1.1 Chronic Lymphocytic Leukemia (CLL)

TREANDA® is indicatedfor the treatment of patients with chronic lymphocytic leukemia. Efficacyrelative to first line therapies other than chlorambucil has not beenestablished.

1.2Non-Hodgkin’s Lymphoma (NHL)

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

2 DOSAGEAND ADMINISTRATION

2.1 Dosing Instructions for CLL

Recommended Dosage:

The recommendeddose is 100 mg/m2 administered intravenously over 30 minuteson Days 1 and 2 of a 28-day cycle, up to 6 cycles.
 

Dose Delays, Dose Modifications and Reinitiationof Therapy for CLL:

TREANDA administration shouldbe delayed in the event of Grade 4 hematologic toxicity or clinicallysignificant ≥ Grade 2 non-hematologic toxicity. Once non-hematologictoxicity 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 discretionof 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 greatertoxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 ofeach cycle; if Grade 3 or greater toxicity recurs, reduce the doseto 25 mg/m2 on Days 1 and 2 of each cycle.

Dose modifications for non-hematologictoxicity: 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 subsequentcycles 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 and2 of a 21-day cycle, up to 8 cycles.

Dose Delays, Dose Modifications and Reinitiationof Therapy for NHL:

TREANDA administration shouldbe delayed in the event of a Grade 4 hematologic toxicity or clinicallysignificant ≥ Grade 2 non-hematologic toxicity. Once non-hematologictoxicity 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 discretionof the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)]

Dose modifications for hematologic toxicity: for Grade4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2of 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:
  • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP.
  • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP.

  Shake well to yielda clear, colorless to a pale yellow solution with a bendamustine HClconcentration of 5 mg/mL. The lyophilized powder should completelydissolve in 5 minutes. If particulate matter is observed, the reconstitutedproduct should not be used.

• Aseptically withdrawthe 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 ChlorideInjection, USP (normal saline). As an alternative to 0.9% Sodium ChlorideInjection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45%Sodium Chloride Injection, USP, may be considered. The resultingfinal concentration of bendamustine HCl in the infusion bag shouldbe within 0.2 – 0.6 mg/mL. The reconstituted solution must be transferredto the infusion bag within 30 minutes of reconstitution. After transferring,thoroughly mix the contents of the infusion bag. The admixture shouldbe 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 shouldbe inspected visually for particulate matter and discoloration priorto administration whenever solution and container permit. Any unusedsolution should be discarded according to institutional proceduresfor antineoplastics.

2.4 Admixture Stability

TREANDA containsno antimicrobial preservative. The admixture should be prepared asclose 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 ChlorideInjection, USP, the final admixture is stable for 24 hours when storedrefrigerated (2-8°C or 36-47°F) or for 3 hours when stored at roomtemperature (15-30°C or 59-86°F) and room light. Administration ofTREANDA 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 inpatients with a known hypersensitivity (e.g., anaphylactic and anaphylactoidreactions) to bendamustine or mannitol. [See Warnings and Precautions (5.3)]

5 WARNINGS AND PRECAUTIONS

5.1 Myelosuppression

Patients treatedwith TREANDA are likely to experience myelosuppression. In the twoNHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table4). Three patients (2%) died from myelosuppression-related adversereactions; one each from neutropenic sepsis, diffuse alveolar hemorrhagewith Grade 3 thrombocytopenia, and pneumonia from an opportunisticinfection (CMV).

Inthe event of treatment-related myelosuppression, monitor leukocytes,platelets, hemoglobin (Hgb), and neutrophils closely. In the clinicaltrials, blood counts were monitored every week initially. Hematologicnadirs were observed predominantly in the third week of therapy. Hematologicnadirs may require dose delays if recovery to the recommended valueshave not occurred by the first day of the next scheduled cycle. Priorto 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 pneumoniaand sepsis, has been reported in patients in clinical trials and inpost-marketing reports. Infection has been associated with hospitalization,septic shock and death. Patients with myelosuppression following treatmentwith TREANDA are more susceptible to infections. Patients with myelosuppressionfollowing TREANDA treatment should be advised to contact a physicianif they have symptoms or signs of infection.

5.3 Infusion Reactions and Anaphylaxis

Infusion reactions to TREANDAhave occurred commonly in clinical trials. Symptoms include fever,chills, pruritus and rash. In rare instances severe anaphylactic andanaphylactoid reactions have occurred, particularly in the secondand subsequent cycles of therapy. Monitor clinically and discontinuedrug for severe reactions. Patients should be asked about symptomssuggestive of infusion reactions after their first cycle of therapy.Patients who experienced Grade 3 or worse allergic-type reactionswere not typically rechallenged. Measures to prevent severe reactions,including antihistamines, antipyretics and corticosteroids shouldbe considered in subsequent cycles in patients who have previouslyexperienced Grade 1 or 2 infusion reactions. Discontinuation shouldbe 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 skinreactions have been reported in clinical trials and post-marketingsafety reports.These events have included rash, toxic skin reactionsand bullous exanthema. Some events occurred when TREANDA was givenin combination with other anticancer agents, so the precise relationshipto 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 beenreported for rituximab (see rituximab package insert). Cases of Stevens-Johnsonsyndrome (SJS) and TEN, some fatal, have been reported when TREANDAwas administered concomitantly with allopurinol and other medicationsknown to cause these syndromes. The relationship to TREANDA cannotbe determined.

Whereskin reactions occur, they may be progressive and increase in severitywith further treatment. Therefore, patients with skin reactions shouldbe monitored closely. If skin reactions are severe or progressive,TREANDA should be withheld or discontinued.

5.6 Other Malignancies

There are reports of pre-malignantand malignant diseases that have developed in patients who have beentreated with TREANDA, including myelodysplastic syndrome, myeloproliferativedisorders, acute myeloid leukemia and bronchial carcinoma. The associationwith 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 fetalharm when administered to a pregnant woman. Single intraperitonealdoses of bendamustine in mice and rats administered during organogenesiscaused 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 reflectexposure to TREANDA in 349 patients who participated in an actively-controlledtrial (N=153) for the treatment of CLL and two single-arm studies(N=176) for the treatment of indolent B-cell NHL. Because clinicaltrials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.

The following serious adverse reactions have been associatedwith TREANDA in clinical trials and are discussed in greater detailin 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)]

6.1Clinical Trials Experience in CLL

The data described belowreflect exposure to TREANDA in 153 patients. TREANDA was studiedin an active-controlled trial. The population was 45-77 years ofage, 63% male, 100% white, and had treatment naïve CLL. All patientsstarted 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 accordingto NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologicadverse reactions (any grade) in the TREANDA group that occurred witha frequency greater than 15% were pyrexia (24%), nausea (20%), andvomiting (16%).

Other adverse reactions seen frequently in one or more studies includedasthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough;constipation; headache; mucosal inflammation and stomatitis.

Worsening hypertension was reportedin 4 patients treated with TREANDA in the randomized CLL clinicalstudy and none treated with chlorambucil. Three of these 4 adversereactions were described as a hypertensive crisis and were managedwith oral medications and resolved.

The most frequent adverse reactions leading to studywithdrawal for patients receiving TREANDA were hypersensitivity (2%)and pyrexia (1%).

Table1 contains the treatment emergent adverse reactions, regardless ofattribution, that were reported in ≥ 5% of patients in either treatmentgroup in the randomized CLL clinical study.