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Bendamus (Generic Treanda) 100 Mg Iv Vial

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FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1  Chronic Lymphocytic Leukemia (CLL)

1.2  Non-Hodgkin Lymphoma (NHL)

2 DOSAGE AND ADMINISTRATION

2.1  Dosing Instructions for CLL

2.2  Dosing Instructions for NHL

2.3  Reconstitution/Preparation for Intravenous Administration

2.4  Admixture Stability

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1  Myelosuppression

5.2  Infections

5.3  Anaphylaxis and Infusion Reactions

5.4  Tumor Lysis Syndrome

5.5  Skin Reactions

5.6  Other Malignancies

5.7  Extravasation Injury

5.8  Embryo-fetal Toxicity

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience in CLL

6.2  Clinical Trials Experience in NHL

6.3 Postmarketing 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

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Chronic Lymphocytic Leukemia (CLL)

14.2 Non-Hodgkin 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

*Sections or subsections omitted from the full prescribing information are not listed.

 

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1  Chronic Lymphocytic Leukemia (CLL)

Bendamus (Generic Treanda)® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

1.2  Non-Hodgkin Lymphoma (NHL)

Bendamus (Generic Treanda) is indicated for the treatment of patients with indolent B-cell non-Hodgkin lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

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:

Bendamus (Generic 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], Bendamus (Generic 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:

Bendamus (Generic 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], Bendamus (Generic 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  Reconstitution/Preparation for Intravenous Administration

Aseptically reconstitute each Bendamus (Generic Treanda) vial as follows:

  • 25 mg Bendamus (Generic Treanda) vial: Add 5 mL of only Sterile Water for Injection, USP.
  • 100 mg Bendamus (Generic 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 HCl 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 HCl 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.

2.4  Admixture Stability

Bendamus (Generic 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 Bendamus (Generic Treanda) must be completed within this period.

3 DOSAGE FORMS AND STRENGTHS

Bendamus (Generic Treanda) for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.

4 CONTRAINDICATIONS

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

5 WARNINGS AND PRECAUTIONS

5.1  Myelosuppression

Bendamus (Generic Treanda) caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (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 frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has 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) and (2.2)]

5.2  Infections

Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing reports. Patients with myelosuppression following treatment with Bendamus (Generic Treanda) are more susceptible to infections. Advise patients with myelosuppression following Bendamus (Generic Treanda) treatment to contact a physician if they have symptoms or signs of infection.

5.3  Anaphylaxis and Infusion Reactions

Infusion reactions to Bendamus (Generic 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. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue Bendamus (Generic Treanda) for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care.

5.4  Tumor Lysis Syndrome

Tumor lysis syndrome associated with Bendamus (Generic Treanda) treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of Bendamus (Generic Treanda) and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of Bendamus (Generic Treanda) therapy. However, there may be an increased risk of severe skin toxicity when Bendamus (Generic Treanda) and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)].

5.5  Skin Reactions

Skin reactions have been reported with Bendamus (Generic Treanda) treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when Bendamus (Generic Treanda) was given in combination with other anticancer agents.

In a study of Bendamus (Generic 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 Bendamus (Generic Treanda) was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to Bendamus (Generic Treanda) cannot be determined.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue Bendamus (Generic Treanda).

5.6  Other Malignancies

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

5.7  Extravasation Injury

Bendamus (Generic Treanda) extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting Bendamus (Generic Treanda) infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of Bendamus (Generic Treanda).

5.8  Embryo-fetal Toxicity

Bendamus (Generic 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 following serious adverse reactions have been associated with Bendamus (Generic Treanda) in clinical trials and are discussed in greater detail in other sections of the label.

