TREANDA® (bendamustine hydrochloride) for Injection

TREANDA - bendamustine hydrochloride injection, powder, lyophilized, for solution 
Cephalon, Inc.

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TREANDA® (bendamustine hydrochloride) for Injection

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TREANDA safely and effectively. See full prescribing information for TREANDA.
TREANDA (bendamustine hydrochloride) injection, powder, lyophilized, for solution for intravenous use
Initial U.S. Approval: 2008

RECENT MAJOR CHANGES

Indications and Usage, Non-Hodgkin’s Lymphoma (NHL) (1.2)  10/2008

Dosage and Administration, Dosing Instructions for NHL (2.2)   10/2008

Dosage and Administration, Reconstitution/Preparation for       10/2008
Intravenous Administration (2.4)

Dosage and Administration, Admixture Stability (2.5)             10/2008

Warnings and Precautions, Myelosuppression (5.1)                 10/2008

Warnings and Precautions, Skin Reactions (5.5)                      10/2008

Warnings and Precautions, Other Malignancies (5.6)                10/2008


INDICATIONS AND USAGE

TREANDA for Injection 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’s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. (1.2)

DOSAGE AND ADMINISTRATION

For CLL:

  • 100 mg/m2 infused intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles (2.1)
  • 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. (2.1)
  • 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. (2.1)
  • Dose re-escalation may be considered. (2.1)

For NHL:

  • 120 mg/m2 infused intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles (2.2)
  • 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. (2.2)
  • 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. (2.2)

General Dosing Considerations:

  • Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity (2.1, 2.2)
  • TREANDA for Injection must be reconstituted and further diluted prior to infusion. (2.4)


DOSAGE FORMS AND STRENGTHS

TREANDA for Injection single-use vial containing 100 mg of bendamustine HCl as lyophilized powder (3)


CONTRAINDICATIONS

  • Known hypersensitivity to bendamustine or mannitol. (4)

WARNINGS AND PRECAUTIONS

  • Myelosuppression:  May warrant treatment delay or dose reduction. Monitor closely and restart treatment based on ANC and platelet count recovery. Complications of myelosuppression may lead to death. (5.1)
  • Infections:  Monitor for fever and other signs of infection and treat promptly. (5.2)
  • Infusion Reactions and Anaphylaxis: Severe anaphylactic reactions have occurred. Monitor clinically and discontinue drug for severe reactions. Ask patients about reactions after the first cycle. Consider pre-treatment for cycles subsequent to milder reactions. (5.3)
  • Tumor Lysis Syndrome:  May lead to acute renal failure and death. Take precautions in patients at high risk. (5.4)
  • Skin Reactions:  Discontinue for severe skin reactions. (5.5)
  • Other Malignancies: Pre-malignant and malignant diseases have been reported. (5.6)
  • Use in Pregnancy:  Fetal harm can occur when administered to a pregnant woman. Women should be advised to avoid becoming pregnant when receiving TREANDA. (5.7, 8.1)

ADVERSE REACTIONS

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. (6.2)   

Most common hematologic abnormalities for both indications (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia. (6.1, 6.2)



To report SUSPECTED ADVERSE REACTIONS, contact Cephalon, Inc. at 1-800-896-5855 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch


DRUG INTERACTIONS

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


USE IN SPECIFIC POPULATIONS

  • Renal impairment: Do not use if CrCL is <40 mL/min. Use with caution in lesser degrees of renal impairment. (8.6)
  • Hepatic impairment: Do not use in moderate or severe hepatic impairment. Use with caution in mild hepatic impairment. (8.7)


See 17 for PATIENT COUNSELING INFORMATION

Revised: 11/2008

FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed

1 INDICATIONS AND USAGE

1.1  Chronic Lymphocytic Leukemia (CLL)

1.2  Non-Hodgkin’s Lymphoma (NHL)

2 DOSAGE AND ADMINISTRATION

2.1  Dosing Instructions for CLL

2.2  Dosing Instructions for NHL

2.3  General Considerations for Tumor Lysis Syndrome

2.4  Reconstitution/Preparation for Intravenous Administration

2.5  Admixture Stability

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1  Myelosuppression

5.2  Infections

5.3  Infusion Reactions and Anaphylaxis

5.4  Tumor Lysis Syndrome

5.5  Skin Reactions

5.6  Other Malignancies

5.7  Use in Pregnancy

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience in CLL

6.2 Clinical Trials Experience in NHL

6.3 Post-Marketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6  Renal Impairment

8.7  Hepatic Impairment

8.8  Effect of Gender

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.4  Pharmacokinetics/Pharmacodynamics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Chronic Lymphocytic Leukemia (CLL)

14.2 Non-Hodgkin’s Lymphoma (NHL)

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1  Safe Handling and Disposal

16.2  How Supplied

16.3  Storage

17 PATIENT COUNSELING INFORMATION


FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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’s Lymphoma (NHL)

TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

2 DOSAGE AND ADMINISTRATION

2.1  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.

