SYMBENDA

DESCRIPTION

SYMBENDA 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:

 

SYMBENDA is indicated for intravenous administration.

After reconstitution of the solution according to the instructions, SYMBENDA is administered as a short intravenous infusion over 30 – 60 minutes.

To prepare the ready-to-use solution, the contents of a vial of SYMBENDA are dissolved in water for injections as follows:

First dissolve the vial of SYMBENDA containing 25 mg of Bendamustine hydrochloride in 10 ml by shaking,

First dissolve the vial of SYMBENDA containing 100 mg of Bendamustine hydrochloride in 40 ml by shaking.

As soon as clear solution forms (within 5 minutes) the total SYMBENDA dose is immediately diluted to a final volume of approximately 500ml with 0.9% sodium chloride solution. If particulate matter is observed, the reconstituted product should not be used.

Apart from isotonic saline solution, SYMBENDA must not be diluted with other base infusion solutions or other injection solutions.

INDICATIONS

Chronic Lymphocytic Leukemia (CLL)

SYMBENDA^® 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’s Lymphoma (NHL)

SYMBENDA for Injection is indicated for the treatment of patients with indolent B-cell non-Hodgkin’s lymphoma that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen.

DOSAGE AND ADMINISTRATION

Dosing Instructions For CLL

Recommended Dosage

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

Dose Delays, Dose Modifications And Reinitiation Of Therapy For CLL

SYMBENDA 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], SYMBENDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [see WARNINGS AND PRECAUTIONS]

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

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

SYMBENDA 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], SYMBENDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [see WARNINGS AND PRECAUTIONS]

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.

Reconstitution/Preparation For Intravenous Administration

After reconstitution of the solution according to the instructions, SYMBENDA is administered as a short intravenous infusion over 30 – 60 minutes.

To prepare the ready-to-use solution, the contents of a vial of SYMBENDA are dissolved in water for injections as follows:

First dissolve the vial of SYMBENDA containing 25 mg of Bendamustine hydrochloride in 10 ml by shaking,

First dissolve the vial of SYMBENDA containing 100 mg of Bendamustine hydrochloride in 40 ml by shaking.

As soon as clear solution forms (within 5 minutes) the total SYMBENDA dose is immediately diluted to a final volume of approximately 500ml with 0.9% sodium chloride solution. If particulate matter is observed, the reconstituted product should not be used.

Apart from isotonic saline solution, SYMBENDA must not be diluted with other base infusion solutions or other injection solutions.

Admixture Stability

Unopened vial

Do not store above 25° C.

Keep the vial in the outer carton in order to protect from light.

Reconstituted concentrate in the vial

The concentrate should be further processed immediately.

Diluted solution for infusion

The chemical and physical stability of the preparation after reconstitution to form the solution for infusion (water for injections and isotonic saline solution) was confirmed for 2 hours at 25° C and 2 days at 2-8° C. From a microbiological point of view, the product should be used immediately. If not used immediately, in- use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8° C, unless dilution has taken place in controlled and validated aseptic conditions. If the ready-to-use preparation is not used immediately, the user is responsible for the storage period and conditions.

HOW SUPPLIED

Dosage Forms And Strengths

1 vial of SYMBENDA with 55 mg of powder for the preparation of a solution for infusion contains 25 mg of Bendamustine hydrochloride.

1 vial of SYMBENDA with 220 mg of powder for the preparation of a solution for infusion contains 100 mg of Bendamustine hydrochloride.

Excipients: Mannitol

Storage And Handling

Safe Handling And Disposal

As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from SYMBENDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of SYMBENDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If SYMBENDA contacts the mucous membranes, flush thoroughly with water.

Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published36. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

How Supplied

SYMBENDA (with 25 mg Bendamustine hydrochloride): 26 ml, type I amber glass vial with rubber stopper and aluminium crimp cap for single use.

Original packaging with 5 vials in 1 box.

SYMBENDA (with 100 mg Bendamustine hydrochloride): 60 ml, type I amber glass vial with rubber stopper and aluminium crimp cap for single use.

Original packaging with 1 vial in 1 box.

Storage

Unopened vial

Do not store above 25° C.

Keep the vial in the outer carton in order to protect from light.

Product Licence Holder: Eisai (Singapore) Pte Ltd, 152 Beach Road, #15- 05/08 Gateway East Singapore 189721. Revised: Sep 2012.

