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Treanda

Treanda

SIDE EFFECTS

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

The data described below reflect exposure to TREANDA in 329 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm trials (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.

Clinical Trials Experience in CLL

The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% white, and were treatment na´ve. 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. Non-hematologic adverse reactions (any grade) in the TREANDA 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 TREANDA 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 TREANDA 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

System organ class Preferred term Number (%) of patients
TREANDA
(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 0) 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 TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

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

Laboratory Abnormality TREANDA
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 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 TREANDA 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 TREANDA 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 TREANDA 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 TREANDA by System Organ Class and Preferred Term (N=176)

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)
*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 TREANDA in the NHL Studies

Hematology variable Percent of patients
All Grades Grades 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 TREANDA. 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]. Adverse reactions occurring less frequently but possibly related to TREANDA 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 TREANDA. 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: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis.

Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See WARNINGS AND PRECAUTIONS]

Read the Treanda (bendamustine hydrochloride injection) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

No formal clinical assessments of pharmacokinetic drug-drug interactions between TREANDA 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.

Read the Treanda Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 9/11/2013
This monograph has been modified to include the generic and brand name in many instances.

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