products (2)

NDC	Strength & form	Labeler	Type
24338-270	Bendamustine Hydrochloride 25 mg/mL Injection	Azurity Pharmaceuticals, Inc.	NDA
71225-120	Bendamustine Hydrochloride 25 mg/mL Injection	Slayback Pharma LLC	NDA

Frequently asked questions

What is Vivimusta used for?

What are the side effects of Vivimusta?

Who makes Vivimusta?

Vivimusta is listed by 2 labelers in the FDA NDC directory, including Azurity Pharmaceuticals, Inc., Slayback Pharma LLC.