SIDE EFFECTS

The data described below reflect exposure to SYMBENDA in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following serious adverse reactions have been associated with SYMBENDA in clinical trials and are discussed in greater detail in other sections of the label.

• Myelosuppression [see WARNINGS AND PRECAUTIONS]
• Infections [see WARNINGS AND PRECAUTIONS]
• Infusion Reactions and Anaphylaxis [see WARNINGS AND PRECAUTIONS]
• Tumor Lysis Syndrome [see WARNINGS AND PRECAUTIONS]
• Skin Reactions [see WARNINGS AND PRECAUTIONS]
• Other Malignancies [see WARNINGS AND PRECAUTIONS]
• Hepatitis B Virus Reactivation [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience In CLL

The data described below reflect exposure to SYMBENDA in 153 patients. SYMBENDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m² intravenously over 30 minutes on days 1 and 2 every 28 days.

Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the SYMBENDA 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 SYMBENDA 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 SYMBENDA 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	Number (%) of patients
	SYMBENDA (N=153)		Chlorambucil (N=143)
	All Grades	Grade 3/4	All Grades	Grade 3/4
Total number of patients with at least 1 adverse reaction	121 (79)	52 (34)	96 (67)	25 (17)
Gastrointestinal disorders
Nausea	31 (20)	1(<1)	21 (15)	1(<1)
Vomiting	24 (16)	1(<1)	9 (6)	0
Diarrhea	14 (9)	2 (1)	5 (3)	0
General disorders and administration site conditions
Pyrexia	36 (24)	6 (4)	8 (6)	2 (1)
Fatigue	14 (9)	2 (1)	8 (6)	0
Asthenia	13 (8)	0	6 (4)	0
Chills	9 (6)	0	1(<1)	0
Immune system disorders
Hypersensitivity	7 (5)	2 (1)	3 (2)	0
Infections and infestations
Nasopharyngitis	10 (7)	0	12 (8)	0
Infection	9 (6)	3 (2)	1(<1)	1(<1)
Herpes simplex	5 (3)	0	7 (5)	0
Investigations
Weight decreased	11 (7)	3 (2)	5 (3)	0
Metabolism and nutrition disorders
Hyperuricemia	11 (7)		2 (1)	0
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)	0
Pruritus	8 (5)	0	2 (1)	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 SYMBENDA. Red blood cell transfusions were administered to 20% of patients receiving SYMBENDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received SYMBENDA and Chlorambucil in the Randomized CLL Clinical Study

Laboratory Abnormality	SYMBENDA (N=150)		Chlorambucil (N=141)
	All Grades n (%)	Grade 3/4 n (%)	All Grades n (%)	Grade 3/4 n (%)
Hemoglobin Decreased	134 (89)	20 (13)	115 (82)	12 (9)
Platelets Decreased	116 (77)	16 (11)	110 (78)	14 (10)
Leukocytes Decreased	92 (61)	42 (28)	26 (18)	4 (3)
Lymphocytes Decreased	102 (68)	70 (47)	27 (19)	6 (4)
Neutrophils Decreased	113 (75)	65 (43)	86 (61)	30 (21)

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 SYMBENDA 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.

Clinical Trials Experience In NHL

The data described below reflect exposure to SYMBENDA 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 SYMBENDA at a dose of 120 mg/m² intravenously on Days 1 and 2 for up to 8 21-day cycles.

The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions (≥ 30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions (≥ 5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients.

Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with SYMBENDA by System Organ Class and Preferred Term (N=176)

