FDA label d59adc7a-6b2a-45ec-961b-d8a99f6d3933

5 WARNINGS AND PRECAUTIONS Myelosuppression: Delay or reduce dose. Restart treatment based on ANC and platelet count recovery. ( 2.1 ) Complications of myelosuppression may lead to death. ( 5.1 ) Infections: Monitor for fever and other signs of infection or reactivation of infections and treat promptly. ( 5.2 ) Anaphylaxis and Infusion Reactions: Severe anaphylactic reactions have occurred. Monitor clinically and discontinue bendamustine hydrochloride . Pre-medicate in subsequent cycles for milder reactions. ( 5.3 ) Tumor Lysis Syndrome: Acute renal failure and death; anticipate and use supportive measures. ( 5.4 ) Skin Reactions: Discontinue for severe skin reactions. Cases of SJS, DRESS and TEN, some fatal, have been reported. ( 5.5 ) Hepatotoxicity: Monitor liver chemistry tests prior to and during treatment. ( 5.6 ) Other Malignancies: Pre-malignant and malignant diseases have been reported. ( 5.7 ) Extravasation Injury: Assure good venous access and monitor infusion site during and after administration. ( 5.8 ) Embryo-fetal toxicity: Fetal harm can occur when administered to a pregnant woman. Women should be advised to avoid becoming pregnant when receiving bendamustine hydrochloride. ( 5.9 , 8.1 ) 5.1 Myelosuppression Bendamustine hydrochloride caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies ( 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 frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has 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 10 9 /L and the platelet count should be ≥ 75 x 10 9 /L. [see Dosage and Administration ( 2.1 ) and ( 2.2 )] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, hepatitis and death has occurred in adult and pediatric patients in clinical trials and in postmarketing reports for bendamustine hydrochloride. Patients with myelosuppression following treatment with bendamustine hydrochloride are more susceptible to infections. Advise patients with myelosuppression following bendamustine hydrochloride treatment to contact a physician immediately if they have symptoms or signs of infection. Patients treated with bendamustine hydrochloride are at risk for reactivation of infections including (but not limited to) hepatitis B, cytomegalovirus, Mycobacterium tuberculosis, and herpes zoster. Patients should undergo appropriate measures (including clinical and laboratory monitoring, prophylaxis, and treatment) for infection and infection reactivation prior to administration. 5.3 Anaphylaxis and Infusion Reactions Infusion reactions to bendamustine hydrochloride 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. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue bendamustine hydrochloride for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusion reactions as clinically appropriate considering individual benefits, risks, and supportive care. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with bendamustine hydrochloride has occurred in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of bendamustine hydrochloride and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of bendamustine hydrochloride therapy. However, there may be an increased risk of severe skin toxicity when bendamustine hydrochloride and allopurinol are administered concomitantly. [see Warnings and Precautions ( 5.5 )] 5.5 Skin Reactions Fatal and serious skin reactions have been reported with bendamustine hydrochloride treatment in clinical trials and postmarketing safety reports, including toxic skin reactions [Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), bullous exanthema, and rash. Events occurred when bendamustine hydrochloride was given as a single agent and in combination with other anticancer agents or allopurinol. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue bendamustine hydrochloride. 5.6 Hepatotoxicity Fatal and serious cases of liver injury have been reported with bendamustine hydrochloride injection. Combination therapy, progressive disease or reactivation of hepatitis B were confounding factors in some patients. [see Warnings and Precautions ( 5.2 )] Most cases were reported within the first three months of starting therapy. Monitor liver chemistry tests prior to and during bendamustine therapy. 5.7 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with bendamustine hydrochloride, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. 5.8 Extravasation Injury Bendamustine hydrochloride extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting bendamustine hydrochloride infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of bendamustine hydrochloride. 