Bendamustine Hydrochloride Injection (Treanda)
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Bendamustine Hydrochloride Injection (Treanda)

TREANDA®
(bendamustine hydrochloridc) for Injection, for Intravenous Infusion

DRUG DESCRIPTION

TREANDA contains bendamustine hydrochloride, an alkylating drug, as the active ingredient. The chemical name of bendamustine hydrochloride is lH-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-l methyl-, monohydrochloride. Its empirical molecular formula is C16H21Cl2N3O2•HC1, and the molecular weight is 394.7. Bendamustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula:

TREANDA®
  (bendamustine hydrochloridc) Structural Formula Illustration

TREANDA (bendamustine hydrochloride) for Injection is intended for intravenous infusion only after reconstitution with Sterile Water for Injection, USP, and after further dilution with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP. It is supplied as a sterile non-pyrogenic white to off-white lyophilized powder in a single-use vial. Each 25-mg vial contains 25 mg of bendamustine hydrochloride and 42.5 mg of mannitol, USP. Each 100-mg vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol, USP. The pH of the reconstituted solution is 2.5 - 3.5.

What are the possible side effects of bendamustine (Treanda)?

Some people receiving a bendamustine injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you have fever, chills, itching, or skin rash during or shortly after the injection.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers at once if you have a serious side effect such as:

  • fever, chills, body aches, flu symptoms, sores in your mouth and throat;
  • pale...

Read All Potential Side Effects and See Pictures of Treanda »

What are the precautions when taking bendamustine hydrochloride injection (Treanda)?

Before using bendamustine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients (such as mannitol), which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood/bone marrow disorders, kidney problems, liver problems, recent/current infection.

Bendamustine can make you more likely to get infections or may worsen any current infections. Therefore, do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose. Also avoid...

Read All Potential Precautions of Treanda »

Last reviewed on RxList: 7/9/2012
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

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.

Non-Hodgkin Lymphoma (NHL)

TREANDA for Injection 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.

DOSAGE AND ADMINISTRATION

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]

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.

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]

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.

Reconstitution/Preparation for Intravenous Administration

  • Aseptically reconstitute each TREANDA vial as follows:
    • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP.
    • 100 mg TREANDA 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 HC1 concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. 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 HC1 in the infusion bag should be within 0.2 - 0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. 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.

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.

Admixture Stability

TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration.

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 refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period.

HOW SUPPLIED

Dosage Forms and Strengths

TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HC1 as white to off-white lyophilized powder.

Safe Handling and Disposal

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water.

Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published3-6. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

How Supplied

TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows:

NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial

NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial

Storage

TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

Distributed by: Cephalon, Inc. Frazer,PA 19355. Revised 06/2012

Last reviewed on RxList: 7/9/2012
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

The data described below reflect exposure to TREANDA in 349 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 following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections of the label.

Clinical Trials Experience in CLL

The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled 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 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 randomized CLL clinical study and 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 Chloramhucil in the Randomized CLL Clinical Studv

  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 randomized CLL clinical study, 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 significant 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 8 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.

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.

Last reviewed on RxList: 7/9/2012
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Myelosuppression

Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table 4). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).

In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See DOSAGE AND ADMINISTRATION]

Infections

Infection, including pneumonia and sepsis, has been reported in adult and pediatric patients in clinical trials and in postmarketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection.

Infusion Reactions and Anaphylaxts

Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions.

Tumor Lysis Syndrome

Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly.

Skin Reactions

A number of skin reactions have been reported in clinical trials and postmarketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain.

In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued.

Other Malignancies

There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined.

Extravasation

There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain. Precautions should be taken to avoid extravasation, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA.

Use In Pregnancy

TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. [See Use In Specific Populations]

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m2/day (12.5 mg/kg/day, the lowest dose tested) and 75 mg/m2/day (25 mg/kg/day) for four days, peritoneal sarcomas in female AB/jena mice were produced. Oral administration at 187.5 mg/m2/day (62.5 mg/kg/day, the only dose tested) for four days induced mammary carcinomas and pulmonary adenomas.

