Data from FDA - Curated by EPG Health - Last updated 25 January 2018

Indication(s)

1 INDICATIONS AND USAGE TREANDA is an alkylating drug indicated for treatment of patients with: •Chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. (1.1) •Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. (1.2) 1.1 Chronic Lymphocytic Leukemia (CLL) TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established. 1.2 Non-Hodgkin Lymphoma (NHL) TREANDA 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.

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

Acute and Advanced Heart Failure

Acute and Advanced Heart Failure

What are the most effective treatments for acute heart failure? Can you define advanced heart failure? Discover here...

+ 3 more

Allergic Rhinitis

Allergic Rhinitis

Allergic rhinitis causes great strain on the workforce. Help to reduce sick days and improve productivity with appropriate treatment options.

+ 4 more

Anticoagulation Therapy for Stroke Prevention

Anticoagulation Therapy for Stroke Prevention

Anticoagulation therapy for Stroke Prevention Learning Zone offers a deep-dive into atrial fibrillation causes, consequences, diagnosis and management to help you deliver optimal care and prevent strokes in patients living with this common arrhythmia.

Load more

Related Content

Advisory information

contraindications
4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [see Warnings and Precautions (5.3)] TREANDA is contraindicated in patients with a history of a hypersensitivity reaction to bendamustine. Reactions have included anaphylaxis and anaphylactoid reactions. (5.3)
Adverse reactions
6 ADVERSE REACTIONS 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. •Myelosuppression [see Warnings and Precautions (5.1)] •Infections [see Warnings and Precautions (5.2)] •Anaphylaxis and Infusion Reactions [see Warnings and Precautions (5.3)] •Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] •Skin Reactions [see Warnings and Precautions (5.5)] •Hepatotoxicity [see Warnings and Precautions (5.6)] •Other Malignancies [see Warnings and Precautions ( 5.7 )] •Extravasation Injury [see Warnings and Precautions ( 5.8 )] •Most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting. (6.1) •Most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. (6.1) •Most common hematologic abnormalities for both indications (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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. Chronic Lymphocytic Leukemia 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 naïve. 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 Number (%) of patients TREANDA (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) 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 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 TREANDA 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) 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. Non-Hodgkin Lymphoma 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 Number (%) of patients* Preferred term 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 Percent of patients Hematology variable 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 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 (5)]. 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. 6.2 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. 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)]

