FULL PRESCRIBING INFORMATION:

CONTENTS *

DOSAGE AND ADMINISTRATION

1. Recommended Dosage

2. Dose Delays, Dose Modifications, and Reinitiation of Therapy

3. Reconstitution/Preparation for Intravenous Administration

4. Admixture Stability

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

1. Myelosuppression

2. Infections

3. Infusion Reactions and Anaphylaxis

4. Tumor Lysis Syndrome

5. Skin Reactions

6. Use in Pregnancy

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

1. Pregnancy

Nursing MothersPediatric UseGeriatric UseRenal ImpairmentHepatic ImpairmentEffect of Gender

OVERDOSAGE

DESCRIPTION

CLINICAL PHARMACOLOGY

1. Mechanism of Action

12.3 Pharmacokinetics

NONCLINICAL TOXICOLOGY

1. Carcinogenesis, Mutagenesis, Impairment of Fertility

CLINICAL STUDIES

REFERENCES

HOW SUPPLIED/STORAGE AND HANDLING

1. Safe Handling and Disposal

2. How Supplied

3. Storage

PATIENT COUNSELING INFORMATION

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

FULL PRESCRIBING INFORMATION

DOSAGE AND ADMINISTRATION

Recommended Dosage

TREANDA is intended for administration as an intravenous infusion over 30 minutes. The recommended dose is 100 mg/m2 administered intravenously on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Consider using allopurinol as prevention for patients at high risk of tumor lysis syndrome for the first few weeks of treatment.

Dose Delays, Dose Modifications and Reinitiation of Therapy

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. Dose delays 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.

Reconstitution/Preparation for Intravenous Administration

Aseptically reconstitute each 100 mg TREANDA vial with 20 mL of Sterile Water for Injection, USP. This yields 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). 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. Sterile Water for Injection, USP and 0.9% Sodium Chloride Injection, USP must be used as outlined above. Compatibility with other diluents has not been determined. 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

TREANDA contains no antimicrobial preservative. The admixture

should be prepared as close as possible to the time of patient administration.

Once diluted with 0.9% Sodium Chloride Injection, USP, the final admixture, is stable for 24 hours when stored refrigerated (2-8degC or 36-47degF)

or for 3 hours when stored at room temperature (15-30degC or 59-86degF) and room light. Administration of TREANDA must be completed within this

period.

DOSAGE FORMS AND STRENGTHS

TREANDA for Injection single-use vial containing 100 mg of bendamustine HCl as white to off-white lyophilized powder.

CONTRAINDICATIONS

TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol. [See Warnings and Precautions (5.3)]

WARNINGS AND PRECAUTIONS

Myelosuppression

Patients treated with TREANDA are likely to experience myelosuppression. In the randomized CLL clinical study, patients receiving TREANDA experienced Grade 3 or 4 neutropenia (24%), febrile neutropenia (3%), red blood cell transfusions (20%), and platelet transfusions (< 1%). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the randomized CLL clinical study hemoglobin and WBC differential counts were monitored weekly and platelet counts were monitored each cycle. Based on data from this study, hematologic nadirs should be expected in the third week of therapy and may require dose delays if recovery to the recommended values have not occurred by day 28. 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.

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.

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 in the randomized CLL clinical study. 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.

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 one to two weeks of TREANDA therapy in patients at high risk.

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. 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.

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)]

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

System organ class

Preferred term All Grades Grade 3/4 All Grades Grade 3/4

Total number of patients with at least 1

adverse reaction 136 (89) 88 (58) 113 (79) 44 (31) Blood and lymphatic system disorders

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

conditions

Immune system disorders

Hypersensitivity 7 (5) 2 (1) 3 (2) 0

Infections and infestations

Respiratory, thoracic and mediastinal disorders

Cough 6 (4) 1 (<1) 7 (5) 1 (<1)

Skin and subcutaneous tissue disorders

Rash 12 (8) 4 (3) 7 (5) 3 (2)

Pruritus 8 (5) 0 2 (1) 0

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 studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and tumorigenicity shown for bendamustine in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of TREANDA in pediatric patients have not been established.

