Rituximab and Hyaluronidase for Lymphoma

INDICATIONS AND USAGE RITUXAN HYCELA is a combination of rituximab, a CD20-directed cytolytic antibody, and hyaluronidase human, an endoglycosidase, indicated for the treatment of adult patients with: Follicular Lymphoma (FL) ( 1.1 ) Relapsed or refractory, follicular lymphoma as a single agent Previously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy Non-progressing (including stable disease), follicular lymphoma as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy Diffuse Large B-cell Lymphoma (DLBCL) ( 1.2 ) Previously untreated diffuse large B-cell lymphoma in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens Chronic Lymphocytic Leukemia (CLL) ( 1.3 ) Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC) Limitations of Use: Initiate treatment with RITUXAN HYCELA only after patients have received at least one full dose of a rituximab product by intravenous infusion. ( 1.4 , 2.1 , 5.4 ). RITUXAN HYCELA is not indicated for the treatment of non-malignant conditions. ( 1.4 ) 1.1 Follicular Lymphoma (FL) RITUXAN HYCELA is indicated for the treatment of adult patients with: Relapsed or refractory, follicular lymphoma as a single agent. Previously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy. Non-progressing (including stable disease), follicular lymphoma as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. 1.2 Diffuse Large B-Cell Lymphoma (DLBCL) RITUXAN HYCELA is indicated for the treatment of adult patients with previously untreated diffuse large B-cell lymphoma in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens. 1.3 Chronic Lymphocytic Leukemia (CLL) RITUXAN HYCELA is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of adult patients with previously untreated and previously treated CLL. 1.4 Limitations of Use Initiate treatment with RITUXAN HYCELA only after patients have received at least one full dose of a rituximab product by intravenous infusion [see Dosage and Administration (2.1) and Warnings and Precautions (5.4) ]. RITUXAN HYCELA is not indicated for the treatment of non-malignant conditions.

DOSAGE AND ADMINISTRATION For subcutaneous use only ( 2.1 ) All patients must receive at least one full dose of a rituximab product by intravenous infusion before receiving RITUXAN HYCELA by subcutaneous injection ( 2.1 ). FL/DLBCL: Administer 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously according to recommended schedule ( 2.2 , 2.3 ). CLL: Administer 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human) subcutaneously according to recommended schedule ( 2.4 ). Premedicate with acetaminophen and antihistamine before each dose; in addition, consider premedication with glucocorticoids ( 2.5 , 5.4 ) Administer specified volume into subcutaneous tissue of abdomen: ( 2.6 ) 11.7 mL from 1,400 mg/23,400 Units vial over approximately 5 minutes. 13.4 mL from 1,600 mg/26,800 Units vial over approximately 7 minutes. Observe 15 minutes following administration 2.1 Important Dosing Information RITUXAN HYCELA is for subcutaneous use only. RITUXAN HYCELA should only be administered by a healthcare professional with appropriate medical support to manage severe reactions that can be fatal if they occur. All patients must first receive at least one full dose of a rituximab product by intravenous infusion without experiencing severe adverse reactions before starting treatment with RITUXAN HYCELA. If patients are not able to receive one full dose by intravenous infusion, they should continue subsequent cycles with a rituximab product by intravenous infusion and not switch to RITUXAN HYCELA until a full intravenous dose is successfully administered [see Warnings and Precautions (5.4) ]. Refer to the prescribing information for a rituximab product for intravenous infusion for additional information. Premedicate before each dose of RITUXAN HYCELA [see Dosage and Administration (2.5) ] . Dose reductions of RITUXAN HYCELA are not recommended. When RITUXAN HYCELA is given in combination with chemotherapy dose, reduce the chemotherapeutic drugs to manage adverse reactions. 