FDA label 08c0da18-b3bb-4d78-9d74-00e947f39135

WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Hepatitis B Virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA ® , in some cases resulting in fulminant hepatitis, hepatic failure, and death [see Warnings and Precautions (5.2)] . Progressive Multifocal Leukoencephalopathy (PML) resulting in death can occur in patients receiving CD20-directed cytolytic antibodies, including ARZERRA [see Warnings and Precautions (5.4)] . WARNING: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY See full prescribing information for complete boxed warning. Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death. ( 5.2 ) Progressive Multifocal Leukoencephalopathy (PML) resulting in death. ( 5.4 )

5 WARNINGS AND PRECAUTIONS Infusion Reactions: Pre-medicate with corticosteroid, acetaminophen, and an antihistamine. Monitor patients during infusions. Interrupt infusion if infusion reactions occur. ( 2.3 , 2.4 , 5.1 ) Tumor Lysis Syndrome: Anticipate TLS in high-risk patients; pre-medicate with anti-hyperuricemics and hydration. ( 5.5 ) Cytopenias: Neutropenia, anemia, and thrombocytopenia occur. Late-onset and prolonged neutropenia can also occur. Monitor complete blood counts at regular intervals. ( 5.6 ) 5.1 Infusion Reactions ARZERRA can cause serious, including fatal, infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac events (e.g., myocardial ischemia/infarction, acute coronary syndrome, arrhythmia, bradycardia), back pain, abdominal pain, pyrexia, rash, urticaria, angioedema, cytokine release syndrome, and anaphylactoid/anaphylactic reactions. Infusion reactions occur more frequently with the first 2 infusions. These reactions may result in temporary interruption or withdrawal of treatment [see Adverse Reactions (6.1)] . Pre-medicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4)] . Infusion reactions may occur despite premedication. Interrupt infusion with ARZERRA for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3)] . If an anaphylactic reaction occurs, immediately and permanently discontinue ARZERRA and initiate appropriate medical treatment. 5.2 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients treated with ARZERRA. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with ARZERRA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with ARZERRA. HBV reactivation has been reported for at least 12 months following completion of therapy. In patients who develop reactivation of HBV while receiving ARZERRA, immediately discontinue ARZERRA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of ARZERRA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming ARZERRA in patients who develop HBV reactivation. 5.3 Hepatitis B Virus Infection Fatal infection due to hepatitis B in patients who have not been previously infected has been observed with ARZERRA. Monitor patients for clinical and laboratory signs of hepatitis. 5.4 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) resulting in death has occurred with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. If PML is suspected, discontinue ARZERRA and initiate evaluation for PML including neurology consultation. 5.5 Tumor Lysis Syndrome Tumor lysis syndrome (TLS), including the need for hospitalization, has occurred in patients treated with ARZERRA. Patients with high tumor burden and/or high circulating lymphocyte counts (>25 x 10 9 /L) are at greater risk for developing TLS. Consider tumor lysis prophylaxis with anti-hyperuricemics and hydration beginning 12 to 24 hours prior to infusion of ARZERRA. For treatment of TLS, administer aggressive intravenous hydration and anti-hyperuricemic agents, correct electrolyte abnormalities, and monitor renal function. 5.6 Cytopenias Severe cytopenias, including neutropenia, thrombocytopenia, and anemia, can occur with ARZERRA. Pancytopenia, agranulocytosis, and fatal neutropenic sepsis have occurred in patients who received ARZERRA in combination with chlorambucil. Grade 3 or 4 late-onset neutropenia (onset at least 42 days after last treatment dose) and/or prolonged neutropenia (not resolved between 24 and 42 days after last treatment dose) were reported in patients who received ARZERRA [see Adverse Reactions (6.1)]. Monitor complete blood counts at regular intervals during and after conclusion of therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. 