BELRAPZO SIDE EFFECTS
- Generic Name: bendamustine hydrochloride injection
- Brand Name: Belrapzo
- Drug Class: Antineoplastics, Alkylating
SIDE EFFECTS
The following clinically significant serious adverse reactions are discussed in greater detail in other sections of the prescribing information.
- Myelosuppression.
- Infections.
- Progressive Multifocal Leukoencephalopathy.
- Anaphylaxis and Infusion Reactions.
- Tumor Lysis Syndrome.
- Skin Reactions.
- Hepatotoxicity.
- Other Malignancies.
- Extravasation Injury.
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 naive CLL. All patients started the study at a dose of 100 mg/m² 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
| Body System Adverse Reaction |
Number (%) of patients | |||
| Bendamustine Hydrochloride (N=153) |
Chlorambucil (N=143) |
|||
| 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. 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 | Bendamustine Hydrochloride N=150 |
Chlorambucil N=141 |
||
| 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) |
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/m² 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)
| Body System | Number (%) of patients* | |
| Adverse Reaction | 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 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) |
| *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 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)
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).
SRC: NLM .