2.2 Recommended Dosage for Follicular Lymphoma (FL) All patients must receive at least one full dose of a rituximab product by intravenous infusion before starting treatment with RITUXAN HYCELA [see Dosage and Administration (2.1) and Warnings and Precautions (5.4) ]. Premedicate before each dose [see Dosage and Administration (2.5) ]. The recommended dose is RITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously at a fixed dose irrespective of patient's body surface area according to the following schedules: Relapsed or Refractory, Follicular Lymphoma Administer once weekly for 3 or 7 weeks following a full dose of a rituximab product by intravenous infusion at week 1 (i.e., 4 or 8 weeks in total). Retreatment for Relapsed or Refractory, Follicular Lymphoma Administer once weekly for 3 weeks following a full dose of a rituximab product by intravenous infusion at week 1 (i.e., 4 weeks in total). Previously Untreated, Follicular Lymphoma Administer on Day 1 of Cycles 2–8 of chemotherapy (every 21 days), for up to 7 cycles following a full dose of a rituximab product by intravenous infusion on Day 1 of Cycle 1 of chemotherapy (i.e., up to 8 cycles in total). In patients with complete or partial response, initiate RITUXAN HYCELA maintenance treatment 8 weeks following completion of RITUXAN HYCELA in combination with chemotherapy. Administer RITUXAN HYCELA as a single-agent every 8 weeks for 12 doses. Non-progressing, Follicular Lymphoma after first line CVP chemotherapy Following completion of 6–8 cycles of CVP chemotherapy and a full dose of a rituximab product by intravenous infusion at week 1, administer once weekly for 3 weeks (i.e., 4 weeks in total) at 6 month intervals to a maximum of 16 doses. 2.3 Recommended Dosage for Diffuse Large B-Cell Lymphoma (DLBCL) All patients must receive at least one full dose of a rituximab product by intravenous infusion in combination with CHOP chemotherapy before starting treatment with RITUXAN HYCELA [see Dosage and Administration (2.1) and Warnings and Precautions (5.4) ]. Premedicate before each dose [see Dosage and Administration (2.5) ]. The recommended dose for DLBCL is RITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) at a fixed dose irrespective of patient's body surface area in combination with CHOP chemotherapy. Administer RITUXAN HYCELA 1,400 mg/23,400 Units on Day 1 of Cycles 2–8 of CHOP chemotherapy for up to 7 cycles following a full dose of a rituximab product by intravenous infusion at Day 1, Cycle 1 of CHOP chemotherapy (i.e., up to 6–8 cycles in total). 2.4 Recommended Dosage for Chronic Lymphocytic Leukemia (CLL) All patients must receive at least one full dose of a rituximab product by intravenous infusion in combination with FC chemotherapy before starting treatment with RITUXAN HYCELA [see Dosage and Administration (2.1) and Warnings and Precautions (5.4) ]. Premedicate before each dose [see Dosage and Administration (2.5) ]. The recommended dose for CLL is RITUXAN HYCELA 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human) in combination with FC chemotherapy, at a fixed dose, irrespective of patient's body surface area. Administer RITUXAN HYCELA 1,600 mg/26,800 Units on Day 1 of Cycles 2–6 (every 28 days) for a total of 5 cycles following a full intravenous dose at Day 1, Cycle 1 (i.e., 6 cycles in total). 2.5 Recommended Premedication and Prophylactic Medications Premedicate with acetaminophen and an antihistamine before each dose of RITUXAN HYCELA. Premedication with a glucocorticoid should also be considered [see Dosage and Administration (2.2 , 2.3 , 2.4) ] . Provide prophylaxis for Pneumocystis jiroveci pneumonia (PCP) and herpes virus infections for patients with CLL during treatment and for up to 12 months following treatment as appropriate [see Warnings and Precautions (5.6) ]. 2.6 Preparation and Administration To prevent medication errors, check the vial labels to ensure that the drug being prepared and administered is RITUXAN HYCELA for subcutaneous use. Do not administer RITUXAN HYCELA intravenously . RITUXAN HYCELA is ready to use. Preparation Use a sterile needle and syringe to prepare RITUXAN HYCELA. RITUXAN HYCELA is compatible with polypropylene and polycarbonate syringe material and stainless steel transfer and injection needles. Using a 20 mL syringe, withdraw the required volume from the vial with a narrow (e.g., 25–30 gauge) needle of any length. Label the syringe with the provided peel-off label. Change the needle to a 1/2" to 5/8" long, narrow gauge needle (e.g., 25–30 gauge) immediately prior to subcutaneous administration to avoid needle clogging. Visually inspect for particulate matter and discoloration prior to administration. RITUXAN HYCELA should be a clear to opalescent and colorless to yellowish liquid. Do not use if particulates or discoloration is present. Administration Inject RITUXAN HYCELA into the subcutaneous tissue of the abdomen over approximately 5–7 minutes. Never inject into areas where the skin is red, bruised, tender or hard, or areas where there are moles or scars. No data are available on performing the injection at other sites of the body. Inject 11.7 mL of RITUXAN HYCELA 1,400 mg/23,400 Units vial (1,400 mg rituximab and 23,400 Units hyaluronidase human) subcutaneously into the abdomen over approximately 5 minutes. Inject 13.4 mL of RITUXAN HYCELA 1,600 mg/26,800 Units vial (1,600 mg rituximab and 26,800 Units hyaluronidase human) subcutaneously into the abdomen over approximately 7 minutes. If administration of RITUXAN HYCELA is interrupted, continue administering at the same site, or at a different site, but restricted to the abdomen. Observe patients for at least 15 minutes following RITUXAN HYCELA administration [see Warnings and Precautions (5.4) ]. During treatment with RITUXAN HYCELA, do not