Bendamustine is a mutagen and clastogen. In a reverse bacterial mutation assay (Ames assay), bendamustine was shown to increase revertant frequency in the absence and presence of metabolic activation. Bendamustine was clastogenic in human lymphocytes in vitro, and in rat bone marrow cells in vivo (increase in micronucleated polychromatic erythrocytes) from 37.5 mg/m2, the lowest dose tested.

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. Patients should be warned of the potential risk to their reproductive capacities.

Use In Specific Populations

Pregnancy

Pregnancy Category D [See WARNINGS AND PRECAUTIONS]

TREANDA can cause fetal harm when administered to a pregnant woman. 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.

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.

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.

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.

Renal Impairment

No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild or moderate renal impairment. TREANDA should not be used in patients with CrCL < 40 mL/min. [See CLINICAL PHARMACOLOGY]

Hepatic Impairment

No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild hepatic impairment. 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]

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).

Last reviewed on RxList: 7/9/2012
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

The intravenous LD50 of bendamustine HC1 is 240 mg/m2 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/m2. 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 TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.

CONTRAINDICATIONS

TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See WARNINGS AND PRECAUTIONS]

Last reviewed on RxList: 7/9/2012
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

Mechanism of Action

Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways. Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action of bendamustine remains unknown.

Pharmacokinetics

Absorption

Following a single IV dose of bendamustine hydrochloride Cmax typically occurred at the end of infusion. The dose proportionality of bendamustine has not been studied.

Distribution

In vitro, the binding of bendamustine to human serum plasma proteins ranged from 94-96% and was concentration independent from 1-50 µg/mL. Data suggest that bendamustine is not likely to displace or to be displaced by highly protein-bound drugs. The blood to plasma concentration ratios in human blood ranged from 0.84 to 0.86 over a concentration range of 10 to 100 µg/mL indicating that bendamustine distributes freely in human red blood cells. In humans, the mean steady state volume of distribution (Vss) was approximately 25 L.

Metabolism

In vitro data indicate that bendamustine is primarily metabolized via hydrolysis to metabolites with low cytotoxic activity. In vitro, studies indicate that two active minor metabolites, M3 and M4, are primarily formed via CYP1A2. However, concentrations of these metabolites in plasma are 1/10 and 1/100 that of the parent compound, respectively, suggesting that the cytotoxic activity is primarily due to bendamustine.

In vitro studies using human liver microsomes indicate that bendamustine does not inhibit CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5. Bendamustine did not induce metabolism of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 enzymes in primary cultures of human hepatocytes.

Elimination

No mass balance study has been undertaken in humans. Preclinical radiolabeled bendamustine studies showed that approximately 90% of drug administered was recovered in excreta primarily in the feces.

Bendamustine clearance in humans is approximately 700 mL/minute. After a single dose of 120 mg/m2 bendamustine IV over 1-hour the intermediate t½ of the parent compound is approximately 40 minutes. The mean apparent terminal elimination t½ of M3 and M4 are approximately 3 hours and 30 minutes respectively. Little or no accumulation in plasma is expected for bendamustine administered on Days 1 and 2 of a 28-day cycle.

Renal Impairment

In a population pharmacokinetic analysis of bendamustine in patients receiving 120 mg/m2 there was no meaningful effect of renal impairment (CrCL 40 - 80 mL/min, N=31) on the pharmacokinetics of bendamustine. Bendamustine has not been studied in patients with CrCL < 40 mL/min.

These results are however limited, and therefore bendamustine should be used with caution in patients with mild or moderate renal impairment. Bendamustine should not be used in patients with CrCL < 40 mL/min. [See Use in Specific Populations]

Hepatic Impairment

In a population pharmacokinetic analysis of bendamustine in patients receiving 120 mg/m2 there was no meaningful effect of mild (total bilirubin ≤ ULN, AST ≥ ULN to 2.5 x ULN, and/or ALP ≥ ULN to 5.0 x ULN, N=26) hepatic impairment on the pharmacokinetics of bendamustine. Bendamustine has not been studied in patients with moderate or severe hepatic impairment.