5.7 Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Infusion Reactions [see Warnings and Precautions (5.1)] Hepatitis B Virus Reactivation [see Warnings and Precautions (5.2)] Hepatitis B Virus Infection [see Warnings and Precautions (5.3)] Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.4)] Tumor Lysis Syndrome [see Warnings and Precautions (5.5)] Cytopenias [see Warnings and Precautions (5.6)] Previously Untreated CLL: Common adverse reactions (≥10%) were infusion reactions and neutropenia. ( 6 ) Relapsed CLL: Common adverse reactions (>10%) were infusion reactions, neutropenia, leukopenia and febrile neutropenia. ( 6 ) Extended Treatment in CLL: Common adverse reactions (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection. ( 6 ) Refractory CLL: Common adverse reactions (≥10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Previously Untreated CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 1) in 444 patients with previously untreated CLL. Patients were randomized to receive either ARZERRA as an intravenous infusion every 28 days in combination with chlorambucil (n = 217) or chlorambucil as a single agent (n = 227). In both arms, patients received chlorambucil 10 mg/m 2 orally on Days 1 to 7 every 28 days. The infusion schedule for ARZERRA was 300 mg administered on Cycle 1 Day 1, 1,000 mg administered on Cycle 1 Day 8, and 1,000 mg administered on Day 1 of subsequent 28-day cycles. The median number of cycles of ARZERRA completed was 6. The most common adverse reactions (≥10%) were infusion reactions and neutropenia (Table 4). The data described in Table 4 include relevant adverse reactions occurring up to 60 days after the last dose of study medication; Table 5 includes relevant hematologic laboratory abnormalities. Table 4. Adverse Reactions with ≥5% Incidence in Patients Receiving ARZERRA plus Chlorambucil and Also ≥2% More than Patients Receiving Chlorambucil a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria. b Includes oral herpes, herpes, herpes virus infection, genital herpes, and herpes simplex. Adverse Reactions ARZERRA plus Chlorambucil (N = 217) Chlorambucil (N = 227) All Grades % Grade ≥3 % All Grades % Grade ≥3 % Infusion reactions a 67 10 0 0 Neutropenia 27 26 18 14 Asthenia 8 <1 5 0 Headache 7 <1 3 0 Leukopenia 6 3 2 <1 Herpes simplex b 6 0 4 <1 Lower respiratory tract infection 5 1 3 <1 Arthralgia 5 <1 3 0 Upper abdominal pain 5 0 3 0 Table 5. Post-baseline Hematologic Laboratory Abnormalities Occurring with ≥5% Incidence in Patients Receiving ARZERRA plus Chlorambucil and Also ≥2% More than Patients Receiving Chlorambucil Investigations ARZERRA plus Chlorambucil (N = 217) Chlorambucil (N = 227) All Grades % Grade ≥3 % All Grades % Grade ≥3 % Leukopenia 67 23 28 4 Neutropenia 66 29 56 24 Lymphopenia 52 29 20 7 Infusion Reactions: Overall, 67% of patients who received ARZERRA in combination with chlorambucil experienced one or more symptoms of infusion reactions (10% were Grade 3 or greater; none were fatal). Infusion reactions occurred most frequently during Cycle 1 (56% on Day 1 [6% were Grade 3 or greater] and 23% on Day 8 [3% were Grade 3 or greater]) and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients. Serious adverse events of infusion reactions occurred in 2% of patients. Neutropenia: Overall, 3% of patients had neutropenia as a serious adverse event, reported up to 60 days after the last dose. One patient died with neutropenic sepsis and agranulocytosis. Prolonged neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 4% of patients receiving chlorambucil. Late-onset neutropenia occurred in 6% of patients receiving ARZERRA in combination with chlorambucil compared with 1% of patients receiving chlorambucil alone. Relapsed CLL: The safety of ARZERRA in combination with fludarabine and cyclophosphamide compared with fludarabine and cyclophosphamide was evaluated in a randomized, open-label, parallel-arm, multicenter trial (Study 2) in 359 patients with relapsed CLL. Patients were randomized to receive ARZERRA as an intravenous infusion (Cycle 1: 300 mg on Day 1 and 1,000 mg on Day 8; followed by 1,000 mg on Day 1 of subsequent 28-day cycles for a maximum of 6 cycles). Standard fludarabine and cyclophosphamide therapy was administered as a 3-day course starting on the first day of each cycle, with initial dosages of 25 mg/m 2 for fludarabine and 250 mg/m 2 for cyclophosphamide. Table 6 includes adverse reactions occurring up to 60 days after the last dose of study medication. The most common adverse reactions (≥10%) were infusion reactions, neutropenia, leukopenia and febrile neutropenia (Table 6). Table 6. Adverse Reactions with ≥5% Incidence in Patients Receiving ARZERRA plus FC and Also ≥2% More than in Patients in Fludarabine and