2.2  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.

2.3  General Considerations for Tumor Lysis Syndrome

Consider using allopurinol as prevention for patients at high risk of tumor lysis syndrome for the first few weeks of treatment.

2.4  Reconstitution/Preparation for Intravenous Administration

 

2.5  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.

3 DOSAGE FORMS AND STRENGTHS

TREANDA for Injection single-use vial containing 100 mg of bendamustine HCl as white to off-white lyophilized powder.

4 CONTRAINDICATIONS

TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions(5.3)]

5 WARNINGS AND PRECAUTIONS

5.1  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(2.1), (2.2)]

5.2  Infections

Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing 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.

5.3  Infusion Reactions and Anaphylaxis

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.

5.4  Tumor Lysis Syndrome

Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing 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, close monitoring of blood chemistry, particularly potassium and uric acid levels, and the use of allopurinol during the first few weeks of TREANDA therapy in patients at high risk.

5.5  Skin Reactions

A number of skin reactions have been reported in clinical trials and post-marketing 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). The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued.

5.6  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.

5.7  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(8.1)]

6 ADVERSE REACTIONS

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.

6.1 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 naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. 

Adverse reactions were reported according to NCI CTC v.2.0.  In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the 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 reaction121 (79)52 (34)96 (67)25 (17)
Gastrointestinal disorders    
  Nausea31 (20)1 (<1)21 (15)1 (<1)
  Vomiting24 (16)1 (<1)9 (6)0
  Diarrhea14 (9)2 (1)5 (3)0
General disorders and administration site conditions    
  Pyrexia36 (24)6 (4)8 (6)2 (1)
  Fatigue14 (9)2 (1)8 (6)0
  Asthenia13 (8)06 (4)0
  Chills9 (6)01 (<1)0
Immune system disorders    
  Hypersensitivity7 (5)2 (1)3 (2)0
Infections and infestations    
  Nasopharyngitis10 (7)012 (8)0
  Infection9 (6)3 (2)1 (<1)1 (<1)
  Herpes simplex5 (3)07 (5)0
Investigations    
  Weight decreased11 (7)05 (3)0
Metabolism and nutrition disorders    
  Hyperuricemia11 (7)3 (2)2 (1)0
Respiratory, thoracic and mediastinal disorders    
  Cough6 (4)1 (<1)7 (5)1 (<1)
Skin and subcutaneous tissue disorders    
  Rash12 (8)4 (3)7 (5)3 (2)
  Pruritus8 (5)02 (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 AbnormalityAll 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.

6.2 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 classNumber (%) of patients*
    Preferred termAll GradesGrade 3/4
Total number of patients with at least 1 adverse reaction176 (100)94 (53)
Cardiac Disorders
    Tachycardia13 (7)0
Gastrointestinal disorders  
    Nausea132 (75)7 (4)
    Vomiting71 (40)5 (3)
    Diarrhea65 (37)6 (3)
    Constipation51 (29)1 (<1)
    Stomatitis27 (15)1 (<1)
    Abdominal pain22 (13)2 (1)
    Dyspepsia20 (11)0
    Gastroesophageal reflux disease18 (10)0
    Dry mouth15 (9)1 (<1)
    Abdominal pain upper8 (5)0
    Abdominal distension8 (5)0
General disorders and administration site conditions  
    Fatigue101 (57)19 (11)
    Pyrexia59 (34)3 (2)
    Chills24 (14)0
    Edema peripheral23 (13)1 (<1)
    Asthenia19 (11)4 (2)
    Chest pain11 (6)1 (<1)
    Infusion site pain11 (6)0
    Pain10 (6)0
    Catheter site pain8 (5)0
Infections and infestations  
    Herpes zoster18 (10)5 (3)
    Upper respiratory tract infection18 (10)0
    Urinary tract infection17 (10)4 (2)
    Sinusitis15 (9)0
    Pneumonia14 (8)9 (5)
    Febrile Neutropenia11 (6)11 (6)
    Oral Candidiasis11 (6)2 (1)
    Nasopharyngitis11 (6)0
Investigations  
    Weight decreased31 (18)3 (2)
Metabolism and nutrition disorders  
    Anorexia40 (23)3 (2)
    Dehydration24 (14)8 (5)
    Decreased appetite22 (13)1 (<1)
    Hypokalemia15 (9)9 (5)
Musculoskeletal and connective tissue disorders  
    Back pain25 (14)5 (3)
    Arthralgia11 (6)0
    Pain in extremity8 (5)2 (1)
    Bone pain8 (5)0
Nervous system disorders  
    Headache36 (21)0
    Dizziness25 (14)0
    Dysgeusia13 (7)0
Psychiatric disorders  
    Insomnia23 (13)0
    Anxiety14 (8)1 (<1)
    Depression10 (6)0
Respiratory, thoracic and mediastinal disorders  
    Cough38 (22)1 (<1)
    Dyspnea28 (16)3 (2)
    Pharyngolaryngeal pain14 (8)1 (<1)
    Wheezing8 (5)0
    Nasal congestion8 (5)0
Skin and subcutaneous tissue disorders  
    Rash28 (16)1 (<1)
    Pruritus11 (6)0
    Dry skin9 (5)0
    Night sweats9 (5)0
    Hyperhidrosis8 (5)0
Vascular disorders  
    Hypotension10 (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%).