These results are however limited, and therefore bendamustine should be used with caution in patients with mild hepatic impairment. Bendamustine should not be used in patients with moderate (AST or ALT 2.5 - 10 x ULN and total biliiubin 1.5 - 3 x ULN) or severe (total biliiubin > 3 x ULN) hepatic impairment. [See Use In Specific Populations]

Effect of Age

Bendamustine exposure (as measured by AUC and Cmax) has been studied in adult patients ages 31 through 84 years. The pharmacokinetics of bendamustine (AUC and Cmax) were not significantly different between patients less than or greater than/equal to 65 years of age. [See Use In Specific Populations]

Effect of Gender

The pharmacokinetics of bendamustine were similar in male and female patients. [See Use In Specific Populations]

Effect of Race

The effect of race on the safety, and/or efficacy of TREANDA has not been established. Based on a cross-study comparison, Japanese subjects (n = 6) had on average exposures that were 40% higher than non-Japanese subjects receiving the same dose. The significance of this difference on the safety and efficacy of TREANDA in Japanese subjects has not been established.

Pharmacokinetics/Pharmacodynamics

Based on the pharmacokinetics/pharmacodynamics analyses of data from adult NHL patients, a correlation was observed between nausea and bendamustine Cmax.

Clinical Studies

Chronic Lymphocytic Leukemia (CLL)

The safety and efficacy of TREANDA were evaluated in an open-label, randomized, controlled multicenter trial comparing TREANDA to chlorambucil. The trial was conducted in 301 previously-untreated patients with Binet Stage B or C (Rai Stages I - IV) CLL requiring treatment. Need-to-treat criteria included hematopoietic insufficiency, B-symptoms, rapidly progressive disease or risk of complications from bulky lymphadenopathy. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia, Richter's syndrome, or transformation to prolymphocytic leukemia were excluded from the study.

The patient populations in the TREANDA and chlorambucil treatment groups were balanced with regard to the following baseline characteristics: age (median 63 vs. 66 years), gender (63% vs. 61% male), Binet stage (71% vs. 69% Binet B), lymphadenopathy (79% vs. 82%), enlarged spleen (76% vs. 80%), enlarged liver (48% vs. 46%), hypercellular bone marrow (79% vs. 73%), "B" symptoms (51% vs. 53%), lymphocyte count (mean 65.7xl09/L vs. 65.1xl09/L), and serum lactate dehydrogenase concentration (mean 370.2 vs. 388.4 U/L). Ninety percent of patients in both treatment groups had immuno-phenotypic confirmation of CLL (CDS, CD23 and either CD19 or CD20 or both).

Patients were randomly assigned to receive either TREANDA at 100 mg/m2, administered intravenously over a period of 30 minutes on Days 1 and 2 or chlorambucil at 0.8 mg/kg (Broca's normal weight) administered orally on Days 1 and 15 of each 28-day cycle. Efficacy endpoints of objective response rate and progression-free survival were calculated using a pre-specified algorithm based on NCI working group criteria for CLL1.

The results of this open-label randomized study demonstrated a higher rate of overall response and a longer progression-free survival for TREANDA compared to chlorambucil (see Table 5). Survival data are not mature.