System organ class Preferred term	Number (%) of patients*
	All Grades	Grade 3/4
Total number of patients with at least 1 adverse reaction	176 (100)	94 (53)
Cardiac disorders
Tachycardia	13 (7)	0
Gastrointestinal disorders
Nausea	132 (75)	7 (4)
Vomiting	71 (40)	5 (3)
Diarrhea	65 (37)	6 (3)
Constipation	51 (29)	1(<1)
Stomatitis	27 (15)	1(<1)
Abdominal pain	22 (13)	2 (1)
Dyspepsia	20 (11)	0
Gastroesophageal reflux disease	18 (10)	0
Dry mouth	15 (9)	1(<1)
Abdominal pain upper	8 (5)	0
Abdominal distension	8 (5)	0
General disorders and administration site conditions
Fatigue	101 (57)	19 (11)
Pyrexia	59 (34)	3 (2)
Chills	24 (14)	0
Edema peripheral	23 (13)	1(<1)
Asthenia	19 (11)	4 (2)
Chest pain	11 (6)	1(<1)
Infusion site pain	11 (6)	0
Pain	10 (6)	0
Catheter pain	8 (5)	0
Infections and infestations
Herpes zoster	18 (10)	5 (3)
Upper respiratory tract infection	18 (10)	0
Urinary tract infection	17 (10)	4 (2)
Sinusitis	15 (9)	0
Pneumonia	14 (8)	9 (5)
Febrile Neutropenia	11 (6)	11 (6)
Oral Candidiasis	11 (6)	2 (1)
Nasopharyngitis	11 (6)	0
Investigations
Weight decreased	31 (18)	3 (2)
Metabolism and nutrition disorders
Anorexia	40 (23)	3 (2)
Dehydration	24 (14)	8 (5)
Decreased appetite	22 (13)	1(<1)
Hypokalemia	15 (9)	9 (5)
Musculoskeletal and connective tissue disorders
Back pain	25 (14)	5 (3)
Arthralgia	11 (6)	0
Pain in extremity	8 (5)	2 (1)
Bone pain	8 (5)	0
Nervous system disorders
Headache	36 (21)	0
Dizziness	25 (14)	0
Dysgeusia	13 (7)	0
Psychiatric disorders
Insomnia	23 (13)	0
Anxiety	14 (8)	1(<1)
Depression	10 (6)	0
Respiratory, thoracic and mediastinal disorders
Cough	38 (22)	1(<1)
Dyspnea	28 (16)	3 (2)
Pharyngolaryngeal pain	14 (8)	1(<1)
Wheezing	8 (5)	0
Nasal congestion	8 (5)	0
Skin and subcutaneous tissue disorders
Rash	28 (16)	1(<1)
Pruritus	11 (6)	0
Dry skin	9 (5)	0
Night sweats	9 (5)	0
Hyperhidrosis	8 (5)	0
Vascular disorders
Hypotension	10 (6)	2 (1)
*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.

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 SYMBENDA in the NHL Studies

Hematology variable	Percent of patients
	All Grades	Grades 3/4
Lymphocytes Decreased	99	94
Leukocytes Decreased	94	56
Hemoglobin Decreased	88	11
Neutrophils Decreased	86	60
Platelets Decreased	86	25

In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving SYMBENDA. The most common serious adverse reactions occurring in ≥ 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/ or post-marketing experience were acute renal failure, cardiac 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]. Adverse reactions occurring less frequently but possibly related to SYMBENDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis.

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of SYMBENDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling.

Skin reactions including SJS and TEN have occurred when SYMBENDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [see WARNINGS AND PRECAUTIONS].

Hepatitis due to reactivation of hepatitis B virus may occur. [see WARNINGS AND PRECAUTIONS].

DRUG INTERACTIONS

No formal clinical assessments of pharmacokinetic drug-drug interactions between SYMBENDA and other drugs have been conducted.

Bendamustine’s active metabolites, gamma-hydroxy Bendamustine (M3) and N-desmethyl-Bendamustine (M4), are formed via cytochrome P450 CYP1A2. Inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) have potential to increase plasma concentrations of Bendamustine and decrease plasma concentrations of active metabolites. Inducers of CYP1A2 (e.g., omeprazole, smoking) have potential to decrease plasma concentrations of Bendamustine and increase plasma concentrations of its active metabolites. Caution should be used, or alternative treatments considered if concomitant treatment with CYP1A2 inhibitors or inducers is needed.

The role of active transport systems in Bendamustine distribution has not been fully evaluated. In vitro data suggest that P-glycoprotein, breast cancer resistance protein (BCRP), and/ or other efflux transporters may have a role in Bendamustine transport.

Based on in vitro data, Bendamustine is not likely to inhibit metabolism via human CYP isoenzymes CYP1A2, 2C9/10, 2D6, 2E1, or 3A4/5, or to induce metabolism of substrates of cytochrome P450 enzymes.

WARNINGS

Included as part of the “PRECAUTIONS” Section

PRECAUTIONS

Myelosuppression

Patients treated with SYMBENDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression (see Table 4). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV).

In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 10⁹/L and the platelet count should be ≥ 75 x 10⁹/L. [see DOSAGE AND ADMINISTRATION]

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 SYMBENDA are more susceptible to infections. Patients with myelosuppression following SYMBENDA treatment should be advised to contact a physician if they have symptoms or signs of infection.