5.9 Embryo-fetal Toxicity Bendamustine hydrochloride 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 following serious adverse reactions have been associated with bendamustine hydrochloride in clinical trials and are discussed in greater detail in other sections of the prescribing information. Myelosuppression [see Warnings and Precautions ( 5.1 )] Infections [see Warnings and Precautions ( 5.2 )] Anaphylaxis and Infusion Reactions [see Warnings and Precautions ( 5.3 )] Tumor Lysis Syndrome [see Warnings and Precautions ( 5.4 )] Skin Reactions [see Warnings and Precautions ( 5.5 )] Hepatotoxicity [see Warnings and Precautions ( 5.6 )] Other Malignancies [see Warnings and Precautions ( 5.7 )] Extravasation Injury [see Warnings and Precautions ( 5.8 )] Most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting. ( 6.1 ) Most common non-hematologic adverse reactions for NHL (frequency ≥15%) are nausea, fatigue, vomiting, diarrhea, pyrexia, constipation, anorexia, cough, headache, weight decreased, dyspnea, rash, and stomatitis. ( 6.2 ) Most common hematologic abnormalities (frequency ≥15%) are lymphopenia, anemia, leukopenia, thrombocytopenia, and neutropenia. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Eagle Pharmaceuticals, Inc. at 1-855-318-2170 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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. Chronic Lymphocytic Leukemia The data described below reflect exposure to bendamustine hydrochloride in 153 patients with CLL studied in an active-controlled, randomized trial. The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve. All patients started the study at a dose of 100 mg/m 2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. Non-hematologic adverse reactions (any grade) in the bendamustine hydrochloride 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 bendamustine hydrochloride in the CLL trial and in 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 bendamustine hydrochloride 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 Bendamustine Hydrochloride (N=153) Chlorambucil (N=143) Body System Adverse Reaction 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 bendamustine hydrochloride. Red blood cell transfusions were administered to 20% of patients receiving bendamustine hydrochloride compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride or Chlorambucil in the Randomized CLL Clinical Study Laboratory Abnormality Bendamustine Hydrochloride 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) 110 (78) Platelets Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophil Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the CLL trial, 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 bendamustine hydrochloride may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur. Non-Hodgkin Lymphoma The data described below reflect exposure to bendamustine hydrochloride 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 bendamustine hydrochloride at a dose of 120 mg/m 2 intravenously on Days 1 and 2 for up to eight 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 Bendamustine Hydrochloride by System Organ Class and Preferred Term (N=176) *Patients may have reported more than 1 adverse reaction. Body System Number (%) of patients * Adverse Reaction 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 Weight decreased 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 disorder 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) 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 Bendamustine Hydrochloride in the NHL Studies Hematology Variable Percent of Patients All Grades Grade 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 bendamustine hydrochloride. 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 bendamustine hydrochloride treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of bendamustine hydrochloride. 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. Blood and lymphatic systems disorders: Pancytopenia Cardiovascular disorders: Atrial fibrillation, congestive heart failure (some fatal), myocardial infarction (some fatal), palpitation General disorders and administration site conditions: Injection site reactions (including phlebitis, pruritus, irritation, pain, swelling), infusion site reactions (including phlebitis, pruritus, irritation, pain, swelling) Immune system disorders: Anaphylaxis Infections and infestations: Pneumocystis jiroveci pneumonia Respiratory, thoracic and mediastinal disorders: Pneumonitis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, Toxic epidermal necrolysis, DRESS (Drug reaction with eosinophilia and systemic symptoms). [see Warnings and Precautions ( 5.5 )]

<table ID="table1" width="775" styleCode="Noautorules"> <caption>Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients</caption> <col width="28%" align="left"/> <col width="18%" align="center"/> <col width="18%" align="center"/> <col width="18%" align="center"/> <col width="18%" align="center"/> <tbody> <tr> <td rowspan="2" styleCode="Toprule Botrule Lrule Rrule"/> <td colspan="4" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Number (%) of patients</content> </td> </tr> <tr> <td colspan="2" styleCode="Botrule Lrule Rrule" align="center"> <content styleCode="bold">Bendamustine Hydrochloride (N=153)</content> </td> <td colspan="2" styleCode="Botrule Rrule" align="center"> <content styleCode="bold">Chlorambucil (N=143)</content> </td> </tr> <tr valign="bottom"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Body System Adverse Reaction</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">All Grades</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">Grade 3/4</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">All Grades</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">Grade 