Table 5: Efficacy Data for CLL

  TREANDA
(N=153)
Chlorambucil
(N=148)
p-value
Response Rate n(%)      
Overall response rate 90 (59) 38 (26) O.0001
(95% CI) (51.0,66.6) (18.6,32.7)  
Complete response (CR)* 13(8) 1( < 1)  
Nodular partial response (nPR)** 4(3) 0  
Partial response (PR) 73 (48) 37(25)  
Progression-Free Snnival††      
Median, months (95% CI) 18(11.7,23.5) 6(5.6,8.6)  
Hazard ratio (95% CI) 0.27 (0.17, 0.43) < 0.0001
CI = confidence interval
* CR was defined as peripheral lymphocyte count ≤ 4.0 x 109/L, neutrophils ≥ 1.5x 109/L, platelets > 100 x 109/L, hemoglobin > 110 g/L, without transfusions, absence of palpable hepatosplenomegaly, lymph nodes ≤ 1.5 cm, < 30% lymphocytes without nodularity in at least a normocellular bone marrow and absence of "B" symptoms. The clinical and laboratory criteria were required to be maintained for a period of at least 56 days.
** nPR was defined as described for CR with the exception that the bone marrow biopsy shows persistent nodules.
PR was defined as ≥ 50% decrease in peripheral lymphocyte count from the pretreatment baseline value, and either ≥ 50% reduction in lymphadenopathy, or ≥ 50% reduction in the size of spleen or liver, as well as one of the following hematologic improvements: neutrophils ≥ 1.5 x 109/L or 50% improvement over baseline, platelets > 100 x 109/L or 50% improvement over baseline, hemoglobin > 110 g/L or 50% improvement over baseline without transfusions, for a period of at least 56 days.
††PFS was defined as time from randomization to progression or death from any cause.

Kaplan-Meier estimates of progression-free survival comparing TREANDA with chlorambucil are shown in Figure 1.

Figure 1. Progression-Free Survival

Progression-Free Survival Illustration

Non-Hodgkin Lymphoma (NHL)

The efficacy of TREANDA was evaluated in a single arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Patients were included if they relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. All patients received TREANDA intravenously at a dose of 120 mg/m2, on Days 1 and 2 of a 21-day treatment cycle. Patients were treated for up to 8 cycles.

The median age was 60 years, 65% were male, and 95% had a baseline WHO performance status of 0 or 1. Major tumor subtypes were follicular lymphoma (62%), diffuse small lymphocytic lymphoma (21%), and marginal zone lymphoma (16%). Ninety-nine percent of patients had received previous chemotherapy, 91% of patients had received previous alkylator therapy, and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab.

Efficacy was based on the assessments by a blinded independent review committee (IRC) and included overall response rate (complete response + complete response unconfirmed + partial response) and duration of response (DR) as summarized in Table 6.

Table 6: Efficacy Data for NHL*

  TREANDA
(N=100)
Response Rate (%)
Overall response rate (CR+CRu+PR) 74
(95% CI) (64.3, 82.3)
Complete response (CR) 13
Complete response unconfirmed (CRu) 4
Partial response (PR) 57
Duration of Response (DR)
Median, months (95% CI) 9.2 months
(7.1, 10.8)
CI = confidence interval
*IRC assessment was based on modified International Working Group response criteria (IWG-RC)2. Modifications to IWG-RC specified that a persistently positive bone marrow in patients who met all other criteria for CR would be scored as PR. Bone marrow sample lengths were not required to be ≥ 20 mm.

REFERENCES

1. Cheson et al. National Cancer Institute - sponsored Working Group Guidelines for Chronic Lymphocytic Leukemia. Blood Vol 87 1996:pp 4990.

2. Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas. J Clin Oncol. 1999;17:1244-1253.

3. Preventing occupational exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.

4. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha. gov/dts/osta/otm/otm_vi/otm_vi_2.html.

5. American Society of Health-System Pharmacists. ASHP Guidelines on Handling Hazardous Drugs. Am J Health-Syst Pharm. 2006; 63:1172-1193.

6. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.

Last reviewed on RxList: 7/9/2012
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

  • Allergic (Hypersensitivity) Reactions

Patients should be informed of the possibility of mild or serious allergic reactions and to immediately report rash, facial swelling, or difficulty breathing during or soon after infusion.

  • Myelosuppression

Patients should be informed of the likelihood that TREANDA will cause a decrease in white blood cells, platelets, and red blood cells. They will need frequent monitoring of these parameters. They should be instructed to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection.