Cyclophosphamide Arm a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria. Adverse Reactions ARZERRA plus Fludarabine and Cyclophosphamide (N = 181) Fludarabine and Cyclophosphamide Arm (N = 178) All Grades % Grade >3 % All Grades % Grade >3 % Infusion reactions a 60 9 28 3 Neutropenia 55 49 39 36 Leukopenia 15 12 6 3 Febrile neutropenia 10 10 8 8 Bronchitis 6 1 4 <1 Adverse reactions associated with decreased platelet counts (including but not limited to thrombocytopenia, platelet count decreased and pancytopenia) and decreased hemoglobin (including but not limited to anemia, hemoglobin decreased and pancytopenia) occurred less frequently in the ARZERRA plus fludarabine and cyclophosphamide arm than in the fludarabine and cyclophosphamide arm up to 60 days after the last dose of study treatment: 30% (all grades) and 15% (Grade ≥3) vs 38% (all grades) and 28% (Grade ≥3), respectively for decreased platelet counts; and 23% (all grades) and 10% (Grade ≥3) vs 33% (all grades) and 16% (Grade ≥3), respectively for decreased hemoglobin. Infusion Reactions : On Day 1 of infusion, infusion reactions occurred in 49% (7% were >Grade 3) of patients treated with ARZERRA plus fludarabine and cyclophosphamide, compared to 16% (1% were >Grade 3) of patients treated with fludarabine and cyclophosphamide and decreased with subsequent infusions. Infusion reactions led to discontinuation of treatment in 3% of patients in the ARZERRA plus fludarabine and cyclophosphamide. Serious adverse events of infusion reactions occurred in 2% of patients in the ARZERRA plus fludarabine and cyclophosphamide compared to <1% of patients treated with fludarabine and cyclophosphamide. Neutropenia : The proportion of patients that had Grade 3 or greater neutropenia reported up to 60 days after the last dose of study medication was higher in patients treated with ARZERRA plus fludarabine and cyclophosphamide (51%) compared to the fludarabine and cyclophosphamide arm (37%). Grade 3 or greater neutropenic sepsis occurred in 2 patients (1%) treated with ARZERRA plus fludarabine and cyclophosphamide vs. 3 patients (2%) in the fludarabine and cyclophosphamide arm. Prolonged neutropenia occurred in 18 patients (10%) treated with ARZERRA plus fludarabine and cyclophosphamide vs. 20 patients (11%) in the fludarabine and cyclophosphamide arm. Late-onset neutropenia occurred in 13 patients (7%) treated with ARZERRA plus fludarabine and cyclophosphamide vs. 5 patients (3%) in the fludarabine and cyclophosphamide arm. During the period between the first dose and 60 days after last dose there were five (3%) patients who died in the ARZERRA plus fludarabine and cyclophosphamide arm and ten (6%) patients who died in the fludarabine and cyclophosphamide arm. Extended Treatment in CLL: The safety of ARZERRA was evaluated in an open-label, parallel-arm, randomized trial (Study 3) in 474 patients who had responded to therapy for their recurrent or progressive disease. Patients were randomized to receive ARZERRA as an intravenous infusion every 8 weeks or observation. The infusion schedule for ARZERRA was 300 mg on Day 1 followed 1 week later by 1,000 mg on Day 8 followed 7 weeks later by 1,000 mg and every 8 weeks thereafter for up to a maximum of 2 years. The data described in Table 7 include relevant adverse reactions occurring up to 60 days after the last dose of study medication (last visit for observation arm). The most common adverse reactions (≥10%) were infusion reactions, neutropenia, and upper respiratory tract infection (Table 7). Table 7. Adverse Reactions with ≥5% Incidence in Patients Receiving ARZERRA and Also ≥2% More than in Patients in Observation Arm a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria. ARZERRA (N = 237) Observation Arm (N = 237) Adverse Reactions All Grades % Grade ≥3 % All Grades % Grade ≥3 % Infusion reactions a 46 4 - - Neutropenia 24 22 9 8 Upper respiratory tract infection 19 1 9 0 Bronchitis 9 <1 7 <1 Pneumonia 8 5 5 3 Influenza 6 0 3 0 Herpes zoster 5 <1 3 <1 Insomnia 5 <1 2 0 Back pain 5 0 3 0 Hypogammaglobulinemia 5 <1 <1 <1 Infusion Reactions: Infusion reactions occurred in 25% of patients on the day of Infusion 1 (300 mg) and decreased with subsequent infusions (between 2% to 10%). Infections: A total of 154 patients (65%) treated with ARZERRA compared with 120 patients (51%) in the observation arm experienced bacterial, viral, or fungal infections. The incidence of serious infections, however, was similar for patients treated with ARZERRA (20%) and the observation arm (18%). The proportions of fatal infections