WARNINGS AND PRECAUTIONS Hypersensitivity and other administration reactions: Local cutaneous reactions may occur more than 24 hours after administration. Interrupt injection if severe reaction develops. Premedicate before injection. ( 5.4 ) Tumor lysis syndrome: Administer aggressive intravenous hydration, anti hyperuricemic agents, monitor renal function. ( 5.5 ) Infections: Withhold and institute appropriate anti-infective therapy. ( 5.6 ) Cardiac adverse reactions: Discontinue in case of serious or life-threatening events. ( 5.7 ) Renal toxicity: Discontinue in patients with rising serum creatinine or oliguria. ( 5.8 ) Bowel obstruction and perforation: Consider and evaluate for abdominal pain, vomiting, or related symptoms. ( 5.9 ) Immunizations: Live virus vaccinations prior to or during treatment not recommended. ( 5.10 ) Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception. ( 5.11 ) 5.1 Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab-containing products, including RITUXAN HYCELA. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. Discontinue RITUXAN HYCELA in patients who experience a severe mucocutaneous reaction. The safety of re-administration of a rituximab-containing product, including RITUXAN HYCELA, to patients with severe mucocutaneous reactions has not been determined . 5.2 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab-containing products. HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels 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. In severe cases increase in bilirubin levels, liver failure, and death can occur. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with a rituximab-containing product. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during treatment with a rituximab-containing product. 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 RITUXAN HYCELA. HBV reactivation has been reported up to 24 months following completion of therapy containing rituximab. In patients who develop reactivation of HBV while on RITUXAN HYCELA, immediately discontinue treatment and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming RITUXAN HYCELA treatment in patients who develop HBV reactivation. Resumption of RITUXAN HYCELA treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV. 5.3 Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death has been observed in patients receiving rituximab-containing products, including RITUXAN HYCELA. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue RITUXAN HYCELA and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML [see Adverse Reactions (6.1) ] . 5.4 Hypersensitivity and other Administration Reactions Systemic Reactions Patients must receive at least one full dose of a rituximab product by intravenous infusion before receiving RITUXAN HYCELA due to the higher risk of hypersensitivity and other acute reactions during the first infusion [see Dosage and Administration (2.1) ]. Beginning therapy with a rituximab product by intravenous infusion allows management of hypersensitivity and other administration reactions by slowing or stopping the intravenous infusion. Rituximab-containing products, including RITUXAN HYCELA, are associated with hypersensitivity and other administration reactions, which may be related to release of cytokines and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable from acute hypersensitivity reactions. This set of reactions which includes syndrome of cytokine release, tumor lysis syndrome and anaphylactic and hypersensitivity reactions are described below. They are not specifically related to the route of administration of a rituximab-containing product. Severe infusion-related reactions with fatal outcome have been reported with the use of intravenous formulations of rituximab products, with an onset ranging within 30 minutes to 2 hours after starting the first intravenous infusion. They were characterized by pulmonary events in addition to fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms. Anaphylactic and other hypersensitivity reactions can also occur. In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within minutes after starting infusion. Severe cytokine release syndrome is characterized by severe dyspnea, often associated by bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This syndrome may be associated with acute respiratory failure and death [see Warnings and Precautions (5.5) ] . Cytokine release syndrome may occur within 1–2 hours of initiating the infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumor infiltration may be at a greater risk of poor outcome. Rituximab product administration should be interrupted immediately and aggressive symptomatic treatment initiated. During RITUXAN HYCELA administration, the injection should be interrupted immediately when observing signs of a severe reaction and aggressive symptomatic treatment should be initiated. