04/2009
`
`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) for Injection, for intravenous
`infusion
`Initial U.S. Approval: 2008
`----------------------------RECENT MAJOR CHANGES -------------------------
`Dosage and Administration, General Considerations for Tumor
`Lysis Syndrome (2.3) – Subsection deleted
`Dosage and Administration, Reconstitution/Preparation for
` 04/2009
`Intravenous Administration (2.3)
`
`
`04/2009
`Warnings and Precautions, Tumor Lysis Syndrome (5.4)
`04/2009
`Warnings and Precautions, Skin Reactions (5.5)
`01/2010
`Warnings and Precautions, Extravasation (5.7)
`
`
`----------------------------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. (2.3)
`
`
`
`------------------------DOSAGE FORMS AND STRENGTHS-------------------
`TREANDA for Injection single-use vial containing either 25 mg or 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. Cases of SJS and
`TEN, some fatal, have been reported when TREANDA was administered
`concomitantly with allopurinol and other medications known to cause these
`syndromes. (5.5)
`• Other Malignancies: Pre-malignant and malignant diseases have been
`reported. (5.6)
`• Extravasation: Take precautions to avoid extravasation, including
`monitoring intravenous infusion site during and after administration. (5.7)
`• Use in Pregnancy: Fetal harm can occur when administered to a pregnant
`woman. Women should be advised to avoid becoming pregnant when
`receiving TREANDA. (5.8, 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
`
`
`5.3
`Infusion Reactions and Anaphylaxis
`5.4 Tumor Lysis Syndrome
`5.5 Skin Reactions
`5.6 Other Malignancies
`5.7 Extravasation
`5.8 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
`
`Revised 02/2010
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` 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 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
`
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`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
`
`*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)
`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 Reconstitution/Preparation for Intravenous Administration
` Aseptically reconstitute each TREANDA vial as follows:
`o
`25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP.
`o
`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 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
`
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`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
`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 either 25 mg or 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) and (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, 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 [see Warnings and Precautions (5.5)].
`
`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). 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.
`
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`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 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.
`
`
`5.8 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.
`• Myelosuppression [See Warnings and Precautions (5.1)]
`•
`Infections [See Warnings and Precautions (5.2)]
`•
`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)]
`
`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.
`
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`Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL
`Clinical Study in at Least 5% of Patients
`
`Number (%) of patients
`TREANDA
`Chlorambucil
`(N=153)
`(N=143)
`All
`Grade
`Grades
`3/4
`
`All
`Grades
`
`Grade 3/4
`
`121 (79)
`
`
`31 (20)
`24 (16)
`14 (9)
`
`
`36 (24)
`14 (9)
`13 (8)
`9 (6)
`
`
`7 (5)
`
`
`10 (7)
`9 (6)
`5 (3)
`
`11 (7)
`
`
`11 (7)
`
`
`6 (4)
`
`
`12 (8)
`8 (5)
`
`52 (34)
`
`
`1 (<1)
`1 (<1)
`2 (1)
`
`
`6 (4)
`2 (1)
`0
`0
`
`
`2 (1)
`
`
`0
`3 (2)
`0
`
`0
`
`
`3 (2)
`
`
`1 (<1)
`
`
`4 (3)
`0
`
`96 (67)
`
`
`21 (15)
`9 (6)
`5 (3)
`
`
`25 (17)
`
`
`1 (<1)
`0
`0
`
`
`8 (6)
`8 (6)
`6 (4)
`1 (<1)
`
`
`3 (2)
`
`
`12 (8)
`1 (<1)
`7 (5)
`
`5 (3)
`
`
`2 (1)
`
`
`7 (5)
`
`
`7 (5)
`2 (1)
`
`2 (1)
`0
`0
`0
`
`
`0
`
`
`0
`1 (<1)
`0
`
`0
`
`
`0
`
`
`1 (<1)
`
`
`3 (2)
`0
`
`
`
`
`
`
`
`
`
`
`System organ class
`
`Preferred term
`Total number of patients
`with at least 1 adverse
`reaction
`Gastrointestinal
`disorders
`Nausea
`Vomiting
`Diarrhea
`General disorders and
`administration site
`conditions
`Pyrexia
`Fatigue
`Asthenia
`Chills
`Immune system
`disorders
`Hypersensitivity
`Infections and
`infestations
`Nasopharyngitis
`Infection
`Herpes simplex
`Investigations
`Weight decreased
`Metabolism and
`nutrition disorders
`Hyperuricemia
`Respiratory, thoracic
`and mediastinal
`disorders
`Cough
`Skin and subcutaneous
`tissue disorders
`Rash
`Pruritus
`
` 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.
