Treanda

bendamustine hydrochloride

Dosage Form: injection
FULL PRESCRIBING INFORMATION

INDICATIONS AND USAGE

  Chronic Lymphocytic Leukemia (CLL)

Treanda® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established.

  Non-Hodgkin’s Lymphoma (NHL)

Treanda 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:

Treanda administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity.  Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], Treanda can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions(5.1)]

Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle.

Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle.

Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician.

  Dosing Instructions for NHL

Recommended Dosage: 

The recommended dose is 120 mg/m2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. 

Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL:

Treanda administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity.  Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], Treanda can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions(5.1)]

Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle. 

Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m2 on Days 1 and 2 of each cycle.

  General Considerations for Tumor Lysis Syndrome

Consider using allopurinol as prevention for patients at high risk of tumor lysis syndrome for the first few weeks of treatment.

  Reconstitution/Preparation for Intravenous Administration

• Aseptically reconstitute each 100 mg Treanda vial with 20 mL of only Sterile Water for Injection, USP. Shake well to yield 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.


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  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). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered.  The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 – 0.6 mg/mL. 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.

  
  

  
  
  Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above.  No other diluents have been shown to be compatible.
  
  

  
  

  Parenteral drug products 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 either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) 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 (e.g., anaphylactic and anaphylactoid reactions) 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 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(2.1), (2.2)]

  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 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.  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 few 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.  In a study of Treanda (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred.  TEN has been reported for rituximab (see rituximab package insert). The relationship to Treanda cannot be determined. 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.

  Other Malignancies

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

  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)]

Adverse Reactions

The data described below reflect exposure to Treanda 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 Treanda in clinical trials and are discussed in greater detail in other sections of the label.

• Myelosuppression [See Warnings and Precautions(5.1)]


• Infections [See Warnings and Precautions(5.2)]


• Infusion Reactions and Anaphylaxis [See Warnings and Precautions(5.3)]


• Tumor Lysis Syndrome [See Warnings and Precautions(5.4)]


• Skin Reactions [See Warnings and Precautions(5.5)]


• Other Malignancies [See Warnings and Precautions(5.6)]

 Clinical Trials Experience in CLL

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 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 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 ≥ 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 

	Number (%) of patients
	Treanda (N=153)		Chlorambucil (N=143)
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	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)	0	5 (3)	0
Metabolism and nutrition disorders
Hyperuricemia	11 (7)	3 (2)	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)	3 (2)
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 Treanda. Red blood cell transfusions were administered to 20% of patients receiving Treanda compared with 6% of patients receiving chlorambucil.

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

	Treanda N=150		Chlorambucil N=141
Laboratory Abnormality	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 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.

 Clinical Trials Experience in NHL

The data described below reflect exposure to Treanda in 176 patients with indolent B-cell NHL treated in two single-arm studies.  The population was 31-84 years of age, 60% male, and 40% female.  The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received Treanda at a dose of 120 mg/m2 intravenously on Days 1 and 2 for up to 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 Treanda by System Organ Class and Preferred Term (N=176) 

System organ class	Number (%) of patients*
Preferred term	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 site 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%).

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

 Post-Marketing Experience

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

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 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.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category D [See Warnings and Precautions(5.7)]

Treanda 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 Treanda 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 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.  

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.  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

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 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.  

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).