Geriatric Use

In the randomized CLL clinical study, 153 patients received TREANDA. The overall response rate for patients younger than 65 years of age was 70% (n=82) for TREANDA and 30% (n = 69) for chlorambucil. The overall response rate for patients 65 years or older was 47% (n=71) for TREANDA and 22% (n = 79) for chlorambucil. In patients younger than 65 years of age, the median progression-free survival was 19 months in the TREANDA group and 8 months in the chlorambucil group. In patients 65 years or older, the median progression-free survival was 12 months in the TREANDA group and 8 months in the chlorambucil group. The overall incidence of adverse reactions was 87% in patients < 65 years and 92 % in patients >= 65 years. There were no clinically significant differences in the adverse reaction profile.

Renal Impairment

No formal studies assessing the impact of renal impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild or moderate renal impairment. TREANDA should not be used in patients with CrCL < 40 mL/min. [See Clinical Pharmacology (12.3)]

Hepatic Impairment

No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of bendamustine have been conducted. TREANDA should be used with caution in patients with mild hepatic impairment. TREANDA should not be used in patients with moderate (AST or ALT 2.5-10 X ULN and total bilirubin 1.5-3 X ULN) or severe (total bilirubin > 3 X ULN) hepatic impairment. [See Clinical Pharmacology (12.3)]

Effect of Gender

In the randomized CLL clinical study, the overall response rate (ORR) for men (n=97) and women (n=56) in the TREANDA group was 60% and 57%, respectively. The ORR for men (n=90) and women (n=58) in the chlorambucil group was 24% and 28%, respectively. In this study, the median progression-free survival for men was 19 months in the TREANDA treatment group and 6 months in the chlorambucil treatment group. For women, the median progression-free survival was 13 months in the TREANDA treatment group and 8 months in the chlorambucil treatment group. No clinically significant differences between genders were seen in the overall incidences of adverse reactions.

OVERDOSAGE

The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients) and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.

DESCRIPTION

TREANDA contains bendamustine hydrochloride, an alkylating drug, as the active ingredient. The chemical name of bendamustine hydrochloride is 1H-benzimidazole-2-butanoic acid, 5-[bis(2-chloroethyl)amino]-1 methyl-, monohydrochloride. Its empirical molecular formula is C16H21Cl2N3O2 * HCl, and the molecular weight is 394.7. Bendamustine hydrochloride contains a mechlorethamine group and a benzimidazole heterocyclic ring with a butyric acid substituent, and has the following structural formula: TREANDA (bendamustine hydrochloride) for Injection is intended for intravenous infusion only after reconstitution with 20 mL of Sterile Water for Injection, USP and after further dilution with 0.9% Sodium Chloride Injection USP. It is supplied as a sterile non-pyrogenic white to off-white lyophilized powder in a single-use vial. Each vial contains 100 mg of bendamustine hydrochloride and 170 mg of mannitol, USP. The pH of the reconstituted solution is 2.5 - 3.5.

CLINICAL PHARMACOLOGY

Mechanism of Action

Bendamustine is a bifunctional mechlorethamine derivative. Mechlorethamine and its derivatives dissociate into electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties. The bifunctional covalent linkage can lead to cell death via several pathways. The exact mechanism of action of bendamustine remains unknown. Bendamustine is active against both quiescent and dividing cells.

Pharmacokinetics

Absorption

Following a single IV dose of bendamustine hydrochloride Cmax typically occurred at the end of infusion. The dose proportionality of bendamustine has not been studied.

Distribution

In vitro,

the binding of bendamustine to human serum plasma proteins

ranged from 94-96% and was concentration independent from 1-50 mg/mL. Data suggest that bendamustine is not likely to displace or to be displaced by highly protein-bound drugs. The blood to plasma concentration ratios in human blood ranged from 0.84 to 0.86 over a concentration range of 10 to 100 mg/mL indicating that bendamustine distributes freely in human red blood cells. In humans, the mean steady state volume of distribution (Vss) was approximately 25 L.