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION TREANDA is available in two formulations, a solution (TREANDA Injection) and a lyophilized powder (TREANDA for Injection). (2.1) Do not use TREANDA injection with devices that contain polycarbonate or acrylonitrile-butadiene-styrene (ABS), including most Closed System Transfer Devices (CSTDs). (2.1, 2.4) For CLL: •100 mg/m2 infused intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles (2.2) •Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce dose to 50 mg/m2 on Days 1 and 2; if Grade 3 or greater toxicity recurs, reduce dose to 25 mg/m2 on Days 1 and 2. (2.2) •Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. (2.2) •Dose re-escalation may be considered. (2.2) For NHL: •120 mg/m2 infused intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles (2.3) •Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. (2.3) • Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. (2.3) General Dosing Considerations: •Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. (2.2, 2.3) 2.1 Selection of TREANDA Formulation to Administer TREANDA is available in two formulations, a solution (TREANDA Injection) and a lyophilized powder (TREANDA for Injection). Do not use TREANDA Injection if you intend to use closed system transfer devices (CSTDs), adapters and syringes containing polycarbonate or acrylonitrile-butadiene-styrene (ABS) prior to dilution in the infusion bag [see Dosage and Administration (2.4)]. If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion bag, only use a polypropylene syringe with a metal needle and polypropylene hub to withdraw and transfer TREANDA Injection into the infusion bag. Polypropylene syringes are translucent in appearance. TREANDA Injection and the reconstituted TREANDA 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. TREANDA Injection must be withdrawn and transferred for dilution in a biosafety cabinet (BSC) or containment isolator using a polypropylene syringe with a metal needle and a polypropylene hub. If a CSTD or adapter that contains polycarbonate or ABS is used as supplemental protection prior to dilution1, only use TREANDA for Injection, the lyophilized powder formulation [see How Supplied/Storage and Handling (16.1)]. 2.2 Dosing Instructions for CLL Recommended Dosage: The recommended dose is 100 mg/m2 administered 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: TREANDA 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 109/L, platelets ≥ 75 x 109/L], TREANDA 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/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on 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/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. 2.3 Dosing Instructions for NHL Recommended Dosage: The recommended dose is 120 mg/m2 administered 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: TREANDA 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 109/L, platelets ≥ 75 x 109/L], TREANDA 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/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on 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/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. 2.4 Preparation for Intravenous Administration TREANDA is a cytotoxic drug. Follow applicable special handling and disposal procedures.1 TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution) TREANDA Injection must be diluted in a biosafety cabinet (BSC) or containment isolator. • When preparing and transferring the concentrated TREANDA Injection solution into the infusion bag, do not use devices that contain polycarbonate or ABS. However, after dilution of TREANDA Injection into the infusion bag, devices that contain polycarbonate or ABS, including infusion sets, may be used. TREANDA Injection contains N,N-dimethylacetamide (DMA), which is incompatible with devices that contain polycarbonate or ABS. Devices, including CSTDs, adapters, and syringes that contain polycarbonate or ABS have been shown to dissolve when they come in contact with DMA which is present in the product. This incompatibility leads to device failure (e.g., leaking, breaking, or operational failure of CSTD components), possible product contamination, and potential serious adverse health consequences to the practitioner, including skin reactions; or to the patient, including but not limited to, the risk of small blood vessel blockage if they receive product contaminated with dissolved ABS or polycarbonate. Devices that are compatible for use in dilution of TREANDA Injection are available. • If using a syringe to withdraw and transfer TREANDA Injection from the vial into the infusion bag, only use a polypropylene syringe with a metal needle and a polypropylene hub to withdraw and transfer TREANDA Injection into the infusion bag. •Each vial of TREANDA Injection is intended for single dose only. •Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution using a polypropylene syringe with a metal needle and a polypropylene hub. •Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.7 mg/mL. • After dilution of TREANDA Injection into the infusion bag, devices that contain polycarbonate or ABS, including infusion sets, may be used. •Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear colorless to yellow solution. Use 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. TREANDA 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 preparation1, only use TREANDA for Injection, the lyophilized formulation. •Each vial of TREANDA for Injection is intended for single dose only. •Aseptically reconstitute each TREANDA for Injection vial as follows: ∘25 mg TREANDA for Injection vial: Add 5 mL of only Sterile Water for Injection, USP. ∘100 mg TREANDA for Injection vial: Add 20 mL of only Sterile Water for Injection, USP. •Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. If particulate matter is observed, the reconstituted product should not be used. •Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.6 mg/mL. After transferring, thoroughly mix the contents of the infusion bag. •Visually inspect the filled syringe and the prepared infusion bag to ensure the lack of visible particulate matter prior to administration. The admixture should be a clear and colorless to slightly yellow solution. 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. 2.5 Admixture Stability TREANDA Injection and TREANDA for Injection contain no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. TREANDA Injection (45 mg/0.5 mL or 180 mg/2 mL solution) 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 2-8°C (36-46°F) or for 2 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of diluted TREANDA Injection must be completed within this period. TREANDA 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 2-8°C (36-46°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of reconstituted and diluted TREANDA for Injection must be completed within this period.
Use in special populations
8 USE IN SPECIFIC POPULATIONS •Renal Impairment: Do not use if CrCL is <30 mL/min. (8.6) •Hepatic Impairment: Do not use in moderate or severe hepatic impairment. (8.7) 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions ( 5.9 )] Risk Summary TREANDA 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 TREANDA 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 TREANDA to use reliable contraception for the same time period. Animal data Single intraperitoneal doses of bendamustine from 210 mg/m2 (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 7-11 resulted in an increase in resorptions from 75 mg/m2 (25 mg/kg) and an increase in abnormalities from 112.5 mg/m2 (37.5 mg/kg) similar to those seen after a single intraperitoneal administration. Single intraperitoneal doses of bendamustine from 120 mg/m2 (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. 8.2 Nursing Mothers 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. 8.4 Pediatric Use The effectiveness of TREANDA in pediatric patients has not been established. TREANDA was evaluated in a single Phase 1/2 trial in pediatric patients with leukemia. The safety profile for TREANDA in pediatric patients was consistent with that seen in adults, and no new safety signals were identified. The trial included pediatric patients from 1-19 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). TREANDA 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/m2 were evaluated. The Phase 1 portion of the study determined that the recommended Phase 2 dose of TREANDA in pediatric patients was 120 mg/m2. 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/m2 in the Phase 1 portion of the study. In the above-mentioned pediatric trial, the pharmacokinetics of TREANDA at 90 and 120 mg/m2 doses 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/m2. The exposures (AUC0-24 and Cmax) to bendamustine in pediatric patients following a 120 mg/m2 intravenous infusion over 60 minutes were similar to those in adult patients following the same 120 mg/m2 dose. 8.5 Geriatric Use 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 TREANDA. The overall response rate for patients younger than 65 years of age was 70% (n=82) for TREANDA and 30% (n=69) for chlorambucil. The overall response rate for patients 65 years or older was 47% (n=71) for TREANDA and 22% (n=79) for chlorambucil. In patients younger than 65 years of age, the median progression-free survival was 19 months in the TREANDA group and 8 months in the chlorambucil group. In patients 65 years or older, the median progression-free survival was 12 months in the TREANDA 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. 8.6 Renal Impairment No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should not be used in patients with CrCL < 30 mL/min. [see Clinical Pharmacology (12.3)] 8.7 Hepatic Impairment No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should not be used in patients with moderate (AST or ALT 2.5-10 X ULN and total bilirubin 1.5-3 X ULN) or severe (total bilirubin > 3 X ULN) hepatic impairment. [see Clinical Pharmacology (12.3)] 8.8 Effect of Gender 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 TREANDA 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 TREANDA treatment group and 6 months in the chlorambucil treatment group. For women, the median progression-free survival was 13 months in the TREANDA 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).
Pregnancy and lactation
8.2 Nursing Mothers 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.

Interactions

7 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. Concomitant CYP1A2 inducers or inhibitors have the potential to affect the exposure of bendamustine. (7)

More information

Category Value
Authorisation number NDA022249
Agency product number 981Y8SX18M
Orphan designation No
Product NDC 63459-396,63459-395,63459-391,63459-390
Date Last Revised 03-01-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1805012
Marketing authorisation holder Cephalon, Inc.