------------------------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---------------------­
`
`y 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)
`
`
`y Infections: Monitor for fever and other signs of infection and treat
`promptly. (5.2)
`
`
`y 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)
`
`y Tumor Lysis Syndrome: May lead to acute renal failure and death. Take
`
`precautions in patients at high risk. (5.4)
`
`y Skin Reactions: Discontinue for severe skin reactions. (5.5)
`
`y Other Malignancies: Pre-malignant and malignant diseases have been
`reported. (5.6)
`
`y 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 u15%)
`
`
`
`are pyrexia, nausea, and vomiting. (6.1)
`
`
`Most common non-hematologic adverse reactions for NHL (frequency u15%)
`
`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-------------------­
`
`y Renal impairment: Do not use if CrCL is <40 mL/min. Use with caution
`
`in lesser degrees of renal impairment. (8.6)
`
`
`y 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: 4/2009
`
`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 -------------------------
`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
` 11/2008
`Intravenous Administration (2.4)
`
`
`
`10/2008
`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)
`
`
`
`----------------------------INDICATIONS AND USAGE---------------------------
`TREANDA for Injection is an alkylating drug indicated for treatment of
`patients with:
`
`y Chronic lymphocytic leukemia (CLL). Efficacy relative to first line
`therapies other than chlorambucil has not been established. (1.1)
`
`
`
`y 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:
`y 100 mg/m2 infused intravenously over 30 minutes on Days 1 and 2 of a 28­
`
`day cycle, up to 6 cycles (2.1)
`
`y 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)
`
`
`y 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)
`
`
`y Dose re-escalation may be considered. (2.1)
`
`For NHL:
`
`y 120 mg/m2 infused intravenously over 60 minutes on Days 1 and 2 of a 21­
`
`day cycle, up to 8 cycles (2.2)
`
`y 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)
`
`
`
`y 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:
`
`y Delay treatment for Grade 4 hematologic toxicity or clinically significant
`≥ Grade 2 non-hematologic toxicity (2.1, 2.2)
`
`
`
`y TREANDA for Injection must be reconstituted and further diluted prior to
`infusion. (2.4)
`
`
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`INDICATIONS AND USAGE
`1
`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
`
`1
`
`
`
`

`

`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 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
`
`
`
`
`y
`
`
`
`
`y
`
`
`
`
`Aseptically reconstitute each TREANDA vial as follows:
`
`
`o
`
`
`o
`
`25 mg TREANDA vial: Add 5mL of only Sterile Water for
`
`
`Injection, USP.
`
`100 mg TREANDA vial: Add 20 mL of only Sterile Water for
`
`
`Injection, USP.
`
`
`
`Shake well to yield a clear, colorless to a pale yellow solution with a
`
`
`bendamustine 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.
`
`
`2.5 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 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
`
`
`
`

`

`
`
`
`
`
`
`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.
`
`y Myelosuppression [See Warnings and Precautions (5.1)]
`
`
`
`
`y
` Infections [See Warnings and Precautions (5.2)]
`
`
`
`
`y
` Infusion Reactions and Anaphylaxis [See Warnings and Precautions
`
`
` (5.3)]
`
`y
`
`
` Tumor Lysis Syndrome [See Warnings and Precautions (5.4)]
`
`y
` Skin Reactions [See Warnings and Precautions (5.5)]
`
`
`
`
`y 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.
`
`
`
`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 u 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, 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.
`
`
`3
`
`
`
`

`

`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
` 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
`
`
`
`
`Grade 3/4
`
`All Grades
`
`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)
`
`
`
`Laboratory
`
`
`Abnormality
`
`
`
`Hemoglobin
`
`
`Decreased
`
`
`Platelets
`
`
`Decreased
`
`
`Leukocytes
`
`
`Decreased
`
`
`Lymphocytes
`
`
`Decreased
`
`
`Neutrophils
`
`
`Decreased
`
`
`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
`
`
`
`4
`
`
`
`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
`Number (%) of patients*
`
`
`
`Preferred term
`
`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
`Pain
`
` Catheter site pain
`Infections and infestations
`
`
`Herpes zoster
`
`Upper respiratory tract infection
`
`Urinary tract infection
` Sinusitis
` Pneumonia
` Febrile Neutropenia
`
`Oral Candidiasis
`
`Nasopharyngitis
`Investigations
`
`Weight decreased
`
`Metabolism and nutrition
`
`disorders
`
`
`Anorexia
`
`
`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)
`
`10 (6)
`8 (5)
`
`
`18 (10)
`
`18 (10)
`
`17 (10)
`15 (9)
`
`14 (8)
`
`11 (6)
`
`11 (6)
`11 (6)
`
`
`31 (18)
`
`
`
`40 (23)
`
`
`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
`0
`
`0
`
`
`5 (3)
`0
`
`4 (2)
`0
`
`9 (5)
`
`11 (6)
`
`2 (1)
`0
`
`
`3 (2)
`
`
`
`3 (2)
`
`
`
`

`

`
`
`
` 24 (14)
`
` 22 (13)
`
` 15 (9)
`
`
` 25 (14)
`
`11 (6)
`8 (5)
`
` 8 (5)
`
`36 (21)
`
` 25 (14)
` 13 (7)
`
`
`
` 23 (13)
`
` 14 (8)
`
` 10 (6)
`
`
`
` 38 (22)
`
` 28 (16)
`
` 14 (8)
`8 (5)
`
` 8 (5)
`
`
`Dehydration
`
`Decreased appetite
`
`Hypokalemia
`
`Musculoskeletal and connective
`tissue disorders
`Back pain
`Arthralgia
`
` Pain in extremity
`Bone pain
`Nervous system disorders
`
`Headache
`
`Dizziness
`
`Dysgeusia
`Psychiatric disorders
`
`Insomnia
`
`
` Anxiety
`
`Depression
`Respiratory, thoracic and
`mediastinal disorders
`Cough
`Dyspnea
`
` Pharyngolaryngeal pain
`
`Wheezing
`
`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.
`
` 8 (5)
`
`
` 1 (<1)
`
` 9 (5)
`
`
` 5 (3)
`
`0
`2 (1)
`0
`
`0
`0
`0
`
`0
` 1 (<1)
`
`0
`
`
`
` 1 (<1)
`
` 3 (2)
` 1 (<1)
`
`0
`0
`
`
` 1 (<1)
`
`0
`
` 0
`0
`
` 0
`
` 2 (1)
`
`
`
`
`
`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
`
`
`
`5
`
`
`
`
`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
`
`Hematologic toxicities, based on laboratory values and CTC grade, in
`
`NHL patients treated in both single arm studies combined are described in
`
`Table 4. Clinically important chemistry laboratory values that were new or
`worsened from baseline and occurred in >1% of patients at grade 3 or 4, in
`
`NHL patients treated in both single arm studies combined were hyperglycemia
`
`(3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%).
`
`
`
`
` Table 4: Incidence of Hematology Laboratory Abnormalities in Patients
` Who Received TREANDA in the NHL Studies
`
`
`
` Percent of patients
`
`Hematology variable
`
`
`
`
`
`
`
`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