Image from Drug Label Content

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 post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome.

Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion reactions [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.

6.3 Post-Marketing 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 pruritus, irritation, pain, and swelling.

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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D [See Warnings and Precautions(5.7)]

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.

8.3 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 safety and effectiveness of TREANDA in pediatric patients have not been established.

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’s 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 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(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 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(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’s 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).

10 OVERDOSAGE

The intravenous LD50 of bendamustine HCl 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.

11 DESCRIPTION

TREANDA contains bendamustine hydrochloride, an alkylating drug, as the active ingredient. The chemical name of bendamustine hydrochloride is 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1-methyl‑, monohydrochloride. Its empirical molecular formula is C16H21Cl2N3O2  HCl, 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:

Image from Drug Label Content

TREANDA (bendamustine hydrochloride) for Injection is intended for intravenous infusion only after reconstitution with 20 mL of 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 vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol, USP.  The pH of the reconstituted solution is 2.5 - 3.5.

12 CLINICAL PHARMACOLOGY

12.1 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.

12.3 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(8.6)]

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 bilirubin 1.5 - 3 x ULN) or severe (total bilirubin > 3 x ULN) hepatic impairment.  [See Use in Specific Populations(8.7)]

Effect of Age

Bendamustine exposure (as measured by AUC and Cmax) has been studied in 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(8.4, 8.5)]

Effect of Gender

The pharmacokinetics of bendamustine were similar in male and female patients. [See Use in Specific Populations(8.8)]

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.

12.4  Pharmacokinetics/Pharmacodynamics

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

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 CLINICAL STUDIES

14.1 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 65.7x109/L vs. 65.1x109/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 (CD5, 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 rate90 (59)38 (26)<0.0001
(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 Survival††   
 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 ≥ 1.5 x 109/L, platelets >100 x 109/L, hemoglobin > 110g/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 >110g/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.

Image from Drug Label Content

14.2 Non-Hodgkin’s 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.

15 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1  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.

16.2  How Supplied

TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons of 20 mL amber single-use vials containing 100 mg of bendamustine hydrochloride as a white to off-white lyophilized powder.

NDC 63459-391-20    TREANDA (bendamustine hydrochloride) for Injection, 100 mg/vial

16.3  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.

17 PATIENT COUNSELING INFORMATION

Manufactured by:
Pharmachemie B.V.
The Netherlands

Manufactured for:
Cephalon, Inc.
Frazer, PA 19355

TREANDA is a registered trademark of Cephalon, Inc.

© 2008 Cephalon, Inc.
All rights reserved.

Label Code: PI-40014-01


TREANDA 
bendamustine hydrochloride   injection, powder, lyophilized, for solution
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)63459-391
Route of AdministrationINTRAVENOUSDEA Schedule    
INGREDIENTS
Name (Active Moiety)TypeStrength
bendamustine hydrochloride (bendamustine) Active100 MILLIGRAM  In 20 MILLILITER
MannitolInactive170 MILLIGRAM  In 20 MILLILITER
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
163459-391-2020 mL (MILLILITER) In 1 VIAL, SINGLE-USENone

Revised: 11/2008Cephalon, Inc.