  • Pregnancy and Nursing

TREANDA can cause fetal harm. Women should be advised to avoid becoming pregnant throughout treatment and for 3 months after TREANDA therapy has stopped. Men receiving TREANDA should use reliable contraception for the same time period. Advise patients to report pregnancy immediately. Advise patients to avoid nursing while receiving TREANDA.

  • Fatigue

Advise patients that TREANDA may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect.

  • Nausea and Vomiting

Advise patients that TREANDA may cause nausea and/or vomiting. Patients should report nausea and vomiting so that symptomatic treatment may be provided.

Advise patients that TREANDA may cause diarrhea. Patients should report diarrhea to the physician so that symptomatic treatment may be provided.

  • Rash

Advise patients that a mild rash or itching may occur during treatment with TREANDA. Advise patients to immediately report severe or worsening rash or itching.

Last reviewed on RxList: 7/9/2012
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

  • Allergic (Hypersensitivity) Reactions

Patients should be informed of the possibility of mild or serious allergic reactions and to immediately report rash, facial swelling, or difficulty breathing during or soon after infusion.

  • Myelosuppression

Patients should be informed of the likelihood that TREANDA will cause a decrease in white blood cells, platelets, and red blood cells. They will need frequent monitoring of these parameters. They should be instructed to report shortness of breath, significant fatigue, bleeding, fever, or other signs of infection.

  • Pregnancy and Nursing

TREANDA can cause fetal harm. Women should be advised to avoid becoming pregnant throughout treatment and for 3 months after TREANDA therapy has stopped. Men receiving TREANDA should use reliable contraception for the same time period. Advise patients to report pregnancy immediately. Advise patients to avoid nursing while receiving TREANDA.

  • Fatigue

Advise patients that TREANDA may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect.

  • Nausea and Vomiting

Advise patients that TREANDA may cause nausea and/or vomiting. Patients should report nausea and vomiting so that symptomatic treatment may be provided.

Advise patients that TREANDA may cause diarrhea. Patients should report diarrhea to the physician so that symptomatic treatment may be provided.

  • Rash

Advise patients that a mild rash or itching may occur during treatment with TREANDA. Advise patients to immediately report severe or worsening rash or itching.

Last reviewed on RxList: 7/9/2012
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Treanda Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

BENDAMUSTINE - INJECTION

(BEN-da-MUS-teen)

COMMON BRAND NAME(S): Treanda

USES: This medication is used to treat certain types of cancer (e.g., chronic lymphocytic leukemia-CLL, B-cell non-Hodgkin's lymphoma). Bendamustine belongs to a class of cancer chemotherapy drugs known as alkylating agents. It works by killing cancer cells or slowing their growth.

HOW TO USE: This medication is injected slowly into a vein by a health care professional as directed by your doctor.

The dosage is based on your medical condition, body size, and response to treatment. Before each cycle, you should have blood tests to find the best dose for you and to see whether you need to wait before receiving this drug again.

Before you receive this medication, your doctor may direct you to take a fever reducer, an antihistamine, and a corticosteroid such as dexamethasone to help prevent side effects. Use these additional medications exactly as directed by your doctor. (See also Side Effects section.)

If bendamustine leaks out of the vein into the surrounding area, it may cause serious skin and tissue damage. Tell your health care professional immediately if you experience pain, irritation, redness, or swelling at the injection site. Prompt treatment of the leakage will help reduce discomfort and possible skin damage.

Disclaimer

Treanda Consumer (continued)

SIDE EFFECTS: Nausea, vomiting, diarrhea, tiredness, weakness, or mouth sores may occur. If these effects persist or worsen, tell your doctor or pharmacist promptly.

Many people using this medication have serious side effects. However, your doctor has prescribed this drug because he or she has judged that the benefit to you is greater than the risk of side effects. Careful monitoring by your doctor may decrease your risk.

Tell your doctor right away if you have any serious side effects, including: unusual tiredness, pale skin, signs of infection (e.g., persistent sore throat, cough, fever, chills), easy bruising/bleeding.

