Bendamustine

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

2 DOSAGE AND ADMINISTRATION Bendamustine hydrochloride is available in two formulations, a solution (Bendamustine Injection) and a lyophilized powder (Bendamustine for Injection). ( 2.1 ) For CLL : 100 mg/m 2 infused intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles ( 2.2 ) For NHL : 120 mg/m 2 infused intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles ( 2.3 ) 2.1 Selection of Bendamustine Formulation to Administer Bendamustine hydrochloride is available in two formulations, a solution (Bendamustine Injection) and a lyophilized powder (Bendamustine for Injection). Bendamustine Hydrochloride Injection and the reconstituted Bendamustine Hydrochloride for Injection have different concentrations of bendamustine hydrochloride. The concentration of bendamustine hydrochloride in the solution is 90 mg/mL and the concentration of bendamustine hydrochloride in the reconstituted solution of lyophilized powder is 5 mg/mL. Do not mix or combine the two formulations. If a CSTD or adapter that contains polycarbonate or ABS is used as supplemental protection prior to dilution 1 , only use bendamustine hydrochloride for injection, the lyophilized powder formulation [see How Supplied/Storage and Handling ( 16 )] . 2.2 Dosing Instructions for CLL Recommended Dosage The recommended dose is 100 mg/m 2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL Delay bendamustine hydrochloride administration in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to less than or equal to Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 10 9 /L, platelets ≥ 75 x 10 9 /L], reinitiate bendamustine hydrochloride at the discretion of the treating physician. In addition, consider dose reduction [see Warnings and Precautions ( 5.1 )]. Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m 2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m 2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m 2 on Days 1 and 2 of each cycle. Consider dose re-escalation in subsequent cycles at the discretion of the treating physician. 2.3 Dosing Instructions for NHL Recommended Dosage The recommended dose is 120 mg/m 2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL Delay bendamustine hydrochloride administration in the event of a Grade 4 hematologic toxicity or clinically significant greater than or equal to Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 10 9 /L, platelets ≥ 75 x 10 9 /L], reinitiate bendamustine hydrochloride at the discretion of the treating physician. In addition, consider dose reduction [see Warnings and Precautions ( 5.1 )]. Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m 2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m 2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m 2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m 2 on Days 1 and 2 of each cycle. 2.4 Preparation for Intravenous Administration Bendamustine hydrochloride is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Bendamustine Hydrochloride for Injection (25 mg per vial or 100 mg per vial lyophilized powder) If a clos …

3 DOSAGE FORMS AND STRENGTHS Bendamustine Hydrochloride for Injection, USP: 25 mg or 100 mg white to off-white lyophilized powder in a single-dose vial for reconstitution. Bendamustine Hydrochloride for Injection: 25 mg or 100 mg lyophilized powder in a single-dose vial for reconstitution. ( 3 )

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

6 ADVERSE REACTIONS The following clinically significant adverse reactions have been associated with bendamustine hydrochloride in clinical trials and are discussed in greater detail in other sections of the label. Myelosuppression [see Warnings and Precautions ( 5.1 )] Infections [see Warnings and Precautions ( 5.2 )] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions ( 5.3 )] Anaphylaxis and Infusion Reactions [see Warnings and Precautions ( 5.4 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.5 )] Skin Reactions [see Warnings and Precautions ( 5.6 )] Hepatotoxicity [see Warnings and Precautions ( 5.7 )] Other Malignancies [see Warnings and Precautions ( 5. 8)] Extravasation Injury [see Warnings and Precautions ( 5.9 )] Adverse reactions (frequency >5%) during infusion and within 24 hours post-infusion are nausea and fatigue. ( 6.1 ) Most common adverse reactions (≥15%) for CLL are anemia, thrombocytopenia, neutropenia, lymphopenia, leukopenia, pyrexia, nausea, vomiting. ( 6.1 , 6.2 ) Most common adverse reactions (≥15%) for NHL are lymphopenia, leukopenia, anemia, neutropenia, thrombocytopenia, nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844-824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Chronic Lymphocytic Leukemia The data described below reflect exposure to bendamustine hydrochloride in 153 patients. Bendamustine hydrochloride was studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m 2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the bendamustine hydrochloride group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. Worsening hypertension was reported in 4 patients treated with bendamustine hydrochloride in the randomized CLL clinical study and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving bendamustine hydrochloride were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients Bendamustine Hydrochloride (N=153) Chlorambucil (N=143) Body System/Adverse Reaction All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea Vomiting Diarrhea 31 (20) 24 (16) 14 (9) 1 (1% 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 Hydrochlori …

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

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 to 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 patients that breastfeeding is not recommended during treatment with bendamustine hydrochloride, and for 1 week after the last dose. 8.3 Females and Males of Reproductive Potential Bendamustine hydrochloride can cause 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. Contraception Females Bendamustine hydrochloride can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations ( 8.1 )] . Advise female patients of reproductive potential to use effective contraception during treatment with bendamustine hydrochloride 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 and for 3 months after the last dose [see Nonclinical Toxicology ( 13.1 )] . Infertility Males Based on findings from clinical studies, bendamustine hydrochloride may impair male fertility. Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in co …

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

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 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 for Injection, USP. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of bendamustine hydrochloride contacts the skin, wash the skin immediately and thoroughly with soap and water. If bendamustine hydrochloride contacts the mucous membranes, flush thoroughly with water. How Supplied Bendamustine Hydrochloride for Injection, USP is supplied as follows: NDC Bendamustine Hydrochloride for Injection, USP Package Factor 71288- 102 -10 25 mg white to off-white lyophilized powder in a 10 mL amber single-dose vial 1 vial per carton 71288- 103 -20 100 mg white to off-white lyophilized powder in a 20 mL amber single-dose vial 1 vial per carton Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex. Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Retain in original package until time of use to protect from light. Discard unused portion.

How Supplied Bendamustine Hydrochloride for Injection, USP is supplied as follows: NDC Bendamustine Hydrochloride for Injection, USP Package Factor 71288- 102 -10 25 mg white to off-white lyophilized powder in a 10 mL amber single-dose vial 1 vial per carton 71288- 103 -20 100 mg white to off-white lyophilized powder in a 20 mL amber single-dose vial 1 vial per carton Sterile, Nonpyrogenic, Preservative-free. The container closure is not made with natural rubber latex.