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These highlights do not include all the information needed to use BENDAMUSTINE HYDROCHLORIDE FOR INJECTION safely and effectively. See full prescribing information for BENDAMUSTINE HYDROCHLORIDE FOR INJECTION. BENDAMUSTINE hydrochloride for injection, for | Bendamustine Hydrochloride [Mylan Institutional LLC] | BioPortfolio

13:18 EST 27th January 2019 | BioPortfolio
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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.

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.

Bendamustine hydrochloride is available in two formulations, a solution (Bendamustine hydrochloride injection) and a lyophilized powder (Bendamustine hydrochloride 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 closed system transfer devices (CSTD) or adapter that contains polycarbonate or acrylonitrile-butadiene-styrene (ABS) is used as supplemental protection prior to dilution, only use bendamustine hydrochloride for injection, the lyophilized powder formulation [see How Supplied/Storage and Handling (16.1)].

Recommended Dosage:

The recommended dose is 100 mg/madministered 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:

Bendamustine hydrochloride for injection administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ 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/L, platelets ≥ 75 x 10/L], bendamustine hydrochloride for injection can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [see Warnings and Precautions (5.1)]

Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/mon Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/mon 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/mon Days 1 and 2 of each cycle.

Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician.

Recommended Dosage:

The recommended dose is 120 mg/madministered 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:

Bendamustine hydrochloride for injection administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ 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/L, platelets ≥ 75 x 10/L], bendamustine hydrochloride for injection can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [see Warnings and Precautions (5.1)]

Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/mon Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/mon 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/mon Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/mon Days 1 and 2 of each cycle.

Bendamustine hydrochloride is a cytotoxic drug. Follow applicable special handling and disposal procedures.

Bendamustine Hydrochloride for Injection (25 mg/vial or 100 mg/vial lyophilized powder)

If a closed system transfer device or adapter that contains polycarbonate or ABS is to be used as supplemental protection during preparation, only use bendamustine hydrochloride for injection, the lyophilized formulation.

Use Sterile Water for Injection, USP, for reconstitution and then 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.

General Information

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 for injection contain no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.

Bendamustine Hydrochloride for Injection (25 mg/vial or 100 mg/vial lyophilized powder)

Once diluted with either 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 under refrigerated conditions at 2º to 8°C (36º to 46°F) or for 3 hours when stored at room temperature (15º to 30°C or 59º to 86°F) and room light. Administration of reconstituted and diluted bendamustine hydrochloride for injection must be completed within this period.

Bendamustine hydrochloride for injection is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [see Warnings and Precautions (5.3)]

Bendamustine hydrochloride caused severe myelosuppression (Grade 3 to 4) in 98% of patients in the two NHL studies (see Table 4). 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).

In the event of treatment-related myelosuppression, monitor 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. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 10/L and the platelet count should be ≥ 75 x 10/L. [see Dosage and Administration (2.2) and (2.3)]

Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with bendamustine hydrochloride for injection are more susceptible to infections. Advise patients with myelosuppression following bendamustine hydrochloride for injection treatment to contact a physician if they have symptoms or signs of infection.

Patients treated with bendamustine hydrochloride are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Patients should undergo appropriate measures (including clinical and laboratory monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to administration.

Infusion 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 reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue bendamustine hydrochloride for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.

Tumor lysis syndrome associated with bendamustine hydrochloride treatment 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. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. 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 (5.5)].

Fatal and serious skin reactions have been reported with bendamustine hydrochloride treatment in clinical trials and postmarketing safety reports, including toxic skin reactions [Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS)], bullous exanthema, and rash. Events occurred when bendamustine hydrochloride was given as a single agent and in combination with other anticancer agents or allopurinol.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue bendamustine hydrochloride.

Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride. Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients [see Warnings and Precautions (5.2)]. Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during bendamustine therapy.

There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine hydrochloride, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma.

Bendamustine hydrochloride extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting bendamustine hydrochloride infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of bendamustine hydrochloride.

Bendamustine hydrochloride can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. [see Use in Specific Populations (8.1)]

The following serious adverse reactions have been associated with bendamustine hydrochloride in clinical trials and are discussed in greater detail in other sections of the label.

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 with CLL studied in an active-controlled, randomized trial. The population was 45 to 77 years of age, 63% male, 100% white, and were treatment naïve. All patients started the study at a dose of 100 mg/m intravenously over 30 minutes on Days 1 and 2 every 28 days.

