CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TI0N NUMBER:
`
`NDA 22-249
`
`LABELING
`
`

`

`o
`
`o
`
`-------------------------WARNINGS AND PRECAUTlONS----------------~-----
`~
`Myelosuppression: May warrant treatment delay or dose reduction.
`Monitor closely and restart treatment based on ANC and platelet count
`recovery. (5.1)
`Infections: Monitor for fever and other signs of infection and treat
`promptly. (5.2)
`Infusion Reactions and Anaphylaxis: Severe anaphylactic reactions have
`occurred. Monitor clinically and discontinue drug for severe reactions.
`Ask patients about reactions after the first cycle. Consider pre—treatment
`for cycles subsequent to milder reactions. (5.3)
`Tumor Lysis Syndrome: May lead to acute renal failure and death.
`Take precautions in patients at high risk. (5 .4)
`Skin Reactions: Discontinue for severe skin reactions. (55)
`Use in Pregnancy: Fetal harm can occur when administered to a
`pregnant woman. Women should be advised to avoid becoming pregnant
`when receiving TREANDA. (5.6, 8.1)
`
`0
`
`0
`0
`
`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
`
`----------------«--------~-Il‘IDICATIONS AND USAGE---------------------------
`TREANDA for Injection is an alkylating drug indicated for the treatment of
`patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first
`line therapies other than chlorambucil has not been established. (1)
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`-
`
`'
`
`0
`
`0
`
`c
`o
`
`100 mg/m2 infused intravenously over 30 minutes on Days 1 and 2 of a
`28-day cycle, up to 6 cycles (2.1)
`Delay treatment for Grade 4 hematologic toxicity or clinically
`significant 2 Grade 2 non-hematologic toxicity (22)
`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. (2.2)
`Dose modifications for non-hematologic toxicity: for clinically
`significant Grade 3 or greater toxicity, reduce the dose to 50 mym2 on
`Days 1 and 2 of each cycle. (2.2)
`Dose re-escalation may be considered, (22)
`TREANDA for Injection must be reconstituted and further diluted prior
`to infusion. (2.3)
`
`------------------------DOSAGE FORMS AND STRENGTHS--------—--~------
`TREANDA for Injection single-use vial containing 100 mg of bendamustine
`HCl as lyophilized powder (3)
`
`-----------—--------------------CONTRAINDICATIONS-----------~----------------
`0
`Known hypersensitivity to bendamustine or mannitol (4)
`
`‘
`
`--------------------------------ADVERSE REACTIONS--—--------------------------
`
`Most common adverse reactions (frequency 215%) are neutropenia, pyrexia,
`thrombocytopenia, nausea, anemia, leukopenia, and vomiting. (6)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Cephalon,
`Inc., at 1-800-896-5855 or FDA at 1-800-FDA-1088 or
`wwmfda.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)
`
`o
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`—-———————.———._________—_—_
`
`Revised: 03/2008
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`UIAW
`
`INDICATIONS AND USAGE
`1
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosage
`2.2 Dose Delays, Dose Modifications, and Reinitiation of Therapy
`2.3 Reconstitution/Preparation for Intravenous Administration
`2.4 Admixture Stability
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`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 Use in Pregnancy
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`DRUG INTERACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3 Nursing Mothers
`
`”\I
`
`8.4 Pediatric Use
`85 Geriatric Use
`8.6 Renal lmpainnent
`8.7 Hepatic Impairment
`8.8 Effect of Gender
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.3
`Pharmacokinetics
`l3 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`161
`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
`
`4 CONTRAINDICATIONS
`
`1
`
`INDICATIONS AND USAGE
`TREANDA® (bendamustine hydrochloride) for Injection is indicated for
`the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy
`relative to first line therapies other than chlorambucil has not been established
`
`2 DOSAGE AND ADMINISTRATION
`2.1 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 I 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.
`
`2.2 Dose Delays, Dose Modifications and Reinitiation of Therapy
`TREANDA administration should be delayed in the event of Grade 4
`hematologic toxicity or clinically significant 2 Grade 2 non-hematologic
`toxicity. Once non-hematologic toxicity has recovered to 5 Grade 1 and/or
`the blood counts have improved [Absolute Neutrophil Count (ANC) _>_ 1 x
`109/L, platelets 2 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.
`
`I
`
`0
`
`2.3 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 of0.9% 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.
`
`0
`
`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.
`
`2.4 Admixture Stability