  • Myelosuppression [See Warnings and Precautions (5.1)]
  • Infections [See Warnings and Precautions (5.2)]
  • Anaphylaxis and Infusion Reactions and Anaphylaxis [See Warnings and Precautions (5.3)]
  • Tumor Lysis Syndrome [See Warnings and Precautions (5.4)]
  • Skin Reactions [See Warnings and Precautions (5.5)]
  • Other Malignancies [See Warnings and Precautions (5.6)]
  • Extravasation injury [SeeWarnings and Precautions (5.7)]

The data described below reflect exposure to Bendamus (Generic Treanda) in 329 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm trials (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Clinical Trials Experience in CLL

The data described below reflect exposure to Bendamus (Generic Treanda) in 153 patients with CLL studied in an active-controlled, randomized trial.  The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days. 

Adverse reactions were reported according to NCI CTC v.2.0.  Non-hematologic adverse reactions (any grade) in the Bendamus (Generic 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 Bendamus (Generic Treanda) in the CLL trial and in none treated with chlorambucil.  Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved.

The most frequent adverse reactions leading to study withdrawal for patients receiving Bendamus (Generic 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

 

Bendamus (Generic 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 Bendamus (Generic Treanda). Red blood cell transfusions were administered to 20% of patients receiving Bendamus (Generic Treanda) compared with 6% of patients receiving chlorambucil.

Table 2:  Incidence of Hematology Laboratory Abnormalities in Patients Who Received Bendamus (Generic Treanda) or Chlorambucil in the Randomized CLL Clinical Study

 

Bendamus (Generic Treanda) 
N=150

Chlorambucil
N=141

Laboratory Abnormality

All Grades 
n (%)

Grade 3/4 
n (%) 

All Grades 
n (%)

Grade 3/4 
n (%)

Hemoglobin 
Decreased

134 (89)

20 (13)

115 (82)

12 (9)

Platelets 
Decreased

116 (77)

16 (11)

110 (78)

14 (10)

Leukocytes 
Decreased

92 (61)

42 (28)

26 (18)

4 (3)

Lymphocytes 
Decreased

102 (68)

70 (47)

27 (19)

6 (4)

Neutrophils 
Decreased

113 (75)

65 (43)

86 (61)

30 (21)

In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT.  Grade 3 or 4 increased bilirubin occurred in 3% of patients.  Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively.  Patients treated with Bendamus (Generic Treanda) may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur.

6.2  Clinical Trials Experience in NHL

The data described below reflect exposure to Bendamus (Generic 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 Bendamus (Generic Treanda) at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to eight 21-day cycles.

The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%).  The most common non-hematologic Grade 3 or 4 adverse reactions (≥5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with Bendamus (Generic Treanda) by System Organ Class and Preferred Term (N=176)

System organ class

Number (%) of patients*

    Preferred term

All Grades

Grade 3/4

Total number of patients with at least 1 adverse reaction

176 (100)

94 (53)

Cardiac Disorders

    Tachycardia

13 (7)

0

Gastrointestinal disorders

    Nausea

132 (75)

7 (4)

    Vomiting

71 (40)

5 (3)

    Diarrhea

65 (37)

6 (3)

    Constipation

51 (29)

1 (<1)

    Stomatitis

27 (15)

1 (<1)

    Abdominal pain

22 (13)

2 (1)

    Dyspepsia

20 (11)

0

    Gastroesophageal reflux disease

18 (10)

0

    Dry mouth

15 (9)

1 (<1)

    Abdominal pain upper

8 (5)

0

    Abdominal distension

8 (5)

0

General disorders and administration site conditions

    Fatigue

101 (57)

19 (11)

    Pyrexia

59 (34)

3 (2)

    Chills

24 (14)

0

    Edema peripheral

23 (13)

1 (<1)

    Asthenia

19 (11)

4 (2)

    Chest pain

11 (6)

1 (<1)

    Infusion site pain

11 (6)

0

    Pain

10 (6)

0

    Catheter site pain

8 (5)

0

Infections and infestations

    Herpes zoster

18 (10)

5 (3)

    Upper respiratory tract infection

18 (10)

0

    Urin

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Bendamus (Generic Treanda) 100 Mg Iv Vial

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