3/4</content> </td> </tr> <tr valign="bottom"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Total number of patients with at least 1 adverse reaction</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">121 (79)</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">52 (34)</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">96 (67)</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">25 (17)</content> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Nausea</td> <td styleCode="Botrule Rrule">31 (20)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> <td styleCode="Botrule Rrule">21 (15)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Vomiting</td> <td styleCode="Botrule Rrule">24 (16)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> <td styleCode="Botrule Rrule">9 (6)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Diarrhea</td> <td styleCode="Botrule Rrule">14 (9)</td> <td styleCode="Botrule Rrule">2 (1)</td> <td styleCode="Botrule Rrule">5 (3)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">General disorders and administration site conditions</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Pyrexia</td> <td styleCode="Botrule Rrule">36 (24)</td> <td styleCode="Botrule Rrule">6 (4)</td> <td styleCode="Botrule Rrule">8 (6)</td> <td styleCode="Botrule Rrule">2 (1)</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Fatigue</td> <td styleCode="Botrule Rrule">14 (9)</td> <td styleCode="Botrule Rrule">2 (1)</td> <td styleCode="Botrule Rrule">8 (6)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Asthenia</td> <td styleCode="Botrule Rrule">13 (8)</td> <td styleCode="Botrule Rrule">0</td> <td styleCode="Botrule Rrule">6 (4)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Chills</td> <td styleCode="Botrule Rrule">9 (6)</td> <td styleCode="Botrule Rrule">0</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Immune system disorders</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Hypersensitivity</td> <td styleCode="Botrule Rrule">7 (5)</td> <td styleCode="Botrule Rrule">2 (1)</td> <td styleCode="Botrule Rrule">3 (2)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Infections and infestations</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Nasopharyngitis</td> <td styleCode="Botrule Rrule">10 (7)</td> <td styleCode="Botrule Rrule">0</td> <td styleCode="Botrule Rrule">12 (8)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Infection</td> <td styleCode="Botrule Rrule">9 (6)</td> <td styleCode="Botrule Rrule">3 (2)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Herpes simplex</td> <td styleCode="Botrule Rrule">5 (3)</td> <td styleCode="Botrule Rrule">0</td> <td styleCode="Botrule Rrule">7 (5)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Investigations</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Weight decreased</td> <td styleCode="Botrule Rrule">11 (7)</td> <td styleCode="Botrule Rrule">0</td> <td styleCode="Botrule Rrule">5 (3)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Metabolism and nutrition disorders</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Hyperuricemia</td> <td styleCode="Botrule Rrule">11 (7)</td> <td styleCode="Botrule Rrule">3 (2)</td> <td styleCode="Botrule Rrule">2 (1)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Cough</td> <td styleCode="Botrule Rrule">6 (4)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> <td styleCode="Botrule Rrule">7 (5)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Rash</td> <td styleCode="Botrule Rrule">12 (8)</td> <td styleCode="Botrule Rrule">4 (3)</td> <td styleCode="Botrule Rrule">7 (5)</td> <td styleCode="Botrule Rrule">3 (2)</td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> Pruritus</td> <td styleCode="Botrule Rrule">8 (5)</td> <td styleCode="Botrule Rrule">0</td> <td styleCode="Botrule Rrule">2 (1)</td> <td styleCode="Botrule Rrule">0</td> </tr> </tbody> </table>

<table ID="table2" width="775" styleCode="Noautorules"> <caption>Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received Bendamustine Hydrochloride or Chlorambucil in the Randomized CLL Clinical Study</caption> <col width="20%" align="left"/> <col width="20%" align="center"/> <col width="20%" align="center"/> <col width="20%" align="center"/> <col width="20%" align="center"/> <tbody> <tr> <td rowspan="2" styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Laboratory Abnormality</content> </td> <td colspan="2" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Bendamustine Hydrochloride N=150</content> </td> <td colspan="2" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Chlorambucil N=141</content> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule" align="center"> <content styleCode="bold">All Grades n (%)</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">Grade 3/4 n (%)</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">All Grades n (%)</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">Grade 3/4 n (%)</content> </td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule">Hemoglobin Decreased</td> <td styleCode="Botrule Rrule">134 (89)</td> <td styleCode="Botrule Rrule">20 (13)</td> <td styleCode="Botrule Rrule">115 (82)</td> <td styleCode="Botrule