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, for intravenous
`
`
`
`
`infusion
`
`Initial U.S. Approval: 2008
`
`
`
`----------------------------RECENT MAJOR CHANGES ------------------------­
`
`Dosage and Administration,
`
`
`Preparation for Intravenous Administration (2.3)
`
`
`Dosage and Administration, Admixture Stability (2.4)
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`TREANDA 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 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 must be diluted prior to infusion. (2.3)
`
`
`
`
`
`------------------------DOSAGE FORMS AND STRENGTHS------------------­
`Injection: 45 mg/0.5 mL or 180 mg/2 mL in a single-use vial. (3)
`
`
`
`
`---------------------------------CONTRAINDICATIONS---------------------------­
`TREANDA is contraindicated in patients with a history of a hypersensitivity
`
`
`
`reaction to bendamustine. Reactions have included anaphylaxis and
`
`
`
`
`anaphylactoid reactions. (5.3)
`
`
`
`
`
`
`XX/2013
`
`XX/2013
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-------------------------WARNINGS AND PRECAUTIONS---------------------­
`
`• Myelosuppression: Delay or reduce dose. Restart treatment based on ANC
`
`
`
`
`
`
`and platelet count recovery. (2.1) Complications of myelosuppression may
`
`
`
`
`lead to death. (5.1)
`
`
`• Infections: Monitor for fever and other signs of infection and treat
`
`
`promptly. (5.2)
`
`• Anaphylaxis and Infusion Reactions: Severe and anaphylactic reactions
`
`
`
`
`
`have occurred; monitor clinically and discontinue TREANDA. Pre-
`
`
`
`
`medicate in subsequent cycles for milder reactions. (5.3)
`
`
`
`• Tumor Lysis Syndrome: Acute renal failure and death; anticipate and use
`
`
`
`
`supportive measures. (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: Assure good venous access and monitor infusion site during
`
`
`
`
`
`
`and after administration. (5.7)
`
`
`• Embryo-fetal toxicity: 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 Teva
`
`
`Pharmaceuticals 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 0X/2013
`
`
`_______________________________________________________________________________________________________________________________________
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`INDICATIONS AND USAGE
`1
`
`
`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
`
`
`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
`
`
`
`
`
`
`
`Reference ID: 3373510
`
`

`

`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
` INDICATIONS AND USAGE
`1
`
`
`
` 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.
`
`
`
`
`Non-Hodgkin Lymphoma (NHL)
`1.2
`
`
`
`
`
`
`
`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.
`
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`Dosing Instructions for CLL
`2.1
`
`
`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.
`
`
`
`
`
`Dosing Instructions for NHL
`2.2
`
`
`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.
`
`
`
`
`
`
`Preparation for Intravenous Administration
`2.3
`
`
`Each vial of TREANDA Injection is intended for single use only. Aseptically withdraw the volume needed for the required dose from the 90 mg/mL
`
`
`
`
`
`
`
` solution TREANDA Injection vial.
`
`
`
`
`
`
`
`Immediately transfer the solution 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 – 0.7 mg/mL. The admixture should be a
`
`
`clear colorless to yellow solution.
`
`
`
`
`
`
`
`Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other
`
`
`diluents have been shown to be compatible.
`
`
`
`
`Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container
`
`
`
`permit. Any unused solution should be discarded according to institutional procedures for antineoplastics.
`
`
`
`
`
`Admixture Stability
`2.4
`
`
`
`
`TREANDA Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient
`
`administration.
`
`
`
`
`
`Reference ID: 3373510
`
`