`TREANDA contains no antimicrobial preservative. The admixture
`should be prepared as close as possible to the time of patient administration.
`Once diluted with 0.9% 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 (I 5-30°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 100 mg of
`bendamustine HCl as white to off-white lyophilized powder.
`
`TREANDA is contraindicated in patients with a known hypersensitivity 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 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 2 1 x lO’lL and the platelet count should be 2 75 x 109/L.
`
`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 fol10wing TREANDA treatment should be
`' advised to contact a physician if they have symptoms or signs of infection.
`
`Infusion Reactions and Anaphylaxis
`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. Patients should be asked about
`symptoms suggestive of infusion reactions afier 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.
`
`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 one to two 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. 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 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 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 naive 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. 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.
`
`6.1 Clinical Trials Experience
`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.
`
`I
`O
`0
`
`0
`
`Myelosuppression [See Warnings and Precautions (5.1)]
`Infections [See Warnings and Precautions (52)]
`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)]
`
`Adverse reactions were reported according to NCI CTC v.2.0. In the
`randomized CLL clinical study, hematologic adverse reactions (any grade) in
`the TREANDA group that occurred with a frequency greater than 15% were
`neutropenia (28%), thrombocytopenia (23%), anemia (19%), and leukopenia
`(18%). 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 2 5% of patients in either treatment group in
`the randomized CLL clinical study.
`
`Table 1: Adverse Reactions Occurring in Randomized CLL Clinical Study
`in at Least 5% ofPatients
`
`Number (%) of patients
`TREANDA
`Chlorambucil
`1fl=153!
`(N=143!
`
`All Grades
`
`Grade 3I4
`
`All Grades
`
`Grade 3/4
`
`System organ class
`Preferred term
`Total number of patients with at least 1
`adverse reaction
`Blood and lymphatic system disorders
`Neutropenia
`Thrombocytopenia
`Anemia
`Leukopenia
`Lymphopenia
`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
`3 (2)
`7(5)
`4 (3)
`12 (8)
`Rash
`——-————‘_—
`Pruritus
`8 (5)
`0
`2(1)
`0
`
`[36 (89)
`
`43 (28)
`35 (23)
`2909)
`28 (18)
`10 (7)
`
`31 (20)
`24 (16)
`l4 (9)
`
`36 (24)
`i4 (9)
`l3 (8)
`9(6)
`
`7 (5)
`
`l0 (7)
`9(6)
`5 (3)
`
`l l (7)
`
`11 (7)
`
`6(4)
`
`88 (58)
`
`36 (24)
`20 (13)
`4(3)
`23 (15)
`10(7)
`
`1 (<1)
`1 (<1)
`2(1)
`
`_
`
`6 (4)
`2 (I)
`0
`0
`
`2 (l)
`
`0
`3(2)
`0
`
`0
`
`3 (2)
`
`113 (79)
`
`44 (31)
`
`20 (14)
`28 (20)
`16(11)
`4(3)
`0
`
`21 (15)
`9 (6)
`5(3)
`
`8 (6)
`8 (6)
`6 (4)
`i (<1)
`
`3 (2)
`
`12 (8)
`1 (<1)
`7(5)
`
`5 (3)
`
`2 (1)
`
`13 (9)
`1 1 (s)
`0
`2 (l)
`0
`
`1 (<1)
`0
`0
`
`2 (1)
`0
`0
`0
`
`0
`
`0
`1 (<1)
`0
`
`0
`
`0
`
`1 (<1)
`
`7(5)
`
`1 (<1)
`
`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 Stud
`TREANDA
`Chlorambucil
`
`
`N=150
`N=l41
`
`
`Laboratory Abnormality
`Grade 3/4
`All Grades
`Grade 3/4
`All Grades
`
`
`
`
`n (%)
`.
`n (%)
`n (%)
`
`
`
`
`Hemoglobin
`
`
`20 (13) 134 (89)
`
`
`Decreased
`
`
`Platelets
`
`
`
`116 (77)
`16(11)
`
`Decreased
`Leukocytes
`
`
`4(3)
`26 (18)
`42 (28)
`92 (61)
`Decreased
`
`L m-hoc tes Decreased
`
`102 68
`7o 47
`27 19
`6 4
`Neutro hils Decreased
`
`113 (75)
`65 (43)
`86 (61)
`30 (21)
`
`14(10)
`
`
`
`
`
`
`
`
`
`In the randomized CLL clinical study, 34% of patients had bilirubin
`elevations, some without associated significant elevations in AST and ALT.
`Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST
`and ALT of grade 3 or 4 were limited to 1% and 3% of patients, respectively.
`Patients treated with TREANDA may also have changes in their creatinine
`levels. If abnormalities are detected, monitoring of these parameters should be
`continued to ensure that significant deterioration does not occur.
`
`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 CYP] A2 (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 vitra 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, 2B], 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. 6)]
`TREANDA can cause fetal harm when administered to a pregnant
`woman. Single intraperitoneal doses of bendamustine from 210 mg/m2
`(70 mgkg) 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 1125 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, l I, 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.
`
`