Adverse reactions were reported according to NCI CTC v.2. 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 CLL trial 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

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with bendamustine hydrochloride. Red blood cell transfusions were administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride or Chlorambucil in the Randomized CLL Clinical Study

In the 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.

Non-Hodgkin Lymphoma

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 to 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/mintravenously on Days 1 and 2 for up to eight 21-day cycles.

The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 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: Patients counted only once in each preferred term category and once in each system organ class category.

Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >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 Hydrochloridefor Injection in the NHL Studies

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving bendamustine hydrochloride for injection. 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 postmarketing 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 [see Warnings and Precautions (5)]. 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.

2 (1)1 (<1)4 (3)
Number (%) of patients
Bendamustine Hydrochloride (N=153) Chlorambucil (N=143)
System organ class Preferred term 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)
 
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)
 
7 (5) 1 (<1)
Skin and subcutaneous tissue disorders
Rash 12 (8)
 
7 (5) 3 (2)
Pruritus 8 (5) 0 2 (1) 0
Bendamustine Hydrochloride N=150 Chlorambucil N=141
Laboratory Abnormality All Grades n (%) Grade 3/4 n (%) All Grades n (%) Grade 3/4 n (%)
Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9)
Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10)
Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3)
Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4)
Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21)
System organ class Preferred term Number (%) of patients*
All Grades Grade 3/4
Total number of patients with at least 1 adverse reaction 176 (100) 94 (53)
Cardiac disorders
Tachycardia 13 (7) 0
Gastrointestinal disorders
Nausea 132 (75) 7 (4)
Vomiting 71 (40) 5 (3)
Diarrhea 65 (37) 6 (3)
Constipation 51 (29) 1 (<1)
Stomatitis 27 (15) 1 (<1)
Abdominal pain 22 (13) 2 (1)
Dyspepsia 20 (11) 0
Gastroesophageal reflux disease 18 (10) 0
Dry mouth 15 (9) 1 (<1)
Abdominal pain upper 8 (5) 0
Abdominal distension 8 (5) 0
General disorders and administration site conditions
Fatigue 101 (57) 19 (11)
Pyrexia 59 (34) 3 (2)
Chills 24 (14) 0
Edema peripheral 23 (13) 1 (<1)
Asthenia 19 (11) 4 (2)
Chest pain 11 (6) 1 (<1)
Infusion site pain 11 (6) 0
Pain 10 (6) 0
Catheter site pain 8 (5) 0
Infections and infestations
Herpes zoster 18 (10) 5 (3)
Upper respiratory tract infection 18 (10) 0
Urinary tract infection 17 (10) 4 (2)
Sinusitis 15 (9) 0
Pneumonia 14 (8) 9 (5)
Febrile neutropenia 11 (6) 11 (6)
Oral candidiasis 11 (6) 2 (1)
Nasopharyngitis 11 (6) 0
Investigations
Weight decreased 31 (18) 3 (2)
Metabolism and nutrition disorders
Anorexia 40 (23) 3 (2)
Dehydration 24 (14) 8 (5)
Decreased appetite 22 (13) 1 (<1)
Hypokalemia 15 (9) 9 (5)
Musculoskeletal and connective tissue disorders
Back pain 25 (14) 5 (3)
Arthralgia 11 (6) 0
Pain in extremity 8 (5) 2 (1)
Bone pain 8 (5) 0
Nervous system disorders
Headache 36 (21) 0
Dizziness 25 (14) 0
Dysgeusia 13 (7) 0
Psychiatric disorders
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)
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

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: Pancytopenia

Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation

General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling)

Immune system disorders: Anaphylaxis

Infections and infestations: Pneumocystis jiroveci pneumonia

Respiratory, thoracic and mediastinal disorders: Pneumonitis

Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, Toxic epidermal necrolysis, DRESS (Drug reaction with eosinophilia and systemic symptoms). [see Warnings and Precautions (5.5)]

No formal clinical assessments of pharmacokinetic drug-drug interactions between bendamustine hydrochloride and other drugs have been conducted.