`

`
`
`
`
`
`
`
`
`
`
` 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 under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature 15°-30°C (59°­
`
`
`86°F) and room light. Administration of TREANDA must be completed within this period.
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`
`
`
`
`
`
`
`
`TREANDA Injection is supplied in single-use vials containing either 45 mg/0.5 mL or 180 mg/2 mL of bendamustine HCl.
`
`
`
`CONTRAINDICATIONS
`4
`
`TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See
`
`
`
`Warnings and Precautions (5.3)]
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`
`Myelosuppression
`5.1
`
`
`
`
`
`
`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)]
`
`Infections
`5.2
`
`
`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 TREANDA are more susceptible to infections. Advise patients with
`
`
`
`
`
`myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection.
`
`
`
`Anaphylaxis and Infusion Reactions
`5.3
`
`
`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. 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
`
`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.
`
`
`
`Tumor Lysis Syndrome
`5.4
`
`
`Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends
`
`
`
`
`to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include
`
`vigorous hydration 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)].
`
`
`
`Skin Reactions
`5.5
`
`
`Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions
`
`
`
`
`
`and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents.
`
`
`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. Monitor patients with skin reactions closely. If
`
`
`
`skin reactions are severe or progressive, withhold or discontinue TREANDA.
`
`
`
`Other Malignancies
`5.6
`
`There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including
`
`
`
`myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA
`
`
`therapy has not been determined.
`
`
`
`Extravasation Injury
`5.7
`
`
`
`
`
`
`
`
`TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good
`
`
`venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis
`
`during and after administration of TREANDA.
`
`
`
`
`Embryo-fetal Toxicity
`5.8
`
`
`
`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)]
`
`
`
`
`Reference ID: 3373510
`
`
`

`

`
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`
`
`
`
`
`
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`
`
`
`
`
`
` ADVERSE REACTIONS
`
`
`6
`
` 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)]
`
`
`
`
`
` • Anaphylaxis and Infusion Reactions [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 [See Warnings and Precautions (5.7)]
`
`
`
`
`
` The data described below reflect exposure to 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.
`
`
`
`
` Clinical Trials Experience in CLL
`
`6.1
`
`
`
`
`
` The data described below reflect exposure to 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 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 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 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
`
`
`
`
`
`
`
`
`
`
` System organ class
`
`
` Preferred term
`
` All
`
`
` Grades
`
`
` Grade 3/4
`
`
`
`
`
` Number (%) of patients
`
`
`
` TREANDA
`
` Chlorambucil
`
`
` (N=153)
` (N=143)
` Grade
`
` All
`
` Grades
`
` 3/4
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3373510
`
`
`
`
` 121 (79)
`
`
`
`
`
`31 (20)
`
`24 (16)
`
`14 (9)
`
`
`
`
`
`36 (24)
`
`14 (9)
`
`13 (8)
`
`9 (6)
`
`
`
`
`7 (5)
`
`
`
`
`10 (7)
`
`9 (6)
`
`5 (3)
`
`
`
` 52 (34)
`
`
`
`
`
`1 (<1)
`
`1 (<1)
`
`2 (1)
`
`
`
`
`
`6 (4)
`
`2 (1)
`
`0
`
`0
`
`
`
`
`2 (1)
`
`
`
`
`0
`
`3 (2)
`
`0
`
`
`
`
` 96 (67)
`
`
`
`
`
`21 (15)
`
`9 (6)
`
`5 (3)
`
`
`
`
`
`8 (6)
`
`8 (6)
`
`6 (4)
`
`1 (<1)
`
`
`
`
`3 (2)
`
`
`
`
`12 (8)
`
`1 (<1)
`
`7 (5)
`
`
`
`
` 25 (17)
`
`
`
`
`
`1 (<1)
`
`0
`
`0
`
`
`
`
`
`2 (1)
`
`0
`
`0
`
`0
`
`
`
`
`0
`
`
`
`
`0
`
`1 (<1)
`
`0
`
`
`