in patients treated with ARZERRA and in the observation arm were 2% and 3% respectively. Neutropenia: The proportion of patients that had Grade 3 or greater neutropenia reported up to 60 days after the last dose of study medication was higher in patients treated with ARZERRA (22%) compared with the observation arm (8%). There were no cases of neutropenic sepsis reported with ARZERRA. Prolonged neutropenia occurred in 13 patients (5%) treated with ARZERRA and in 5 patients (2%) in the observation arm. Late-onset neutropenia occurred in 2 patients (<1%) treated with ARZERRA and 1 patient (<1%) in the observation arm. During the period between the first dose and 60 days after last dose there were two (1%) patients in the ofatumumab group who died due to adverse events and five (2%) patients in the observation group. Refractory CLL: The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 4 [n = 154]) or 3 doses (Study 5 [n = 27]). The data described in Table 8 and other sections below are derived from 154 patients in Study 4. All patients received 2,000 mg weekly from the second dose onward. Ninety percent (90%) of patients received at least 8 infusions of ARZERRA and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were white. In refractory CLL, the most common adverse reactions (≥10%) were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections (Table 8). The most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation. Table 8. Incidence of All Adverse Reactions Occurring in ≥5% of Patients and in the Fludarabine- and Alemtuzumab-refractory Subset a Includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia. b Includes rash, rash macular, and rash vesicular. c Includes sepsis, neutropenic sepsis, bacteremia, and septic shock. Adverse Reaction Total Population (N = 154) Fludarabine‑ and Alemtuzumab‑refractory (N = 59) All Grades % Grade ≥3 % All Grades % Grade ≥3 % Pneumonia a 23 14 25 15 Pyrexia 20 3 25 5 Cough 19 0 19 0 Diarrhea 18 0 19 0 Anemia 16 5 17 8 Fatigue 15 0 15 0 Dyspnea 14 2 19 5 Rash b 14 <1 17 2 Bronchitis 11 <1 19 2 Nausea 11 0 12 0 Upper respiratory tract infection 11 0 3 0 Edema peripheral 9 <1 8 2 Back pain 8 1 12 2 Chills 8 0 10 0 Nasopharyngitis 8 0 8 0 Sepsis c 8 8 10 10 Urticaria 8 0 5 0 Insomnia 7 0 10 0 Headache 6 0 7 0 Herpes zoster 6 1 7 2 Hyperhidrosis 5 0 5 0 Hypertension 5 0 8 0 Hypotension 5 0 3 0 Muscle spasms 5 0 3 0 Sinusitis 5 2 3 2 Tachycardia 5 <1 7 2 Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Infections : A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced Grade 3 or greater infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine‑ and alemtuzumab‑refractory group was 17%. Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed Grade 3 or greater neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from more than 926 patients with CLL were tested during and after treatment for antibodies to ARZERRA. Formation of anti-ofatumumab antibodies was observed in less than 1% of patients with CLL after treatment with ofatumumab. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ARZERRA. 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. Infusion-related Cardiac Events Cardiac arrest Mucocutaneous Reactions Stevens-Johnson syndrome, porphyria cutanea tarda

<table><caption>Table 4. Adverse Reactions with &#x2265;5% Incidence in Patients Receiving ARZERRA plus Chlorambucil and Also &#x2265;2% More than Patients Receiving Chlorambucil</caption><col width="36%"/><col width="16%"/><col width="16%"/><col width="16%"/><col width="16%"/><tfoot><tr><td colspan="5">^a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria. ^b Includes oral herpes, herpes, herpes virus infection, genital herpes, and herpes simplex. </td></tr></tfoot><tbody><tr><td align="center" rowspan="2" styleCode="Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td align="center" colspan="2" styleCode="Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">ARZERRA plus Chlorambucil</content></paragraph><paragraph><content styleCode="bold">(N = 217)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Chlorambucil</content></paragraph><paragraph><content styleCode="bold">(N = 227)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Grade &#x2265;3</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Grade &#x2265;3</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Infusion