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥ 25,000/mm 3 ) [see Warnings and Precautions (5.5 , 5.7) ]. Premedicate patients with an antihistamine and acetaminophen prior to each administration of RITUXAN HYCELA [see Dosage and Administration (2.5) ]. Premedication with glucocorticoids should also be considered. Observe patients for at least 15 minutes following RITUXAN HYCELA. A longer period may be appropriate in patients with an increased risk of hypersensitivity reactions. Local Cutaneous Reactions Local cutaneous reactions, including injection site reactions, have been reported in patients receiving RITUXAN HYCELA. Symptoms included pain, swelling, induration, hemorrhage, erythema, pruritus, and rash [see Adverse Reactions (6.1) ] . Some local cutaneous reactions occurred more than 24 hours after RITUXAN HYCELA administration. The incidence of local cutaneous reactions following administration of RITUXAN HYCELA was 16%. Reactions were mild or moderate and resolved without any specific treatment. Local cutaneous reactions of any Grade were most common during the first RITUXAN HYCELA cycle (Cycle 2; 5%) with the incidence decreasing with subsequent injections. 5.5 Tumor Lysis Syndrome (TLS) TLS can occur within 12–24 hours after adm

Renal toxicity when used in combination with cisplatin. ( 5.8 )

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Mucocutaneous reactions [see Warnings and Precautions (5.1) ] Hepatitis B reactivation including fulminant hepatitis [see Warnings and Precautions (5.2) ] Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.3) ] Hypersensitivity and other administration reactions [see Warnings and Precautions (5.4) ] Tumor lysis syndrome [see Warnings and Precautions (5.5) ] Infections [see Warnings and Precautions (5.6) ] Cardiac arrhythmias [see Warnings and Precautions (5.7) ] Renal toxicity [see Warnings and Precautions (5.8) ] Bowel obstruction and perforation [see Warnings and Precautions (5.9) ] Most common adverse reactions (incidence of ≥ 20%) are: ( 6.1 ) FL: infections, neutropenia, nausea, constipation, cough, and fatigue DLBCL: infections, neutropenia, alopecia, nausea, and anemia CLL: infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 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 clinical practice. The data described below reflect exposure to RITUXAN HYCELA in 892 patients in four controlled trials with exposures ranging from a single injection up to 27 months of treatment. The population included 382 patients with follicular lymphoma (FL), 369 patients with diffuse large B-cell lymphoma (DLBCL), and 141 patients with chronic lymphocytic leukemia (CLL). The median age was 60 years (range: 18–85 years, 53% were male, and 84% were White. In the SABRINA study patients with FL received a full dose of a rituximab product by intravenous infusion, followed by RITUXAN HYCELA (1,400 mg rituximab/23,400 Units hyaluronidase human), in combination with chemotherapy for up to 7 doses (i.e., total of 8 doses in combination with chemotherapy), or as monotherapy for up to 12 doses (maintenance treatment). In the MabEase study patients with DLBCL received a full dose of a rituximab product by intravenous infusion, followed by RITUXAN HYCELA (1,400 mg rituximab/23,400 Units hyaluronidase human), given in combination with chemotherapy for up to 7 doses (i.e., up to a total of 8 doses). In the SAWYER study patients with CLL on part 2 received a full dose of a rituximab product by intravenous infusion, followed by RITUXAN HYCELA (1,600 mg rituximab/26,800 Units hyaluronidase human) for up to 5 doses, in combination with fludarabine and cyclophosphamide (i.e., total of 6 doses). The most common adverse reactions (≥ 20%) of RITUXAN HYCELA observed in patients with FL on the SABRINA study were: infections, neutropenia, nausea, constipation, cough, and fatigue. The most common adverse reactions (≥ 20%) of RITUXAN HYCELA observed in patients with DLBCL on the MabEase study were: infections, neutropenia, alopecia, nausea, and anemia. The most common adverse reactions (≥ 20%) of RITUXAN