Bendeka (Page 3 of 7)
5.10 Embryo-Fetal Toxicity
Based on findings from animal reproduction studies and the drug’s mechanism of action, BENDEKA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine (that approximated the maximum recommended human dose based on body surface area) to pregnant mice and rats during organogenesis caused adverse developmental outcomes, including an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with BENDEKA and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with BENDEKA and for 3 months after the last dose. [see ( Use in Specific Populations 8.1, 8.3) and Clinical Pharmacology (12.1)]
6 ADVERSE REACTIONS
The following clinically significant adverse reactions have been associated with bendamustine hydrochloride in clinical trials and are discussed in greater detail in other sections of the prescribing information.
- Myelosuppression [see Warnings and Precautions (5.1)]
- Infections [see Warnings and Precautions (5.2)]
- Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)]
- Anaphylaxis and Infusion Reactions[see Warnings and Precautions (5.4)]
- Tumor Lysis Syndrome [see Warnings and Precautions (5.5)]
- Skin Reactions [see Warnings and Precautions (5.6)]
- Hepatotoxicity [see Warnings and Precautions (5.7)]
- Other Malignancies [see Warnings and Precautions (5.8)]
- Extravasation Injury [see Warnings and Precautions (5.9)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to bendamustine hydrochloride in 329 patients who participated in an actively controlled trial (N=153) for the treatment of CLL and two single arm studies (N=176) for the treatment of indolent B cell NHL. 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.
The safety of BENDEKA administered IV as a 50 mL admixture over a 10-minute infusion is supported by clinical trials using bendamustine hydrochloride administered IV as a 500 mL admixture over 30-60 minutes infusion time, as well as an open-label, crossover study in 81 ‘end-of-life’ cancer patients treated with BENDEKA. In total, safety data from clinical studies are available from over 400 cancer patients exposed to bendamustine hydrochloride at doses in the range used in the treatment of CLL and NHL.
No clinically significant differences in the adverse reaction profile were noted among bendamustine hydrochloride administered as a 500 mL admixture over standard infusion time (30-60 minutes) and BENDEKA administered as a 50 mL admixture in a ‘short-time’ infusion over 10 minutes.
The safety and tolerability of BENDEKA was evaluated in an 8-week clinical study of BENDEKA in 81 ‘end-of-life’ cancer patients, diagnosed with solid tumors and hematologic malignancies (excluding CLL). The population was 40-82 years of age, 58% females, 84% white, 12.3% Black, 1.2% Asian and 2.5% were classified as ‘other’. BENDEKA was administered IV at a 120 mg/m2 dose as a 50 mL admixture over 10 minutes. Patients in the study received BENDEKA (50 mL IV, over 10 minutes) or bendamustine hydrochloride (500 mL IV, over 60 minutes) on Days 1 and 2 every 28 days for two consecutive 2-day cycles.
Adverse reactions (any grade) that occurred with a frequency greater than 5% during BENDEKA infusion and within one hour post-infusion were nausea (8.2%) and fatigue (5.5%).
Adverse reactions (any grade) that occurred with a frequency greater than 5% within 24 hours of BENDEKA were nausea (10.9%) and fatigue (8.2%).
Adverse reactions leading to study withdrawal in 4 patients receiving BENDEKA were pyrexia (1.2%), nausea (1.2%), vomiting (1.2%), pneumonia (1.2%) and fatigue (1.2%).
Chronic Lymphocytic Leukemia (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/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.
Number (%) of patients | ||||
Bendamustine Hydrochloride (N=153) | Chlorambucil (N=143) | |||
Body System Adverse Reaction | All Grades | Grade 3/4 | All Grades | Grade 3/4 |
Total number of patients with at least 1 adverse reaction | 121 (79) | 52 (34) | 96 (67) | 25 (17) |
Gastrointestinal disorders | ||||
Nausea | 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.
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 (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 significant deterioration does not occur.
Non-Hodgkin’s Lymphoma (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.
*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 (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. 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%).
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 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. 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.
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