Metabolism

In vitro data indicate that bendamustine is primarily metabolized via hydrolysis to metabolites with low cytotoxic activity. In vitro, studies indicate that two active minor metabolites, M3 and M4, are primarily formed via CYP1A2. However, concentrations of these metabolites in plasma are 1/10 and 1/100 that of the parent compound, respectively, suggesting that the cytotoxic activity is primarily due to bendamustine.

In vitro

studies using human liver microsomes indicate that bendamustine does not inhibit CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5. Bendamustine did not induce metabolism of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 enzymes in primary cultures of human hepatocytes.

Elimination

No mass balance study has been undertaken in humans. Preclinical radiolabeled bendamustine studies showed that approximately 90% of drug administered was recovered in excreta primarily in the feces. Bendamustine clearance in humans is approximately 700 mL/minute. After a single dose of 120 mg/m2 bendamustine IV over 1-hour the intermediate t1/2 of the parent compound is approximately 40 minutes. The mean apparent terminal elimination t1/2 of M3 and M4 are approximately 3 hours and 30 minutes respectively. Little or no accumulation in plasma is expected for bendamustine administered on Days 1 and 2 of a 28-day cycle.

Renal Impairment

In a population pharmacokinetic analysis of bendamustine in patients receiving 120 mg/m2 there was no meaningful effect of renal impairment (CrCL 40 - 80 mL/min, N=31) on the pharmacokinetics of bendamustine. Bendamustine has not been studied in patients with CrCL < 40 mL/min. These results are however limited, and therefore bendamustine should be used with caution in patients with mild or moderate renal impairment. Bendamustine should not be used in patients with CrCL < 40 mL/min. [See Use in Specific Populations (8.6)]

Hepatic Impairment

In a population pharmacokinetic analysis of bendamustine in patients receiving 120 mg/m2 there was no meaningful effect of mild (total bilirubin <= ULN, AST >= ULN to 2.5 x ULN, and/or ALP >= ULN to 5.0 x ULN, N=26) hepatic impairment on the pharmacokinetics of bendamustine. Bendamustine has not been studied in patients with moderate or severe hepatic impairment. These results are however limited, and therefore bendamustine should be used with caution in patients with mild hepatic impairment. Bendamustine should not be used in patients with moderate (AST or ALT 2.5-10 x ULN and total bilirubin 1.5 - 3 x ULN) or severe (total bilirubin > 3 x ULN) hepatic impairment. [See Use in Specific Populations (8.7)] Effect of Age Bendamustine exposure (as measured by AUC and Cmax) has been studied in patients ages 31 through 84 years. The pharmacokinetics of bendamustine (AUC and Cmax) were not significantly different between patients less than or greater than/equal to 65 years of age. [See Use in Specific Populations (8.4, 8.5)]

Effect of Gender

The pharmacokinetics of bendamustine were similar in male and female patients. [See Use in Specific Populations (8.8)]