Bendamustine's active metabolites, gamma-hydroxy bendamustine (M3) and N-desmethyl-bendamustine (M4), are formed via cytochrome P450 CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma concentrations of bendamustine and decrease plasma concentrations of active metabolites. Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma concentrations of bendamustine and increase plasma concentrations of its active metabolites. Caution should be used, or alternative treatments considered if concomitant treatment with CYP1A2 inhibitors or inducers is needed.

The role of active transport systems in bendamustine distribution has not been fully evaluated. In vitro data suggest that P-glycoprotein, breast cancer resistance protein (BCRP), and/or other efflux transporters may have a role in bendamustine transport.

Based on in vitro data, bendamustine is not likely to inhibit metabolism via human CYP isoenzymes CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5, or to induce metabolism of substrates of cytochrome P450 enzymes.

Pregnancy Category D [see Warnings and Precautions (5.9)]

Risk Summary

Bendamustine hydrochloride can cause fetal harm when administered to a pregnant woman. Bendamustine caused malformations in animals, when a single dose was administered to pregnant animals. Advise women to avoid becoming pregnant while receiving bendamustine hydrochloride and for 3 months after therapy has stopped. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus. Advise men receiving bendamustine hydrochloride to use reliable contraception for the same time period.

Animal data

Single intraperitoneal doses of bendamustine from 210 mg/m(70 mg/kg) in mice administered during organogenesis 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 dosing in mice on gestation days 7 to11 resulted in an increase in resorptions from 75 mg/m (25 mg/kg) and an increase in abnormalities from 112.5 mg/m (37.5 mg/kg) similar to those seen after a single intraperitoneal administration. Single intraperitoneal doses of bendamustine from 120 mg/m (20 mg/kg) in rats administered on gestation days 4, 7, 9, 11, or 13 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. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for bendamustine in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

The effectiveness of bendamustine hydrochloride in pediatric patients has not been established. Bendamustine hydrochloride was evaluated in a single Phase 1/2 trial in pediatric patients with leukemia. The safety profile for bendamustine hydrochloride in pediatric patients was consistent with that seen in adults, and no new safety signals were identified.

The trial included pediatric patients from 1 to 19 years of age 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. Doses of 90 and 120 mg/mwere evaluated. The Phase 1 portion of the study determined that the recommended Phase 2 dose of bendamustine hydrochloride in pediatric patients was 120 mg/m

A total of 32 patients entered the Phase 2 portion of the study at the recommended dose and were evaluated for response. There was no treatment response (CR+ CRp) in any patient at this dose. However, there were 2 patients with ALL who achieved a CR at a dose of 90 mg/min the Phase 1 portion of the study.

In the above-mentioned pediatric trial, the pharmacokinetics of bendamustine hydrochloride at 90 and 120 mg/mdoses were evaluated in 5 and 38 patients, respectively, aged 1 to 19 years (median age of 10 years).

The geometric mean body surface adjusted clearance of bendamustine was 14.2 L/h/m. The exposures (AUC and C) to bendamustine in pediatric patients following a 120 mg/mintravenous infusion over 60 minutes were similar to those in adult patients following the same 120 mg/mdose.

In CLL and NHL studies, there were no clinically significant differences in the adverse reaction profile between geriatric (≥ 65 years of age) and younger patients.

Chronic Lymphocytic Leukemia

In the randomized CLL clinical study, 153 patients received bendamustine hydrochloride. The overall response rate for patients younger than 65 years of age was 70% (n=82) for bendamustine hydrochloride and 30% (n=69) for chlorambucil. The overall response rate for patients 65 years or older was 47% (n=71) for bendamustine hydrochloride and 22% (n=79) for chlorambucil. In patients younger than 65 years of age, the median progression-free survival was 19 months in the bendamustine hydrochloride group and 8 months in the chlorambucil group. In patients 65 years or older, the median progression-free survival was 12 months in the bendamustine hydrochloride group and 8 months in the chlorambucil group.

Non-Hodgkin Lymphoma

Efficacy (Overall Response Rate and Duration of Response) was similar in patients < 65 years of age and patients ≥ 65 years. Irrespective of age, all of the 176 patients experienced at least one adverse reaction.

No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. Bendamustine hydrochloride should not be used in patients with CrCL < 30 mL/min. [see Clinical Pharmacology (12.3)]

No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of bendamustine have been conducted. Bendamustine hydrochloride should not be used in patients with moderate (AST or ALT 2.5 to 10 X ULN and total bilirubin 1.5 to 3 X ULN) or severe (total bilirubin > 3 X ULN) hepatic impairment.[see Clinical Pharmacology (12.3)]

No clinically significant differences between genders were seen in the overall incidences of adverse reactions in either CLL or NHL studies.

