bendamustine hydrochloride

1 INDICATIONS AND USAGE Bendamustine Hydrochloride Injection is an alkylating drug indicated for treatment of adult patients with: • Chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. ( 1.1 ) • Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. ( 1.2 ) 1.1 Chronic Lymphocytic Leukemia (CLL) Bendamustine q Hydrochloride Injection is indicated for the treatment of adult patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established. 1.2 Non-Hodgkin Lymphoma (NHL) Bendamustine Hydrochloride Injection is indicated for the treatment of adult patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

2 DOSAGE AND ADMINISTRATION 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. ( 2.1 ) 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. ( 2.2 ) 2.1 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 Injection administration in the event of 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) ≥ 1 x 10 9 /L, platelets ≥ 75 x 10 9 /L], reinitiate Bendamustine Hydrochloride Injection 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. 2.2 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 Injection administration in the event of a Grade 4 hematologic toxicity or clinically significant greater 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 Injection 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. 2.3 Preparation for Intravenous Administration Bendamustine Hydrochloride Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Bendamustine Hydrochloride Injection is in a multiple-dose vial. Bendamustine Hydrochloride Injection is a clear and colorless to yellow solution. Store Bendamustine Hydrochloride Injection at recommended refrigerated storage conditions (2° to 8°C or 36° to 46°F). When refrigerated the contents may partially freeze. Allow the vial to reach room temperature (15° to 30°C or 59° 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 A below and immediately transfer to a 500 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 Injection in the infusion bag should be within 0.05 to 0.7 mg/mL. After transferring, thoroughly mi …

3 DOSAGE FORMS AND STRENGTHS Injection:100 mg/4 mL (25 mg/mL). Each mL contains 25 mg of bendamustine hydrochloride as a clear, pale yellow to yellow solution in a multiple-dose vial. Injection: 100 mg/4 mL (25 mg/mL) in a multiple-dose vial. ( 3 )

4 CONTRAINDICATIONS Bendamustine Hydrochloride Injection is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, polyethylene glycol 300, or butylated hydroxytoluene. [see Warnings and Precautions (5.4) ] Bendamustine Hydrochloride Injection is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, polyethylene glycol 300, or butylated hydroxytoluene. Reactions to bendamustine hydrochloride have included anaphylaxis and anaphylactoid reactions ( 4 , 5.4 )

6 ADVERSE REACTIONS The following clinically significant serious adverse reactions are discussed in greater detail in other sections of the prescribing information. • Myelosuppression [see Warnings and Precautions ( 5.1 )] • Infections [see Warnings and Precautions ( 5.2 )] • Progressive Multifocal Leukoencephalopathy (PML) [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, 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 Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or http://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. Clinical Trials Experience in 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% 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 31 (20) 1 (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 …

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

8 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 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 Bendamustine Hydrochloride Injection, and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Bendamustine Hydrochloride Injection 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 Bendamustine Hydrochloride Injection. Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with Bendamustine Hydrochloride Injection 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 Bendamustine Hydrochloride Injection and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )] . Infertility Based on findings from clinical studies, Bendamustine Hydrochloride Injection 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 remi …

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.

11 DESCRIPTION Bendamustine hydrochloride is an alkylating agent. The chemical name of bendamustine hydrochloride is 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]1-methyl-, monohydrochloride. Its empirical molecular formula is C 16 H 21 Cl 2 N 3 O 2 ∙HCl, and the molecular weight is 394.7. Bendamustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula: Bendamustine Hydrochloride Injection for intravenous use is supplied as a sterile, clear, and colorless to yellow solution in a multiple-dose clear glass vial. Each milliliter contains 25 mg of bendamustine hydrochloride (equivalent to 22.7 mg bendamustine free base), 0.1 g of alcohol, USP (equivalent to 0.1 g absolute ethanol), 5 mg of monothioglycerol, NF (used as an antioxidant) and q.s. to 1 mL polyethylene glycol 400, NF. Sodium hydroxide, NF is used to adjust the acidity of polyethylene glycol 400. chemical structure

10 OVERDOSAGE The intravenous 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 treated at 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Safe Handling and Disposal 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 Bendamustine Hydrochloride Injection. 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 Bendamustine Hydrochloride Injection prior to dilution, remove gloves and follow disposal procedures 1 . If a solution of Bendamustine Hydrochloride Injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If Bendamustine Hydrochloride Injection contacts the mucous membranes, flush thoroughly with water. How Supplied Bendamustine Hydrochloride Injection is supplied in individual cartons of clear multiple-dose vials containing 100 mg of bendamustine hydrochloride in 4 mL as a clear, pale yellow to yellow solution. NDC 83831-183-04, 100 mg/4 mL (25 mg/mL) Storage Store Bendamustine Hydrochloride Injection in refrigerator, 2°C to 8°C (36°F to 46°F). Retain in original carton until time of use to protect from light. The rubber stopper is not made of natural rubber latex.