Rrule">12 (9)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule">Platelets Decreased</td> <td styleCode="Botrule Rrule">116 (77)</td> <td styleCode="Botrule Rrule">16 (11)</td> <td styleCode="Botrule Rrule">110 (78)</td> <td styleCode="Botrule Rrule">110 (78)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule">Platelets Decreased</td> <td styleCode="Botrule Rrule">92 (61)</td> <td styleCode="Botrule Rrule">42 (28)</td> <td styleCode="Botrule Rrule">26 (18)</td> <td styleCode="Botrule Rrule">4 (3)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule">Lymphocytes Decreased</td> <td styleCode="Botrule Rrule">102 (68)</td> <td styleCode="Botrule Rrule">70 (47)</td> <td styleCode="Botrule Rrule">27 (19)</td> <td styleCode="Botrule Rrule">6 (4)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule">Neutrophil Decreased</td> <td styleCode="Botrule Rrule">113 (75)</td> <td styleCode="Botrule Rrule">65 (43)</td> <td styleCode="Botrule Rrule">86 (61)</td> <td styleCode="Botrule Rrule">30 (21)</td> </tr> </tbody> </table>

<table ID="table3" width="775" styleCode="Noautorules"> <caption>Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated with Bendamustine Hydrochloride by System Organ Class and Preferred Term (N=176)</caption> <col width="50%" align="left"/> <col width="25%" align="left"/> <col width="25%" align="left"/> <tfoot> <tr> <td colspan="3" align="left"> <content ID="table3_foot1"/> <content styleCode="bold">*Patients may have reported more than 1 adverse reaction. </content> </td> </tr> </tfoot> <tbody> <tr> <td styleCode="Toprule Botrule Lrule Rrule"> <content styleCode="bold">Body System</content> </td> <td colspan="2" styleCode="Toprule Botrule Rrule"> <content styleCode="bold">Number (%) of patients<linkHtml href="#table3_foot1">*</linkHtml> </content> </td> </tr> <tr> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Adverse Reaction</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">All Grades</content> </td> <td styleCode="Botrule Rrule"> <content styleCode="bold">Grade 3/4</content> </td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Total number of patients with at least 1 adverse reaction</content> </td> <td styleCode="Botrule Rrule">176 (100)</td> <td styleCode="Botrule Rrule">94 (53)</td> </tr> <tr valign="top"> <td colspan="3" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Cardiac Disorders</content> </td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Tachycardia</td> <td styleCode="Botrule Rrule">13 (7)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td colspan="3" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Gastrointestinal disorders</content> </td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Nausea</td> <td styleCode="Botrule Rrule">132 (75)</td> <td styleCode="Botrule Rrule">7 (4)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Vomiting</td> <td styleCode="Botrule Rrule">71 (40)</td> <td styleCode="Botrule Rrule">5 (3)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Diarrhea</td> <td styleCode="Botrule Rrule">65 (37)</td> <td styleCode="Botrule Rrule">6 (3)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Constipation</td> <td styleCode="Botrule Rrule">51 (29)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Stomatitis</td> <td styleCode="Botrule Rrule">27 (15)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Abdominal pain</td> <td styleCode="Botrule Rrule">22 (13)</td> <td styleCode="Botrule Rrule">2 (1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Dyspepsia</td> <td styleCode="Botrule Rrule">20 (11)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Gastroesophageal reflux disease</td> <td styleCode="Botrule Rrule">18 (10)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Dry mouth</td> <td styleCode="Botrule Rrule">15 (9)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Abdominal pain upper</td> <td styleCode="Botrule Rrule">8 (5)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Abdominal distension</td> <td styleCode="Botrule Rrule">8 (5)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td colspan="3" styleCode="Botrule Lrule Rrule"> <content styleCode="bold">General disorders and administration site conditions</content> </td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Fatigue</td> <td styleCode="Botrule Rrule">101 (57)</td> <td styleCode="Botrule Rrule">19 (11)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Pyrexia</td> <td styleCode="Botrule Rrule">59 (34)</td> <td styleCode="Botrule Rrule">3 (2)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Chills</td> <td styleCode="Botrule Rrule">24 (14)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Edema peripheral</td> <td styleCode="Botrule Rrule">23 (13)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Asthenia</td> <td styleCode="Botrule Rrule">19 (11)</td> <td styleCode="Botrule Rrule">4 (2)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Chest pain</td> <td styleCode="Botrule Rrule">11 (6)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Infusion site pain</td> <td styleCode="Botrule Rrule">11 (6)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Pain</td> <td styleCode="Botrule Rrule">10 (6)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Catheter