Chronic Lymphocytic Leukemia

In the randomized CLL clinical study, the overall response rate (ORR) for men (n=97) and women (n=56) in the bendamustine hydrochloride group was 60% and 57%, respectively. The ORR for men (n=90) and women (n=58) in the chlorambucil group was 24% and 28%, respectively. In this study, the median progression-free survival for men was 19 months in the bendamustine hydrochloride treatment group and 6 months in the chlorambucil treatment group. For women, the median progression-free survival was 13 months in the bendamustine hydrochloride treatment group and 8 months in the chlorambucil treatment group.

Non-Hodgkin Lymphoma

The pharmacokinetics of bendamustine were similar in male and female patients with indolent NHL. No clinically-relevant differences between genders were seen in efficacy (ORR and DR).

The intravenous LD of bendamustine HCl is 240 mg/min 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. 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.

Bendamustine hydrochloride is an alkylating agent. The chemical name of bendamustine hydrochloride monohydrate is 5-[Bis (2-chloroethyl)amino]-1- methyl-2-benzimidazolebutyric acid hydrochloride, monohydrate. Its empirical molecular formula is CHClNO ·HCl.HO 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 (25 mg/vial or 100 mg/vial lyophilized powder)

Bendamustine Hydrochloride for Injection is intended for intravenous infusion only after reconstitution with Sterile Water for Injection, USP, and after further 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 non-pyrogenic white to off-white lyophilized powder in a single-dose vial. Each 25 mg vial contains 25 mg of bendamustine hydrochloride and 42.5 mg of mannitol. Each 100 mg vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol. The pH of the reconstituted solution is 2.5 to 3.5.

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.

Cardiac Electrophysiology

The effect of bendamustine on the QTc interval was evaluated in 53 patients with indolent NHL and mantle cell lymphoma on Day 1 of Cycle 1 after administration of rituximab at 375 mg/m intravenous infusion followed by a 30-minute intravenous infusion of bendamustine at 90 mg/m/day. No mean changes greater than 20 milliseconds were detected up to one hour post-infusion. The potential for delayed effects on the QT interval after one hour was not evaluated.

Absorption

Following a single intravenous dose of bendamustine hydrochloride C typically occurred at the end of infusion. The dose proportionality of bendamustine has not been studied.

Distribution

In vitro, the binding of bendamustine to human serum plasma proteins ranged from 94 to 96% and was concentration independent from 1 to 50 mcg/mL. Data suggest that bendamustine is not likely to displace or to be displaced by highly protein-bound drugs. The blood to plasma concentration ratios in human blood ranged from 0.84 to 0.86 over a concentration range of 10 to 100 mcg/mL indicating that bendamustine distributes freely in human red blood cells.

In a mass balance study, plasma radioactivity levels were sustained for a greater period of time than plasma concentrations of bendamustine, γ hydroxybendamustine (M3), and N desmethylbendamustine (M4). This suggests that there are bendamustine derived materials (detected via the radiolabel), that are rapidly cleared and have a longer half-life than bendamustine and its active metabolites.

The mean steady-state volume of distribution (V) of bendamustine was approximately 20 to 25 L. Steady-state volume of distribution for total radioactivity was approximately 50 L, indicating that neither bendamustine nor total radioactivity are extensively distributed into the tissues.

Metabolism

In vitro data indicate that bendamustine is primarily metabolized via hydrolysis to monohydroxy (HP1) and dihydroxy-bendamustine (HP2) metabolites with low cytotoxic activity. Two active minor metabolites, M3 and M4, are primarily formed via CYP1A2. However, concentrations of these metabolites in plasma are 1/10and 1/100that of the parent compound, respectively, suggesting that the cytotoxic activity is primarily due to bendamustine.

Results of a human mass balance study confirm that bendamustine is extensively metabolized via hydrolytic, oxidative, and conjugative pathways.

In vitro studies using human liver microsomes indicate that bendamustine does 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 enzymes in primary cultures of human hepatocytes.