Bendamustine sometimes causes side effects due to the rapid destruction of cancer cells (tumor lysis syndrome). To lower your risk, drink plenty of fluids unless your doctor directs you otherwise. Your doctor may also direct you to take another medication (allopurinol) for the first 1 to 2 weeks of treatment. Tell your doctor immediately if you have symptoms such as: low back/side pain (flank pain), pink/bloody urine, change in the amount of urine, painful urination, muscle spasms/weakness.

This medication can decrease sperm production, an effect that may lower male fertility. Consult your doctor for more details.

Bendamustine can commonly cause a reaction with symptoms of rash, itching, fever, and chills. This reaction is usually not serious. However, you may not be able to tell it apart from a rare allergic reaction that could be severe. Therefore, get medical help right away if you develop any of the following symptoms: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist promptly.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

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

PRECAUTIONS: Before using bendamustine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients (such as mannitol), which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: blood/bone marrow disorders, kidney problems, liver problems, recent/current infection.

Bendamustine can make you more likely to get infections or may worsen any current infections. Therefore, do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received oral polio vaccine or flu vaccine inhaled through the nose. Also avoid contact with people who have infections that may spread to others (e.g., chickenpox, flu). Wash your hands well to prevent the spread of infections.

To lower the chance of getting cut, bruised, or injured, use caution with sharp objects like razors and nail cutters, and avoid activities such as contact sports.

This drug may cause tiredness. Do not drive, use machinery, or do any activity that requires alertness until you are sure you can perform such activities safely. Limit alcoholic beverages.

This drug is not recommended for use during pregnancy. It may harm an unborn baby. It is important to prevent pregnancy while using this medication and for 3 months after treatment. Therefore, males and females must use at least 2 reliable forms of birth control (e.g., condoms, birth control pills) during treatment and for 3 months following the end of treatment with this drug. If you become pregnant or think you may be pregnant, tell your doctor immediately.

It is not known whether this drug passes into breast milk. However, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

Disclaimer

Treanda Consumer (continued)

DRUG INTERACTIONS: Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

Some products that may interact with this drug include: live vaccines (e.g., typhoid vaccine taken by mouth, flu vaccine inhaled through the nose).

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center. Symptoms of overdose may include fast/irregular heartbeat and fainting.

NOTES: Laboratory and/or medical tests (e.g., complete blood count, liver and kidney function tests) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor immediately to establish a new dosing schedule.

STORAGE: Not applicable. This medication is given in a clinic and will not be stored at home.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised September 2010. Copyright(c) 2010 First Databank, Inc.

Treanda Patient Information Including Side Effects

Brand Names: Treanda

Generic Name: bendamustine (Pronunciation: BEN da MUS teen)

What is bendamustine (Treanda)?

Bendamustine is a cancer medication that interferes with the growth of cancer cells and slows their growth and spread in the body.

Bendamustine is used to treat chronic lymphocytic leukemia. Bendamustine is also used to treat indolent B-cell non-Hodgkin lymphoma after other medications have been tried without successful treatment of this condition.

Bendamustine may also be used for purposes not listed in this medication guide.

What are the possible side effects of bendamustine (Treanda)?

Some people receiving a bendamustine injection have had a reaction to the infusion (when the medicine is injected into the vein). Tell your caregiver right away if you have fever, chills, itching, or skin rash during or shortly after the injection.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Tell your caregivers at once if you have a serious side effect such as:

  • fever, chills, body aches, flu symptoms, sores in your mouth and throat;
  • pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating;
  • easy bruising or bleeding, purple or red pinpoint spots under your skin, unusual weakness;
  • cold symptoms such as stuffy nose, sneezing, cough, sore throat;
  • lower back pain, blood in your urine, urinating less than usual or not at all;
  • numbness or tingly feeling around your mouth;
  • muscle weakness, tightness, or contraction, overactive reflexes;
  • fast or slow heart rate, weak pulse, confusion;
  • dry mouth, feeling very thirsty or hot, heavy sweating or hot and dry skin;
  • severe blistering, peeling, and red skin rash; or
  • pain, swelling, redness, skin changes, or signs of infection where the medicine was injected.