reactions^a</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>67</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>27</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>18</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14</paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Asthenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>&lt;1</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>&lt;1</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>&lt;1</paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Herpes simplex^b</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>&lt;1</paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Lower respiratory tract infection</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>&lt;1</paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Arthralgia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>&lt;1</paragraph></td><td align="center" styleCode="Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph>Upper abdominal pain</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Botrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>

<table><caption>Table 5. Post-baseline Hematologic Laboratory Abnormalities Occurring with &#x2265;5% Incidence in Patients Receiving ARZERRA plus Chlorambucil and Also &#x2265;2% More than Patients Receiving Chlorambucil</caption><col width="36%"/><col width="16%"/><col width="16%"/><col width="16%"/><col width="16%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Investigations</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">ARZERRA plus Chlorambucil</content></paragraph><paragraph><content styleCode="bold">(N = 217)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Chlorambucil</content></paragraph><paragraph><content styleCode="bold">(N = 227)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Grade &#x2265;3</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Grade &#x2265;3</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Leukopenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>67</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>23</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>66</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>29</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>56</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>24</paragraph></td></tr><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph>Lymphopenia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>52</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>29</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>20</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>7</paragraph></td></tr></tbody></table>

<table><caption>Table 6. Adverse Reactions with &#x2265;5% Incidence in Patients Receiving ARZERRA plus FC and Also &#x2265;2% More than in Patients in Fludarabine and Cyclophosphamide Arm</caption><col width="36%"/><col width="16%"/><col width="16%"/><col width="16%"/><col width="16%"/><tfoot><tr><td colspan="5">^a Includes events which occurred on the day of an infusion or within 24 hours of the end of an infusion and resulted in an interruption or discontinuation of treatment. Infusion reactions may include, but are not limited to, chills, dyspnea, flushing, hypotension, nausea, pain, pruritus, pyrexia, rash, and urticaria.</td></tr></tfoot><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">ARZERRA plus Fludarabine and Cyclophosphamide</content></paragraph><paragraph><content styleCode="bold">(N = 181)</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Fludarabine and Cyclophosphamide Arm</content></paragraph><paragraph><content styleCode="bold">(N = 178)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Grade &gt;3</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">All Grades</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="bottom"><paragraph><content styleCode="bold">Grade &gt;3</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Infusion reactions^a</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>60</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>Neutropenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>55</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>49</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>39</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>36</paragraph></td></tr><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph>Leukopenia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>15</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph>Febrile neutropenia</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>10</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph>Bronchitis</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>&lt;1</paragraph></td></tr></tbody></table>