BENDAMUSTINE HYDROCHLORIDE- 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 NHL patients, nausea increased with increasing bendamustine C max Cardiac Electrophysiology 2 2 Absorption Following a single intravenous dose of bendamustine hydrochloride C max Distribution The protein binding of bendamustine ranged from 94 to 96% and was concentration independent from 1 to 50 mug/mL. The blood to plasma concentration ratios in human blood ranged from 0. 86 over a concentration range of 10 to 100 mug/mL. The mean steady-state volume of distribution (V ss Elimination After a single intravenous dose of 120 mg/m 2 Metabolism Bendamustine is extensively metabolized via hydrolytic, oxidative, and conjugative pathways. Bendamustine is primarily metabolized via hydrolysis to monohydroxy (HP1) and dihydroxy-bendamustine (HP2) metabolites with low cytotoxic activity in vitro. Two active minor metabolites, M3 and M4, are primarily formed via CYP1A2 in vitro. M3 and M4 concentrations of these metabolites in plasma are 1/10 th th Excretion Following intravenous infusion of radiolabeled bendamustine hydrochloride in cancer patients, approximately 76% of the dose was recovered. Approximately 50% of the dose was recovered in the urine (3. 3% unchanged) and approximately 25% of the dose was recovered in the feces. Less than 1% of the dose was recovered in the urine as M3 and M4, and less than 5% of the dose was recovered in the urine as HP2. Specific Populations No clinically meaningful effects on the pharmacokinetics of bendamustine were observed based on age (31 to 84 years), sex, mild to moderate renal impairment (CLcr >= 30 mL/min), or hepatic impairment with total bilirubin 1. 5 3 × ULN on the pharmacokinetics of bendamustine is unknown. Race/Ethnicity Exposures in Japanese subjects (n=6) were 40% higher than that in non-Japanese subjects receiving the same dose. The clinical importance of this difference on the safety and efficacy of bendamustine hydrochloride in Japanese subjects has not been established. Drug Interaction Studies In Vitro Studies Effect of Bendamustine on CYP Substrates Bendamustine did not inhibit CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5. Bendamustine did not induce metabolism of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5. Effect of Transporters on Bendamustine Hydrochloride Bendamustine is a substrate of P-glycoprotein and breast cancer resistance protein (BCRP).

Bendamustine Hydrochloride Injection is an alkylating drug indicated for treatment of adult patients with: 1. 2 Bendamustine 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. 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.

For CLL 2 2. 1 For NHL 2 2. 2 Recommended Dosage The recommended dose is 100 mg/m 2 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 9 [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 2 Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m 2 Consider dose re-escalation in subsequent cycles at the discretion of the treating physician. Recommended Dosage The recommended dose is 120 mg/m 2 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 9 [see Warnings and Precautions ( 5. 1 Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m 2 2 Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m 2 2 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: - - The resulting final concentration of Bendamustine Hydrochloride Injection in the infusion bag should be within 0. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. Use either 0. 9% Sodium Chloride Injection, USP, or 2. 5% Dextrose/0. 45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. Table A: Volume (mL) of Bendamustine Hydrochloride Injection required for dilution into 500 mL of 0. 45% Sodium Chloride Injection, USP for a given dose (mg/m 2 2 Body Surface 2 Volume of Bendamustine Hydrochloride Injection to withdraw (mL) 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. Any unused solution should be discarded according to institutional procedures for antineoplastics. Bendamustine Hydrochloride Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. If diluted with 0. 45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2° to 8°C or 36° to 46°F) or for 3 hours when stored at room temperature (15° to 30°C or 59° to 86°F) and room light. Administration of diluted Bendamustine Hydrochloride Injection must be completed within this period of time. 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° to 8°C or 36° to 46°F) if additional dose withdrawal from the same vial is intended. Bendamustine Hydrochloride Injection is supplied as a multiple-dose vial. Although it does not contain any antimicrobial preservative, Bendamustine Hydrochloride Injection is bacteriostatic. The partially used vials are stable for up to 28 days when stored in its original carton under refrigeration (2° to 8°C or 36° 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 original carton at 2° to 8°C (36° to 46°F), and then discard after 28 days.

The following clinically significant serious adverse reactions are discussed in greater detail in other sections of the prescribing information. [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4 [ 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. 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. 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. 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 Adverse reactions were reported according to NCI CTC v. 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 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 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) 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 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2 Table 2: Incidence of 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 3/4 n (%) All Grades n (%) Grade 3/4 n (%) Hemoglobin 134 (89) 20 (13) 115 (82) 12 (9) Platelets 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL trial, 34% of patients had bilirubin elevations, 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. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur. Clinical Trials Experience in 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% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received bendamustine hydrochloride at a dose of 120 mg/m 2 The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3 Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with Bendamustine Hydrochloride by System Organ Class and Preferred Term (N=176) *Patients may have reported more than 1 adverse reaction. NOTE: Body System Number (%) of patients * Adverse Reaction All Grades Grade 3/4 Total number of patients with at least 1 adverse 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) Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4 Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride in the NHL Studies Hematology Variable Percent of Patients All Grades Grade 3/4 Lymphocytes Decreased 99 94 Leukocytes Decreased 94 56 Hemoglobin Decreased 88 11 Neutrophils Decreased 86 60 Platelets Decreased 86 25 In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving bendamustine hydrochloride. The most common serious adverse reactions occurring in >=5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions. 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 following adverse reactions have been identified during post-approval 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:.