Less serious side effects may include:

  • mild nausea, vomiting, diarrhea, constipation, or upset stomach;
  • swelling in your hands or feet;
  • headache, dizziness, drowsiness;
  • loss of appetite, weight loss; or
  • mild skin rash.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

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

What is the most important information I should know about bendamustine (Treanda)?

You should not receive this medication if you are allergic to bendamustine or mannitol (Osmitrol).

Before you receive bendamustine, tell your doctor if you have a weak immune system, fever or other signs of infection, a metabolic disorder or electrolyte imbalance, liver or kidney disease, or if you smoke.

Tell your caregiver right away if you have a fever, chills, itching, or skin rash during or shortly after the injection.

Other serious side effects to tell your doctor about include fever, chills, cough, sore throat, feeling short of breath, pale skin, easy bruising or bleeding, unusual weakness, severe skin rash, weak pulse, muscle weakness, fast or slow heart rate, confusion, lower back pain, blood in your urine, urinating less than usual, or swelling, redness, or signs of where the medicine was injected.

To be sure this medication is not causing harmful effects, your blood may need to be tested often. Your kidney or liver function may also need to be tested. Visit your doctor regularly.

Side Effects Centers

Treanda Patient Information including How Should I Take

What should I discuss with my healthcare provider before I receive bendamustine (Treanda)?

You should not receive this medication if you are allergic to bendamustine or mannitol (Osmitrol).

To make sure you can safely receive bendamustine, tell your doctor if you have any of these other conditions:

  • a weak immune system;
  • fever or other signs of infection;
  • a metabolic disorder or electrolyte imbalance;
  • liver disease;
  • kidney disease; or
  • if you smoke.

FDA pregnancy category D. Do not receive bendamustine if you are pregnant. It could harm the unborn baby. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether bendamustine passes into breast milk or if it could harm a nursing baby. Do not receive this medication without telling your doctor if you are breast-feeding a baby.

Some people receiving bendamustine have developed certain types of cancers. It is not known whether this medication causes cancer. Talk with your doctor about the risks and benefits of using bendamustine.

How is bendamustine given (Treanda)?

Bendamustine is injected into a vein through an IV. You will receive this injection in a clinic or hospital setting. Bendamustine must be given slowly, and the IV infusion can take at least 30 minutes to complete.

Bendamustine is usually given for 2 days in a row every 21 to 28 days. You may receive up to 8 treatments total, depending on the condition being treated. Follow your doctor's instructions.

You may be given other medications to help prevent certain side effects of bendamustine.

Tell your caregivers if you feel any burning, pain, or swelling around the IV needle when the medicine is injected.

To be sure this medication is not causing harmful effects, your blood may need to be tested often. Your kidney or liver function may also need to be tested. Visit your doctor regularly.

Side Effects Centers

Treanda Patient Information including If I Miss a Dose

What happens if I miss a dose (Treanda)?

Call your doctor for instructions if you miss an appointment for your bendamustine injection.

What happens if I overdose (Treanda)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include drowsiness, tremors, slow or shallow breathing, loss of balance or coordination, or seizure (convulsions).

What should I avoid while receiving bendamustine (Treanda)?

Bendamustine may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

What other drugs will affect bendamustine (Treanda)?

Tell your doctor about all other medications you use, especially:

  • allopurinol (Zyloprim);
  • carbamazepine (Carbatrol, Equetro, Tegretol);
  • cimetidine (Tagamet);
  • ciprofloxacin (Cipro);
  • fluvoxamine (Luvox);
  • omeprazole (Prilosec);
  • thiabendazole (Mintezol); or
  • a barbiturate such as butabarbital (Butisol), secobarbital (Seconal), phenobarbital (Solfoton), and others.

This list is not complete and other drugs may interact with bendamustine. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about bendamustine.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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