`

`
`
`
`
` Investigations
`
` Weight decreased
`
`
`Metabolism and
`
`
` nutrition disorders
`
`
` Hyperuricemia
`
`Respiratory, thoracic
`
` and mediastinal
` disorders
`
`
`
` Cough
`
`
` Skin and subcutaneous
`
` tissue disorders
`
`
` Rash
` Pruritus
`
`
`
`
`
`
` 11 (7)
`
`
`
`
`
`
`11 (7)
`
`
`
`
` 6 (4)
`
`
`
`
`
`
`12 (8)
` 8 (5)
`
`
`
` 0
`
`
`
`
`
`
`3 (2)
`
`
`
`
` 1 (<1)
`
`
`
`
`
`
`4 (3)
`
` 0
`
`
` 5 (3)
`
`
`
`
`
`
`2 (1)
`
`
`
`
` 7 (5)
`
`
`
`
`
`
`7 (5)
`
` 2 (1)
`
`
` 0
`
`
`
`
`
`
`0
`
`
`
`
` 1 (<1)
`
`
`
`
`
`
`3 (2)
`
` 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
`
`
`
` Chlorambucil
`TREANDA
`
`
` N=150
` N=141
`
` Grade 3/4
`
` Grade 3/4
`
` All Grades
`
` All Grades
` n (%)
`
`
`
`
` n (%)
` n (%)
` n (%)
`
` 12 (9)
`
` 20 (13)
` 134 (89)
` 115 (82)
`
`
`
`
`
`
`
` 116 (77)
`
`
`
` 16 (11)
`
`
`
` 110 (78)
`
`
`
` 14 (10)
`
`
`
` 92 (61)
`
`
`
` 102 (68)
`
`
`
` 42 (28)
`
`
`
` 70 (47)
`
`
`
` 113 (75)
`
`
`
` 65 (43)
`
`
`
` 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 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 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.
`
`
`
`
` Clinical Trials Experience in NHL
`
`
`6.2
`
`
`
`
`
`
`
` 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 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 TREANDA by System Organ Class and Preferred Term (N=176)
`
`
`
` Number (%) of patients*
`System organ class
`
`Preferred term
`
`
` Grade 3/4
`
` All Grades
`Total number of patients with at
`
` least 1 adverse reaction
`
` Cardiac disorders
`
`
` Tachycardia
` Gastrointestinal disorders
`
`
` Nausea
`
` Vomiting
`
`
` Diarrhea
`
` Constipation
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3373510
`
`
`
`
`
`
` 176 (100)
`
` 13 (7)
`
`
` 132 (75)
`
` 71 (40)
`
` 65 (37)
`
` 51 (29)
`
`
`
`
`
` 94 (53)
`
`
` 0
`
`
` 7 (4)
`
` 5 (3)
`
` 6 (3)
` 1 (<1)
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
` 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
`
`
`
` Rash
`
`
` Pruritus
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3373510
`
`
`
` 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)
`
` 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)
`
`
` 28 (16)
`
` 11 (6)
`
`
` 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)
`
` 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
`
`

`

`
`
` Dry skin
`
`
`
` 9 (5)
` Night sweats
`
`
`
` 9 (5)
` Hyperhidrosis
`
`
`
` 8 (5)
`
` 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
`
` 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%).
`
`Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who
`
`Received TREANDA in the NHL Studies
`
`
`
`
`
`
` Percent of patients
`
`
`
`
`
` All Grades
`
` 99
`
`
` 94
`
`
` 88
`
`
` 86
`
`
` 86
`
`
`
` Grades 3/4
`
` 94
`
`
` 56
`
`
` 11
`
`
` 60
`
`
` 25
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Hematology variable
`
`
`
`
`
` Lymphocytes
`
` Decreased
`
` Leukocytes
`
` Decreased
`
` Hemoglobin
`
` Decreased
`
` Neutrophils
`
` Decreased
`
` Platelets
` Decreased
`
`
`
`
`
`
`Reference ID: 3373510
`
`
`
` In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious
`
`
` adverse reactions occurring in ≥5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` clinical trials and/or postmarketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and
`
`
`
` myelodysplastic syndrome.
`
`
` Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome and infusion
` reactions [see Warnings and Precautions (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.
`
`
` Postmarketing Experience
` 6.3
`
`
` The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from
`
`
`
`
` a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:
`
` anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and
`
`
`
`
`
`
` pneumonitis.
`
`
`
` 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)]
`
`
`
`
`DRUG INTERACTIONS
`7
`
`
`
`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 concentr