Elimination

Mean recovery of total radioactivity in cancer patients following intravenous infusion of [C] bendamustine hydrochloride was approximately 76% of the dose. Approximately 50% of the dose was recovered in the urine and approximately 25% of the dose was recovered in the feces. Urinary excretion was confirmed as a relatively minor pathway of elimination of bendamustine, with approximately 3.3% of the dose recovered in the urine as parent. 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.

Bendamustine clearance in humans is approximately 700 mL/minute. After a single dose of 120 mg/mbendamustine intravenous over 1-hour the intermediate t of the parent compound is approximately 40 minutes. The mean apparent terminal elimination t of M3 and M4 are approximately 3 hours and 30 minutes respectively. Little or no accumulation in plasma is expected for bendamustine administered on Days 1 and 2 of a 28-day cycle.

Renal Impairment

In a population pharmacokinetic analysis of bendamustine in patients receiving 120 mg/mthere was no meaningful effect of renal impairment (CrCL 30 to 80 mL/min, N=31) on the pharmacokinetics of bendamustine. Bendamustine has not been studied in patients with CrCL < 30 mL/min and should not be used in these patients.

Hepatic Impairment

In a population pharmacokinetic analysis of bendamustine in patients receiving 120 mg/mthere was no meaningful effect of mild (total bilirubin ≤ ULN, AST ≥ ULN to 2.5 x ULN, and/or ALP ≥ ULN to 5 x ULN, N=26) hepatic impairment on the pharmacokinetics of bendamustine. Bendamustine has not been studied in patients with moderate or severe hepatic impairment.

Bendamustine should not be used in patients with moderate (AST or ALT 2.5 to 10 x ULN and total bilirubin 1.5 to 3 x ULN) or severe (total bilirubin > 3 x ULN) hepatic impairment. [see Use in Specific Populations (8.7)]

Effect of Age

Bendamustine exposure (as measured by AUC and C) has been studied in adult patients ages 31 through 84 years. The pharmacokinetics of bendamustine (AUC and C) were not significantly different between patients less than or greater than/equal to 65 years of age. [see Use in Specific Populations (8.4, 8.5)]

Effect of Gender

The pharmacokinetics of bendamustine were similar in male and female patients. [see Use in Specific Populations (8.8)]

Effect of Race

The effect of race on the safety, and/or efficacy of bendamustine hydrochloride has not been established. Based on a cross-study comparison, Japanese subjects (n = 6) had on average exposures that were 40% higher than non-Japanese subjects receiving the same dose. The significance of this difference on the safety and efficacy of bendamustine hydrochloride in Japanese subjects has not been established.

Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m/day (12.5 mg/kg/day, the lowest dose tested) and 75 mg/m/day (25 mg/kg/day) for four days, peritoneal sarcomas in female AB/jena mice were produced. Oral administration at 187.5 mg/m/day (62.5 mg/kg/day, the only dose tested) for four days induced mammary carcinomas and pulmonary adenomas.

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, the lowest dose tested.

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. Patients should be warned of the potential risk to their reproductive capacities.

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 to 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/L vs. 65.1x10/L), and serum lactate dehydrogenase concentration (mean 370.2 vs. 388.4 U/L). Ninety percent of patients in both treatment groups had immuno-phenotypic confirmation of CLL (CD5, CD23 and either CD19 or CD20 or both).

Patients were randomly assigned to receive either bendamustine hydrochloride at 100 mg/m, administered intravenously over a period of 30 minutes on Days 1 and 2 or chlorambucil at 0.8 mg/kg (Broca’s normal weight) administered orally on Days 1 and 15 of each 28-day cycle. Efficacy endpoints of objective response rate and progression-free survival were calculated using a pre-specified algorithm based on NCI working group criteria for CLL.

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

nPR was defined as described for CR with the exception that the bone marrow biopsy shows persistent nodules.

PR was defined as ≥ 50% decrease in peripheral lymphocyte count from the pretreatment baseline value, and either ≥50% reduction in lymphadenopathy, or ≥50% reduction in the size of spleen or liver, as well as one of the following hematologic improvements: neutrophils ≥ 1.5 x 10/L or 50% improvement over baseline, platelets >100 x 10/L or 50% improvement over baseline, hemoglobin >110 g/L or 50% improvement over baseline without transfusions, for a period of at least 56 days.

PFS was defined as time from randomization to progression or death from any cause.