Bendamustine Hydrochloride Injection is contraindicated in patients with a known hypersensitivity (e. , anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, alcohol, or monothioglycerol. [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, alcohol, or monothioglycerol. Reactions to bendamustine hydrochloride have included anaphylaxis and anaphylactoid reactions.

7 Risk Summary In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0. 8 times the maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth (see Data 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. 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 2 2 Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m 2 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. 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 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, Bendamustine Hydrochloride Injection may impair male fertility due to an increase in morphologically abnormal spermatozoa. The long-term effects of Bendamustine Hydrochloride Injection on male fertility, including the reversibility of adverse effects, have not been studied [see Nonclinical Toxicology ( 13. 1 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 to 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. 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 Bendamustine Hydrochloride Injection in patients with creatinine clearance (CLcr) < 30 mL/min [see Clinical Pharmacology ( 12. 3 Do not use Bendamustine Hydrochloride Injection in patients with AST or ALT 2. 5-10 × upper limit of normal (ULN) and total bilirubin 1. 5-3 × ULN, or total bilirubin > 3 × ULN [see Clinical Pharmacology ( 12.

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

OVERDOSAGE
The intravenous LD50 of bendamustine hydrochloride is 240 mg/m 2 Across all clinical experience, the reported maximum single dose received was 280 mg/m 2 No specific antidote for bendamustine hydrochloride overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.
NONCLINICAL TOXICOLOGY
Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m 2 2 2 Bendamustine is a mutagen and clastogen. In a reverse bacterial mutation assay (Ames assay), bendamustine was shown to increase revertant frequency in the absence and presence of metabolic activation. Bendamustine was clastogenic in human lymphocytes in vitro, and in rat bone marrow cells in vivo (increase in micronucleated polychromatic erythrocytes) from 37.5 mg/m 2 Bendamustine induced morphologic abnormalities in spermatozoa in mice. Following tail vein injection of bendamustine at 120 mg/m 2
CLINICAL STUDIES
The safety and efficacy of bendamustine hydrochloride were 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. The patient populations in the bendamustine hydrochloride and chlorambucil treatment groups were balanced with regard to the following baseline characteristics: age (median 63 vs. 66 years), gender (63% vs. 61% male), Binet stage (71% vs. 69% Binet B), lymphadenopathy (79% vs. 82%), enlarged spleen (76% vs. 80%), enlarged liver (48% vs. 46%), hypercellular bone marrow (79% vs. 73%), “B” symptoms (51% vs. 53%), lymphocyte count (mean 65. 7x10 9 9 Patients were randomly assigned to receive either bendamustine hydrochloride at 100 mg/m 2 The results of this open-label randomized study demonstrated a higher rate of overall response and a longer progression-free survival for bendamustine hydrochloride compared to chlorambucil (see Table 5). Survival data are not mature. Table 5: Efficacy Data for CLL CI = confidence interval * CR was defined as peripheral lymphocyte count <= 4 x 10 9 9 9 ** nPR was defined as described for CR with the exception that the bone marrow biopsy shows persistent nodules. dagger 9 9 daggerdagger Bendamustine 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 daggerdagger Median, months (95% CI) 18 (11. 6) Hazard ratio (95% CI) 0. 0001 Kaplan-Meier estimates of progression-free survival comparing bendamustine hydrochloride with chlorambucil are shown in Figure 1 Figure 1. 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 intravenously at a dose of 120 mg/m 2 The median age was 60 years, 65% were male, and 95% had a baseline WHO performance status of 0 or 1. Major tumor subtypes were follicular lymphoma (62%), diffuse small lymphocytic lymphoma (21%), and marginal zone lymphoma (16%). Ninety-nine percent of patients had received previous chemotherapy, 91% of patients had received previous alkylator therapy, and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. Efficacy was based on the assessments by a blinded independent review committee (IRC) and included overall response rate (complete response + complete response unconfirmed + partial response) and duration of response (DR) as summarized in Table 6 Table 6: Efficacy Data for NHL * CI = confidence interval *IRC assessment was based on modified International Working Group response criteria (IWG-RC). Modifications to IWG-RC specified that a persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be >=20 mm. Bendamustine (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.
REFERENCES
1. https://www.osha.gov/hazardous-drugs

Baxter Healthcare Corporation

BENDAMUSTINE HYDROCHLORIDE- bendamustine hydrochloride_injection Product manual source documgent