Infusion Reactions And Anaphylaxis

Infusion reactions to SYMBENDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions.

Tumor Lysis Syndrome

Tumor lysis syndrome associated with SYMBENDA 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 SYMBENDA 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 SYMBENDA therapy. However, there may be an increased risk of severe skin toxicity when SYMBENDA and allopurinol are administered concomitantly. [see Skin Reactions]

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 SYMBENDA was given in combination with other anticancer agents, so the precise relationship to SYMBENDA is uncertain.

In a study of SYMBENDA (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 SYMBENDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to SYMBENDA cannot be determined.

Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, SYMBENDA should be withheld or discontinued.

Other Malignancies

There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with SYMBENDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with SYMBENDA therapy has not been determined.

Hepatitis B Virus Reactivation

Administration of SYMBENDA may cause hepatitis due to reactivation of hepatitis B virus. Therefore patients should be tested for hepatitis B infection and undergo appropriate measures prior to administration of SYMBENDA. Regular liver function tests and monitoring of hepatitis virus markers after the start of administration of SYMBENDA must be performed in order to be alerted to signs and/or symptoms of reactivation of hepatitis B virus.

Use In Pregnancy

SYMBENDA 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]

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 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.

Use In Specific Populations

Pregnancy

Pregnancy Category D [see WARNINGS AND PRECAUTIONS]

SYMBENDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of Bendamustine from 210 mg/m² (70 mg/kg) in mice administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations (exencephaly, cleft palates, accessory rib, and spinal deformities) and decreased fetal body weights. This dose did not appear to be maternally toxic and lower doses were not evaluated. Repeat intraperitoneal dosing in mice on gestation days 7-11 resulted in an increase in resorptions from 75 mg/m² (25 mg/kg) and an increase in abnormalities from 112.5 mg/m² (37.5 mg/kg) similar to those seen after a single intraperitoneal administration. Single intraperitoneal doses of Bendamustine from 120 mg/m² (20 mg/kg) in rats administered on gestation days 4, 7, 9, 11, or 13 caused embryo and fetal lethality as indicated by increased resorptions and a decrease in live fetuses. A significant increase in external [effect on tail, head, and herniation of external organs (exomphalos)] and internal (hydronephrosis and hydrocephalus) malformations were seen in dosed rats. There are no adequate and well-controlled 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 SYMBENDA in pediatric patients have not been established.

Geriatric Use

In CLL and NHL studies, there were no clinically significant differences in the adverse reaction profile between geriatric (≥ 65 years of age) and younger patients.

Chronic Lymphocytic Leukemia

In the randomized CLL clinical study, 153 patients received SYMBENDA. The overall response rate for patients younger than 65 years of age was 70% (n=82) for SYMBENDA and 30% (n=69) for chlorambucil. The overall response rate for patients 65 years or older was 47% (n=71) for SYMBENDA and 22% (n=79) for chlorambucil. In patients younger than 65 years of age, the median progression-free survival was 19 months in the SYMBENDA group and 8 months in the chlorambucil group. In patients 65 years or older, the median progression-free survival was 12 months in the SYMBENDA group and 8 months in the chlorambucil group.

Non-Hodgkin’s Lymphoma

Efficacy (Overall Response Rate and Duration of Response) was similar in patients < 65 years of age and patients ≥ 65 years. Irrespective of age, all of the 176 patients experienced at least one adverse reaction.

Renal Impairment

No formal studies assessing the impact of renal impairment on the pharmacokinetics of Bendamustine have been conducted. SYMBENDA should be used with caution in patients with mild or moderate renal impairment. SYMBENDA should not be used in patients with CrCL < 40 mL/min. [see CLINICAL PHARMACOLOGY]

Hepatic Impairment

No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of Bendamustine have been conducted. SYMBENDA should be used with caution in patients with mild hepatic impairment. SYMBENDA 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]

Effect Of Gender

No clinically significant differences between genders were seen in the overall incidences of adverse reactions in either CLL or NHL studies.

Chronic Lymphocytic Leukemia

In the randomized CLL clinical study, the overall response rate (ORR) for men (n=97) and women (n=56) in the SYMBENDA 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 SYMBENDA treatment group and 6 months in the chlorambucil treatment group. For women, the median progression-free survival was 13 months in the SYMBENDA treatment group and 8 months in the chlorambucil treatment group.

