Belrapzo Drug Information

Chronic Lymphocytic Leukemia (CLL)

BELRAPZO is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

Non-Hodgkin Lymphoma (NHL)

BELRAPZO 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in CLL The data described below reflect exposure to bendamustine hydrochloride in 153 patients. Bendamustine hydrochloride was studied in an active-controlled, randomized trial.

The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m 2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the bendamustine hydrochloride group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. Worsening hypertension was reported in 4 patients treated with bendamustine hydrochloride in the randomized CLL clinical study and in none treated with chlorambucil.

Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving bendamustine hydrochloride were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients Bendamustine Hydrochloride (N=153) Chlorambucil (N=143) Body System Adverse Reaction All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 52 96 25 Gastrointestinal disorders Nausea 31 1 (<1) 21 1 (<1) Vomiting 24 1 (<1) 9 0 Diarrhea 14 2 5 0 General disorders and administration site conditions Pyrexia 36 6 8 2 Fatigue 14 2 8 0 Asthenia 13 0 6 0 Chills 9 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 2 3 0 Infections and infestations Nasopharyngitis 10 0 12 0 Infection 9 3 1 (<1) 1 (<1) Herpes simplex 5 0 7 0 Investigations Weight decreased 11 0 5 0 Metabolism and nutrition disorders Hyperuricemia 11 3 2 0 Respiratory, thoracic and mediastinal disorders Cough 6 1 (<1) 7 1 (<1) Skin and subcutaneous tissue disorders Rash 12 4 7 3 Pruritus 8 0 2 0 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 Laboratory Abnormality Bendamustine Hydrochloride N=150 Chlorambucil N=141 All Grades n (%) Grade 3/4 n (%) All Grades n (%) Grade 3/4 n (%) Hemoglobin Decreased 134 20 115 12 Platelets Decreased 116 16 110 14 Leukocytes Decreased 92 42 26 4 Lymphocytes Decreased 102 70 27 6 Neutrophils Decreased 113 65 86 30 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 intravenously 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 Body System Number (%) of patients * Adverse Reaction All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 176 94 Cardiac Disorders Tachycardia 13 0 Gastrointestinal disorders Nausea 132 7 Vomiting 71 5 Diarrhea 65 6 Constipation 51 1 (<1) Stomatitis 27 1 (<1) Abdominal pain 22 2 Dyspepsia 20 0 Gastroesophageal reflux disease 18 0 Dry mouth 15 1 (<1) Abdominal pain upper 8 0 Abdominal distension 8 0 General disorders and administration site conditions Fatigue 101 19 Pyrexia 59 3 Chills 24 0 Edema peripheral 23 1 (<1) Asthenia 19 4 Chest pain 11 1 (<1) Infusion site pain 11 0 Pain 10 0 Catheter site pain 8 0 Infections and infestations Herpes zoster 18 5 Upper respiratory tract infection 18 0 Urinary tract infection 17 4 Sinusitis 15 0 Pneumonia 14 9 Febrile neutropenia 11 11 Oral candidiasis 11 2 Nasopharyngitis 11 0 Investigations Weight decreased 31 3 Metabolism and nutrition disorders Anorexia 40 3 Dehydration 24 8 Decreased appetite 22 1 (<1) Hypokalemia 15 9 Musculoskeletal and connective tissue disorders Back pain 25 5 Arthralgia 11 0 Pain in extremity 8 2 Bone pain 8 0 Nervous system disorders Headache 36 0 Dizziness 25 0 Dysgeusia 13 0 Psychiatric disorder Insomnia 23 0 Anxiety 14 1 (<1) Depression 10 0 Respiratory, thoracic and mediastinal disorders Cough 38 1 (<1) Dyspnea 28 3 Pharyngolaryngeal pain 14 1 (<1) Wheezing 8 0 Nasal congestion 8 0 Skin and subcutaneous tissue disorders Rash 28 1 (<1) Pruritus 11 0 Dry skin 9 0 Night sweats 9 0 Hyperhidrosis 8 0 Vascular disorders Hypotension 10 2 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 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.

Postmarketing Experience

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 jirovecii pneumonia, progressive multifocal leukoencephalopathy (PML) Renal and urinary disorders: Nephrogenic diabetes insipidus (NDI) Respiratory, thoracic and mediastinal disorders: Pneumonitis Skin and subcutaneous tissue disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS), non-melanoma skin cancer (NMSC), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).

Effect of Other Drugs on

BELRAPZO CYP1A2 Inhibitors The coadministration of BELRAPZO with CYP1A2 inhibitors may increase bendamustine plasma concentrations and may result in increased incidence of adverse reactions with BELRAPZO . Consider alternative therapies that are not CYP1A2 inhibitors during treatment with BELRAPZO. CYP1A2 Inducers The coadministration of BELRAPZO with CYP1A2 inducers may decrease bendamustine plasma concentrations and may result in decreased efficacy of BELRAPZO . Consider alternative therapies that are not CYP1A2 inducers during treatment with BELRAPZO.

Pregnancy Risk Summary In animal reproduction studies, intraperitoneal administration of bendamustine to pregnant mice and rats during organogenesis at doses 0.6 to 1.8 times the maximum recommended human dose (MRHD) resulted in embryo-fetal and/or infant mortality, structural abnormalities, and alterations to growth ( see Data ). There are no available data on bendamustine hydrochloride use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal data Bendamustine hydrochloride was intraperitoneally administered once to mice from 210 mg/m 2 (approximately 1.8 times the MRHD) during organogenesis and caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) and decreased fetal body weights.

This dose did not appear to be maternally toxic and lower doses were not evaluated. Repeat intraperitoneal administration of bendamustine hydrochloride in mice on gestation days 7 to 11 resulted in an increase in resorptions from 75 mg/m 2 (approximately 0.6 times the MRHD) and an increase in abnormalities from 112.5 mg/m 2 (approximately 0.9 times the MRHD), similar to those seen after a single intraperitoneal administration. Bendamustine hydrochloride was intraperitoneally administered once to rats from 120 mg/m 2 (approximately the MRHD) on gestation days 4, 7, 9, 11, or 13 and caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses.

A significant increase in external (effect on tail, head, and herniation of external organs ) and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats.

Females and Males of Reproductive Potential BELRAPZO can cause embryo-fetal harm when administered to a pregnant woman . Pregnancy Testing Pregnancy testing is recommended for females of reproductive potential prior to initiation of treatment with BELRAPZO . Contraception Females Advise female patients of reproductive potential to use effective contraception during treatment with BELRAPZO 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 BELRAPZO and for 3 months after the last dose . Infertility Based on findings from clinical studies, BELRAPZO 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, BELRAPZO may impair male fertility due to an increase in morphologically abnormal spermatozoa.

The long-term effects of BELRAPZO on male fertility, including the reversibility of adverse effects, have not been studied .

is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol. BELRAPZO is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine, polyethylene glycol 400, propylene glycol, or monothioglycerol. Reactions to bendamustine hydrochloride have included anaphylaxis and anaphylactoid reactions.

The intravenous LD50 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.