Kaplan-Meier estimates of progression-free survival comparing bendamustine hydrochloride with chlorambucil are shown in Figure 1.

Bendamustine Hydrochloride (N=153) Chlorambucil (N=148) p-value
Response Rate n (%)
Overall response rate 90 (59) 38 (26) <0.0001
(95% CI) (51, 66.6) (18.6, 32.7)
Complete response (CR)* 13 (8) 1 (<1)
Nodular partial response (nPR)** 4 (3) 0
Partial response (PR) 73 (48) 37 (25)
Progression-Free Survival ††
Median, months (95% CI) 18 (11.7, 23.5) 6 (5.6, 8.6)
Hazard ratio (95% CI) 0.27 (0.17, 0.43) <0.0001

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, on Days 1 and 2 of a 21-day treatment cycle. Patients were treated for up to 8 cycles.

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 Hydrochloride (N=100)
Response Rate (%)
Overall response rate (CR+CRu+PR) 74
(95% CI) (64.3, 82.3)
Complete response (CR) 13
Complete response unconfirmed (CRu) 4
Partial response (PR) 57
Duration of Response (DR)
Median, months (95% CI) 9.2 months (7.1, 10.8)

1. OSHA Hazardous Drugs. OSHA. [Accessed on July 21, 2015, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

Bendamustine Hydrochloride is a cytotoxic drug. Follow applicable special handling and disposal procedures. Care should be exercised in the handling and preparation of solutions prepared from bendamustine hydrochloride for 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. 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.

Bendamustine Hydrochloride for Injection is supplied in individual cartons as follows:

Bendamustine Hydrochloride for Injection (25 mg/vial or 100 mg/vial lyophilized powder)

Bendamustine Hydrochloride for Injection may be stored at 20º to 25°C (68º to 77°F). [See USP Controlled Room Temperature]. Retain in original package until time of use to protect from light.

Allergic (Hypersensitivity) Reactions

Inform patients of the possibility of mild or serious allergic reactions and to immediately report rash, facial swelling, or difficulty breathing during or soon after infusion [see Warnings and Precautions (5.3)].

Myelosuppression

Inform patients of the likelihood that bendamustine hydrochloride for injection 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)].

Hepatotoxicity

Inform patients of the possibility of developing liver function abnormalities and serious hepatic toxicity. Advise patients to immediately contact their health care provider if signs of liver failure occur, including jaundice, anorexia, bleeding or bruising [see Warnings and Precautions (5.6)].

Fatigue

Advise patients that bendamustine hydrochloride 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 bendamustine hydrochloride 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 bendamustine hydrochloride may cause diarrhea. Patients should report diarrhea to the physician so that symptomatic treatment may be provided [see Adverse Reactions (6.1)].

Rash

Advise patients that a rash or itching may occur during treatment with bendamustine hydrochloride. Advise patients to immediately report severe or worsening rash or itching [see Warnings and Precautions (5.5)].

Pregnancy and Nursing

Bendamustine hydrochloride can cause fetal harm. Women should be advised to avoid becoming pregnant throughout treatment and for 3 months after bendamustine hydrochloride therapy has stopped. Men receiving bendamustine hydrochloride should use reliable contraception for the same time period. Advise patients to report pregnancy immediately. Advise patients to avoid nursing while receiving bendamustine hydrochloride [see Use in Specific Populations (8.1)].

Manufactured for:

Mylan Institutional LLC

Rockford, IL 61103 U.S.A.

Manufactured by:

Mylan Laboratories Limited

Bangalore, India

MARCH 2018

NDC 67457-325-12

Bendamustine Hydrochloride for Injection

25 mg/vial

For Intravenous Infusion Only

Reconstitution and Dilution Required (see insert)

LYOPHILIZED

Retain in carton until time of use

Discard unused portion

CAUTION: CYTOTOXIC AGENT

Sterile

Mylan

Rx only

Single-Dose Vial

NDC 67457-326-05

Bendamustine Hydrochloride for Injection

100 mg/Vial

For Intravenous Infusion Only

Reconstitution and Dilution Required (see insert)

LYOPHILIZED

Retain in carton until time of use

Discard unused portion

CAUTION: CYTOTOXIC AGENT

Sterile

Mylan

Rx only

Single-Dose Vial

Manufacturer

Mylan Institutional LLC

Active Ingredients

Source

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