HYCELA observed in patients with CLL on part 2 of the SAWYER study were: infections, neutropenia, nausea, thrombocytopenia, pyrexia, vomiting, and injection site erythema. Administration-related reactions (ARRs) Administration-related reactions (ARRs) with RITUXAN HYCELA were defined as all the adverse reactions related to the administration of RITUXAN HYCELA within the 24 hours post injection. The incidence of ARRs with RITUXAN HYCELA was 34% in FL/DLBCL in combination with chemotherapy with injection site erythema (5%), chills (3%), dyspnea, erythema, flushing, injection site pain, nausea, pruritus, pyrexia, rash, and throat irritation (2% each) being the most common ARRs. The incidence of ARRs in FL maintenance setting was 20%. The most common ARRs were injection site erythema (7%), erythema (4%), injection site pain/edema, myalgia, and rash (2% each). The incidence of ARRs with RITUXAN HYCELA in CLL was 44%. With the exception of Local Cutaneous Reactions, the incidence and profile of adverse reactions reported for RITUXAN HYCELA were comparable with those for rituximab. The overall incidence of adverse reactions for intravenous rituximab versus RITUXAN HYCELA in combination with chemotherapy for FL/DLBCL was 93% versus 95% (BSA ≤ 1.73 m 2 ), 89% versus 93% (1.73 < BSA ≤ 1.92 m 2 ), and 94% versus 94% (BSA > 1.92 m 2 ). The overall incidence of adverse reactions for rituximab versus RITUXAN HYCELA in CLL was 89% versus 100% (BSA ≤ 1.81 m 2 ), 97% versus 88% (1.82 < BSA ≤ 1.99 m 2 ), and 88% versus 93% (BSA > 2.00 m 2 ). Summary of Clinical Trial Experience in Follicular Lymphoma (FL) The data in Table 1 were obtained in the SABRINA study, a two-stage randomized, controlled study in patients with previously untreated FL. The study compared patients receiving RITUXAN HYCELA (1,400 mg rituximab/23,400 Units hyaluronidase human; n=197) with patients receiving a rituximab product by intravenous infusion (375 mg/m 2 ; n=210), both in combination with CHOP or CVP followed by maintenance treatment with RITUXAN HYCELA or a rituximab product by intravenous infusion. The majority of patients completed all 8 cycles of combination treatment with chemotherapy (91% RITUXAN HYCELA vs. 90% rituximab). In addition, 69% of patients in each of the treatment groups completed all 20 cycles of combination plus maintenance treatment. In both RITUXAN HYCELA and rituximab groups, patients experienced similar median duration of exposure (27.1 months for each arm). Across the two stages, the overall demographics and baseline characteristics were balanced between the treatment groups. However, there were more female patients (53%) randomized in the study than male patients (47%) and a higher proportion of females were randomized to receive RITUXAN HYCELA (59% female) compared with the rituximab group (48%). The treatment groups in the combined Stage 1 and 2 population were otherwise balanced in regard to baseline demographics, characterized by a median age of 57 years (56.0 years [range 28–85 years] for RITUXAN HYCELA and 57 years [range 28–86 years] for rituximab) and median BSA of 1.83 m 2 (1.80 and 1.84 m 2 for RITUXAN HYCELA and rituximab, respectively). The incidence of all adverse reactions was 96% for RITUXAN HYCELA vs. 95% for rituximab ( Table 1 ). Grade 3–4 adverse reactions were reported in 55% of patients receiving RITUXAN HYCELA vs. 53% in patients receiving rituximab. Serious adverse reactions were reported in 37% of patients receiving RITUXAN HYCELA vs. 34% of patients receiving rituximab. The most common adverse reactions (occurring in ≥ 20% of patients in any arm) were infections, neutropenia, nausea, constipation, cough, and fatigue. A total of 36 patients died, including 14/197 patients (7%) who received RITUXAN HYCELA and 22/210 patients (10%) who received rituximab. Of these 36 patients, 19 patients (7 patients RITUXAN HYCELA [4%] vs. 12 patients rituximab [6%]) died due to adverse reactions and 13 patients (6 patients RITUXAN HYCELA [3%] vs. 7 patients rituximab [3%]) died due to disease progression. The incidence of administration-related reactions (ARRs) due to the subcutaneous route of administration associated with RITUXAN HYCELA was assessed in combination with chemotherapy and during maintenance. Thirty patients (15%) experienced an ARR during the first administration of RITUXAN HYCELA (Cycle 2). Incidence of ARRs generally decreased at subsequent cycles with 18 patients (9%) reporting ARR at Cycle 3, 13 patients (7%) at Cycle 4, 11 patients (6%) at Cycles 5 and 6, 12 patients (7%) at Cycle 7, and 8 patients (4%) at Cycle 8. During RITUXAN HYCELA monotherapy in the maintenance setting the incidence of ARRs at each cycle was ≤ 7% and was observed in 24 pat