Non-Hodgkin’s Lymphoma

The pharmacokinetics of Bendamustine were similar in male and female patients with indolent NHL. No clinically-relevant differences between genders were seen in efficacy (ORR and DR).

OVERDOSE

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 SYMBENDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs.

CONTRAINDICATIONS

SYMBENDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to Bendamustine or mannitol. [see WARNINGS AND PRECAUTIONS]

CLINICAL PHARMACOLOGY

Mechanism Of Action

Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways. Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action of Bendamustine remains unknown.

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 μg/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 μg/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 t_1/2 of the parent compound is approximately 40 minutes. The mean apparent terminal elimination t½ 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]

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]

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]

Effect Of Gender

The pharmacokinetics of Bendamustine were similar in male and female patients. [see Use In Specific Populations]

Effect Of Race

The effect of race on the safety, and/or efficacy of SYMBENDA 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 SYMBENDA in Japanese subjects has not been established.

Pharmacokinetics/Pharmacodynamics

Based on the pharmacokinetics/pharmacodynamics analyses of data from NHL patients, a correlation was observed between nausea and Bendamustine Cmax.

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 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

Chronic Lymphocytic Leukemia (CLL)

The safety and efficacy of SYMBENDA were evaluated in an open-label, randomized, controlled multicenter trial comparing SYMBENDA 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.

The patient populations in the SYMBENDA 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 65.7×10⁹/L vs. 65.1×10⁹/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 SYMBENDA 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 SYMBENDA compared to chlorambucil (see Table 5). Survival data are not mature.

Table 5: Efficacy Data for CLL

	SYMBENDA (N=153)	Chlorambucil (N=148)	p-value
Response Rate n(%)
Overall response rate	90 (59)	38 (26)	<0.0001
(95% CI)	(51.0, 66.6)	18.6, 32.7)
Complete response(CR)*	13 (8)	1(<1)
Nodular partial response(nPR)**	4 (3)	0
Partial response(PR)†	73 (48)	37 (25)
Progression-Free Survival††
Median,months (95% CI)	18 (11.7, 23.5)	6 (5.6, 8.6)
Hazard ratio (95% CI)	0.27 (0.17, 0.43)		<0.0001
CI=confidence interval * CR was defined peripheral lymphocyte count ≤ 4.0 × 109/L, neutrophils ≥ 1.5 × 109/L, platelets > 100 × 109/L, hemoglbi ≥ 110/L, without transfussion, absence of palpable hepatosplenoegaly, 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 in the size of spleen or liver, as well as one of the following hematologic improvements: neutrophis ≥ 1.5 &time 109/L or 50% improvement over baseline, platelets ≥100 × 109/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 SYMBENDA with chlorambucil are shown in Figure 1.

Figure 1: Progression-Free Survival

Non-Hodgkin’s Lymphoma (NHL)

The efficacy of SYMBENDA was evaluated in a single arm study of 100 patients with indolent B-cell NHL that had progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. Patients were included if they relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab. All patients received SYMBENDA intravenously at a dose of 120 mg/m², on Days 1 and 2 of a 21-day treatment cycle. Patients were treated for up to 8 cycles.

The median age was 60 years, 65% were male, and 95% had a baseline WHO performance status of 0 or 1. Major tumor subtypes were follicular lymphoma (62%), diffuse small lymphocytic lymphoma (21%), and marginal zone lymphoma (16%). Ninety-nine percent of patients had received previous chemotherapy, 91% of patients had received previous alkylator therapy, and 97% of patients had relapsed within 6 months of either the first dose (monotherapy) or last dose (maintenance regimen or combination therapy) of rituximab.

Efficacy was based on the assessments by a blinded independent review committee (IRC) and included overall response rate (complete response + complete response unconfirmed + partial response) and duration of response (DR) as summarized in Table 6.

Table 6: Efficacy Data for NHL*

	SYMBENDA (N=100)
Response Rate n (%)
Overall response rate   (CR+CRu+PR)	74
(95% CI)	(64.3, 82.3)
Complete response(CR)	13
Complete response unconfirmed (CRu)	4
Partial response(PR)	57
Duration of Response (DR)
Median,months (95% CI)	9.2 months (7.1, 10.8)
CI=confidence interval *IRC assessment was based on modified International Working Group response criteria (IWG-RC)2.Modification to IWC-RCspecified that a persistently positive bone marrow in patients who met all other criteria for CR would be scorld asPR. Bone marrow sample lengths were not required to be ≥20mm