Effect of Race

The effect of race on the safety, and/or efficacy of TREANDA has not been established. Based on a cross-study comparison, Japanese subjects (n = 6) had on average exposures that were 40% higher than non-Japanese subjects receiving the same dose. The significance of this difference on the safety and efficacy of TREANDA in Japanese subjects has not been established.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Bendamustine was carcinogenic in mice. After intraperitoneal injections at 37.5 mg/m2/day (12.5 mg/kg/day, the lowest dose tested) and 75 mg/m2/day (25 mg/kg/day) for four days, peritoneal sarcomas in female AB/jena mice were produced. Oral administration at 187.5 mg/m2/day (62.5 mg/kg/day, the only dose tested) for four days induced mammary carcinomas and pulmonary adenomas. Bendamustine is a mutagen and clastogen. In a reverse bacterial mutation The patient populations in the TREANDA and chlorambucil treatment groups were balanced with regard to the following baseline characteristics: age (median 63 vs. 66 years), gender (63% vs. 61% male), Binet stage (71% vs. 69% Binet B), lymphadenopathy (79% vs. 82%), enlarged spleen (76% vs. 80%), enlarged liver (48% vs. 46%), hypercellular bone marrow (79% vs. 73%), "B" symptoms (51% vs. 53%), lymphocyte count (mean 65.7x109/L vs. 65.1x109/L), and serum lactate dehydrogenase concentration (mean 370.2 vs. 388.4 U/L). Ninety percent of patients in both treatment groups had immuno phenotypic confirmation of CLL (CD5, CD23 and either CD19 or CD20 or both). Patients were randomly assigned to receive either TREANDA at 100 mg/m2, administered intravenously over a period of 30 minutes on Days 1 and 2 or chlorambucil at 0.8 mg/kg (Broca's normal weight) administered orally on Days 1 and 15 of each 28-day cycle. Efficacy endpoints of objective response rate and progression-free survival were calculated using a pre- specified algorithm based on NCI working group criteria for CLL1. The results of this open-label randomized study demonstrated a higher rate of overall response and a longer progression-free survival for TREANDA compared to chlorambucil (see Table 3). Survival data are not mature.

Table 3: Efficacy Data

* CR was defined as peripheral lymphocyte count <= 4.0 x 109/L, neutrophils >= 1.5 x 109/L, platelets >100 x 109/L, hemoglobin > 110g/L, without transfusions, absence of palpable hepatosplenomegaly, lymph nodes <= 1.5 cm, < 30% lymphocytes without nodularity in at least a normocellular bone marrow and absence of "B" symptoms. The clinical and laboratory criteria were required to be maintained for a period of at least 56 days. * * nPR was defined as described for CR with the exception that the bone marrow biopsy shows persistent nodules.

+

PR was defined as >= 50% decrease in peripheral lymphocyte count from the pretreatment baseline value, and either >=50% reduction in lymphadenopathy, or >=50% reduction in the size of spleen or liver, as well as one of the following hematologic improvements: neutrophils >= 1.5 x

9 9

assay (Ames assay), bendamustine was shown to increase revertant frequency in the absence and presence of metabolic activation. Bendamustine was clastogenic in human lymphocytes in vitro, and in rat bone marrow cells in vivo (increase in micronucleated polychromatic erythrocytes) from 37.5 mg/m2, the lowest dose tested. Impaired spermatogenesis, azoospermia, and total germinal aplasia have been reported in male patients treated with alkylating agents, especially in combination with other drugs. In some instances spermatogenesis may return in patients in remission, but this may occur only several years after intensive chemotherapy has been discontinued. Patients should be warned of the potential risk to their reproductive capacities.

CLINICAL STUDIES

The safety and efficacy of TREANDA were evaluated in an open-label, randomized, controlled multicenter trial comparing TREANDA to chlorambucil. The trial was conducted in 301 previously-untreated patients with Binet Stage B or C (Rai Stages I - IV) CLL requiring treatment. Need- to-treat criteria included hematopoietic insufficiency, B-symptoms, rapidly progressive disease or risk of complications from bulky lymphadenopathy. Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia, Richter's syndrome, or transformation to prolymphocytic leukemia were excluded from the study. 10 /L or 50% improvement over baseline, platelets >100 x 10 /L or 50% improvement over baseline, hemoglobin >110g/L or 50% improvement over baseline without transfusions, for a period of at least 56 days.

+

+

PFS was defined as time from randomization to progression or death from any cause.

Kaplan-Meier estimates of progression-free survival comparing NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg/vial TREANDA with chlorambucil are shown in Figure 1. 16.3 Storage TREANDA may be stored up to 25degC (77degF) with excursions permitted

Figure

1. Progression-Free Survival

up to 30degC (86degF) (see USP Controlled Room Temperature). Retain in

original package until time of use to protect from light.