`
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`Laboratory
`Abnormality
`
`Hemoglobin
`Decreased
`Platelets
`Decreased
`Leukocytes
`Decreased
`Lymphocytes
`Decreased
`Neutrophils
`Decreased
`
`Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who
`Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study
`
`TREANDA
`Chlorambucil
`N=150
`N=141
`All Grades
`Grade 3/4
`All Grades
`Grade 3/4
`n (%)
`n (%)
`n (%)
`n (%)
`
`20 (13)
`
`134 (89)
`
`115 (82)
`
`12 (9)
`
`116 (77)
`
`92 (61)
`
`102 (68)
`
`113 (75)
`
`16 (11)
`
`42 (28)
`
`70 (47)
`
`65 (43)
`
`110 (78)
`
`14 (10)
`
`26 (18)
`
`27 (19)
`
`86 (61)
`
`4 (3)
`
`6 (4)
`
`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 class
` Preferred term
`
`Number (%) of patients*
`All Grades
`Grade 3/4
`
`Total number of patients with at
`least 1 adverse reaction
`Cardiac disorders
` Tachycardia
`Gastrointestinal disorders
` Nausea
` Vomiting
` Diarrhea
` Constipation
` Stomatitis
` Abdominal pain
` Dyspepsia
` Gastroesophageal reflux disease
` Dry mouth
` Abdominal pain upper
` Abdominal distension
`General disorders and administration site
`conditions
` Fatigue
` Pyrexia
` Chills
` Edema peripheral
` Asthenia
` Chest pain
` Infusion site pain
`
`176 (100)
`
`13 (7)
`
`132 (75)
`71 (40)
`65 (37)
`51 (29)
`27 (15)
`22 (13)
`20 (11)
`18 (10)
`15 (9)
`8 (5)
`8 (5)
`
`
`101 (57)
`59 (34)
`24 (14)
`23 (13)
`19 (11)
`11 (6)
`11 (6)
`
`94 (53)
`
`0
`
`7 (4)
`5 (3)
`6 (3)
`1 (<1)
`1 (<1)
`2 (1)
`0
`0
`1 (<1)
`0
`0
`
`19 (11)
`3 (2)
`0
`1 (<1)
`4 (2)
`1 (<1)
`0
`
`
`TREANDA® (bendamustine hydrochloride) 05FEB2010
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`

`
`
`0
`0
`
`5 (3)
`0
`4 (2)
`0
`9 (5)
`11 (6)
`2 (1)
`0
`
`3 (2)
`
`3 (2)
`8 (5)
`1 (<1)
`9 (5)
`
`5 (3)
`0
`2 (1)
`0
`
`0
`0
`0
`
`10 (6)
` Pain
`8 (5)
` Catheter site pain
`
`Infections and infestations
`18 (10)
` Herpes zoster
`18 (10)
` Upper respiratory tract infection
`17 (10)
` Urinary tract infection
`15 (9)
` Sinusitis
`14 (8)
` Pneumonia
`11 (6)
` Febrile Neutropenia
`11 (6)
` Oral Candidiasis
`11 (6)
` Nasopharyngitis
`
`Investigations
`31 (18)
` Weight decreased
`
`Metabolism and nutrition disorders
`40 (23)
` Anorexia
`24 (14)
` Dehydration
`22 (13)
` Decreased appetite
`15 (9)
` Hypokalemia
`
`Musculoskeletal and connective tissue disorders
`25 (14)
` Back pain
`11 (6)
` Arthralgia
`8 (5)
` Pain in extremity
`8 (5)
` Bone pain
`
`Nervous system disorders
`36 (21)
` Headache
`25 (14)
` Dizziness
`13 (7)
` Dysgeusia
`
`Psychiatric disorders
`23 (13)
` Insomnia
`14 (8)
` Anxiety
`10 (6)
` Depression
`
`Respiratory, thoracic and mediastinal disorders
`38 (22)
` Cough
`28 (16)
` Dyspnea
`14 (8)
` Pharyngolaryngeal pain
`8 (5)
` Wheezing
`8 (5)
` Nasal congestion
`
`Skin and subcutaneous tissue disorders
`28 (16)
` Rash
`11 (6)
` Pruritus
`9 (5)
` Dry skin
`9 (5)
` Night sweats
`8 (5)
` Hyperhidrosis
`
`Vascular disorders
`10 (6)
` Hypotension
`*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.
`
`
`0
`1 (<1)
`0
`
`1 (<1)
`3 (2)
`1 (<1)
`0
`0
`
`1 (<1)
`0
`0
`0
`0
`
`2 (1)
`
`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%).
`
`
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`TREANDA® (bendamustine hydrochloride) 05FEB2010
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`Table 4: Incidence of Hematology Laboratory Abnormalities in Patients
`Who Received TREANDA in the NHL Studies
`
`Percent of patients
`Hematology variable
`
`
`All Grades
`99
`
`Grades 3/4
`94
`
`94
`
`88
`
`86
`
`86
`
`56
`
`11
`
`60
`
`25
`
`Lymphocytes
`Decreased
`Leukocytes
`Decreased
`Hemoglobin
`Decreased
`Neutrophils
`Decreased
`Platelets
`Decreased
`
`
`
`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.
`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 (5.5)].
`
` 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 (5.8)]
`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.