`

`C16H2|C12N302 ' 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:
`
`CI-CH,-cn,\ n
`CI-cu.-CH,/
`
`u
`
`H
`
`>—<CH,;,«coOH-HCI
`
`CH3
`
`TREANDA (bendamustine hydrochloride) for Injection is intended for
`intravenous infusion only afier 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.
`
`12 CLINICAL PHARMACOLOGY
`12.] Mechanism ofAction
`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.
`12.3 Pharmacokinetics
`Absorption
`Following a single IV dose of bendamustine hydrochloride Cm
`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 fi'om 94-96% and was concentration independent from 1-50 ug/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
`pg/mL indicating that bendamustine distributes freely in human red blood
`cells.
`In humans, the mean steady state volume of distribution (V,.) was
`approximately 25 L.
`
`m I
`
`n 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 vitra 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, CYPZBé,
`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 l-hour the
`intermediate ty, of the parent compound is approximately 40 minutes. The
`mean apparent terminal elimination ty, 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.
`
`8.3- 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 tu'morigenicity 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.
`
`8.4 Pediatric Use
`
`The safety and effectiveness of TREANDA in pediatric patients have
`not been established.
`
`8.5 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 2 65 years. There were no clinically significant differences in the
`adverse reaction profile.
`
`8.6 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 ([2. 3)]
`
`8.7 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)]
`8.8 Effect of Gender
`
`In the randomized CLL clinical study, the overall response rate (OR)
`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—flee 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.
`
`10 OVERDOSAGE .
`
`The intravenous LDso 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/mz. 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.
`
`1] DESCRIPTION
`
`TREANDA contains bendamustine hydrochloride, an alkylating drug, as
`the active ingredient. The chemical name of bendamustine hydrochloride is
`lH-benzimidazole-Z-butanoic acid, 5-[bis(2-chloroethyl)amino]v1-
`methy|-, monohydrochloride. Its empirical molecular formula is
`
`

`

`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/mz, 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 CLL'.
`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: Efficac Data
`
`
`
`
`
`
`
`
`
`TREANDA
`N=153
`
`Median, months (95% c1)
`
`18 (r r .7, 23.5)
`
`6 (5.6, 8.6) —
`
`
`Chlorambucil
`p-value
`
`N=l48
`
`Responsenatenm _——
`
`Overall response rate
`90 (59)
`38 (26)
`<0.000l
`
`
`
`(5103, 66.62)
`(18.64, 32.71)
`(95% C1)
`
`
`13 (8)
`Complete response (CR)*
`
`4 (3)
`Nodular partial response (nPR)**
`
`
`
`
`
`
`Partial response (PR)?
`
`73 (48)
`37 (25)
`
`
`
`Progression-Free Survivalft
`
`
`
`
`
`
`
`
`
`
`
`Hazard ratio (95% CI)
`
`
`
`0.27 (0.17, 0.43)
`
`<o.oom
`
`* CR was defined as peripheral lymphocyte counts 4.0 x 109/L, neutrophils
`2 1.5 x 109/L, platelets >100 x 109/L, hemoglobin > 1 lOg/L, without
`transfusions, absence of palpable hepatosplenomegaly, lymph nodes 5 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 2 50% decrease in peripheral lymphocyte count from
`the pretreatment baseline value, and either 250% reduction in
`lymphadenopathy, or 250% reduction in the size of spleen or liver, as well
`as one of the following hematologic improvements: neutrophils 2 1.5 x
`109/1. or 50% improvement over baseline, platelets >100 x 109/L or 50%
`improvement over baseline, hemoglobin >1 lOg/L or 50% improvement
`over baseline without transfusions, for a period of at least 56 days.
`1+ PFS was defined as time from randomization to progression or death from
`any cause.
`
`t
`
`Renal Impairment
`In a population pharrnacokinetic analysis of bendamustine in patients
`receiving 120 mg/m2 there was no meaningful effect of renal impairment
`(CrCL 40 - 80 mL/min, N=3l) 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 S
`ULN, AST 2 ULN to 2.5 x ULN, and/or ALP 2 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 Cm) 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.
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Bendamustine was carcinogenic in mice. Afier intraperitoneal injections
`at 37.5 mg/mz/day (12.5 mg/kgday, the lowest dose tested) and 75 mg/mz/day
`(25 mg/kg/day) for four days, peritoneal sarcomas in female AB/jena mice
`were produced. Oral administrati