site pain</td> <td styleCode="Botrule Rrule">8 (5)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Infections and infestations</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Herpes zoster</td> <td styleCode="Botrule Rrule">18 (10)</td> <td styleCode="Botrule Rrule">5 (3)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Upper respiratory tract infection</td> <td styleCode="Botrule Rrule">18 (10)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Urinary tract infection</td> <td styleCode="Botrule Rrule">17 (10)</td> <td styleCode="Botrule Rrule">4 (2)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Sinusitis</td> <td styleCode="Botrule Rrule">15 (9)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Pneumonia</td> <td styleCode="Botrule Rrule">14 (8)</td> <td styleCode="Botrule Rrule">9 (5)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Febrile neutropenia</td> <td styleCode="Botrule Rrule">11 (6)</td> <td styleCode="Botrule Rrule">11 (6)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Oral candidiasis</td> <td styleCode="Botrule Rrule">11 (6)</td> <td styleCode="Botrule Rrule">2 (1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Nasopharyngitis</td> <td styleCode="Botrule Rrule">11 (6)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Investigations</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Weight decreased</td> <td styleCode="Botrule Rrule">Weight decreased</td> <td styleCode="Botrule Rrule">3 (2)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Metabolism and nutrition disorders</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Anorexia</td> <td styleCode="Botrule Rrule">40 (23)</td> <td styleCode="Botrule Rrule">3 (2)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Dehydration</td> <td styleCode="Botrule Rrule">24 (14)</td> <td styleCode="Botrule Rrule">8 (5)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Decreased appetite</td> <td styleCode="Botrule Rrule">22 (13)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Hypokalemia</td> <td styleCode="Botrule Rrule">15 (9)</td> <td styleCode="Botrule Rrule">9 (5)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Musculoskeletal and connective tissue disorders</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Back pain</td> <td styleCode="Botrule Rrule">25 (14)</td> <td styleCode="Botrule Rrule">5 (3)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Arthralgia</td> <td styleCode="Botrule Rrule">11 (6)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Pain in extremity</td> <td styleCode="Botrule Rrule">8 (5)</td> <td styleCode="Botrule Rrule">2 (1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Bone pain</td> <td styleCode="Botrule Rrule">8 (5)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Nervous system disorders</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Headache</td> <td styleCode="Botrule Rrule">36 (21)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Dizziness</td> <td styleCode="Botrule Rrule">25 (14)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Dysgeusia</td> <td styleCode="Botrule Rrule">13 (7)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Psychiatric disorder</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Insomnia</td> <td styleCode="Botrule Rrule">23 (13)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Anxiety</td> <td styleCode="Botrule Rrule">14 (8)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Depression</td> <td styleCode="Botrule Rrule">10 (6)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Respiratory, thoracic and mediastinal disorders</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Cough</td> <td styleCode="Botrule Rrule">38 (22)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Dyspnea</td> <td styleCode="Botrule Rrule">28 (16)</td> <td styleCode="Botrule Rrule">3 (2)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Pharyngolaryngeal pain</td> <td styleCode="Botrule Rrule">14 (8)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Wheezing</td> <td styleCode="Botrule Rrule">8 (5)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Nasal congestion</td> <td styleCode="Botrule Rrule">8 (5)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Skin and subcutaneous tissue disorders</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Rash</td> <td styleCode="Botrule Rrule">28 (16)</td> <td styleCode="Botrule Rrule">1 (&lt;1)</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Pruritus</td> <td styleCode="Botrule Rrule">11 (6)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Dry skin</td> <td styleCode="Botrule Rrule">9 (5)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Night sweats</td> <td styleCode="Botrule Rrule">9 (5)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Hyperhidrosis</td> <td styleCode="Botrule Rrule">8 (5)</td> <td styleCode="Botrule Rrule">0</td> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> <content styleCode="bold">Vascular disorders</content> </td> <td styleCode="Botrule Rrule"/> <td styleCode="Botrule Rrule"/> </tr> <tr valign="top"> <td styleCode="Botrule Lrule Rrule"> Hypotension</td> <td styleCode="Botrule Rrule">10 (6)</td> <td styleCode="Botrule Rrule">2 (1)</td> </tr> </tbody> </table>